In 2013 a  Cochrane  systematic review included 5 randomized trials, which in total was 382 patients. None of the included studies reported long term follow up after 3, 6 or 12 months post procedure. [ 9 ]  In another review of 889 patients across 23 studies, a pooled improvement rate in measures of incontinence was 39.5%. [ 8 ]  In some cases there is no improvement after the procedure, and the injections are repeated in up to 34% of cases. [ 8 ]  There can also be worsening of symptoms after an initial improvement period. [ 8 ]  In one randomized control trial, the placebo treatment gave over 30% improvement in symptoms, suggesting that patient psychology (i.e. the  placebo effect ) may be in part responsible for any positive results. [ 10 ]  One author criticized these procedures, stating that simply narrowing the anal canal was an instinctive and naive solution which does not consider the complex pathopysiological mechanisms of FI. [ 10 ]  Concerns have been raised about migration of the particles (in the case of Durasphere) away from the site of injection, or the total resorption of the material (in the case of hyaluronic acid and hydroxyl coaptite). [ 10 ]  Most research suggests that the positive effects of most of the bulking agents seem to reduce after 6 to 12 months. [ 7 ]  At 6 months the material has been reported as missing or migrated in 18.4% of cases, at 3 years or more in 20.2% of cases. [ 8 ]  One author drew attention to the fact that all existing research on these procedures was driven by the companies who also marketed the treatments, and therefore the studies are at high risk of bias. [ 10 ]


Mesenchymal stem cells  (MSC) and  muscle-derived stem cells  (MDSC) have been used in urology to treat urinary incontinence.  Fibroblasts  in a collagen carrier were injected into the submucosa of the urethra, and  myoblasts  were injected into the urethral sphincter. The procedure was reported as being successful in most cases. [ 11 ]  Injection of MSCs may lead to engrafting and forming multinucleated myotubes, which helps to regeneration after injury. [ 12 ]  In theory, use of stem cells removes the problems of reabsorption and migration of the bulking material. [ 11 ]  There is similar research which aims to regenerate muscles and repair tissues by  cell therapy  to treat injuries of the external anal sphincter. [ 9 ]


The "Gatekeeper" and "SphinKeeper" are self-expandable prostheses which are implanted into the intersphincteric space of the anal canal. [ 7 ]


Sacral nerve stimulation  was originally used in urinary incontinence. It was first used to treat FI in 1995. The procedure involves implantation of an electrical device (an implanted pulse generator, IPG) which applies a low amplitude electric current to a  sacral  nerve (usually  S3 ). This appears to modulate the nerves and muscles of the pelvic floor and rectum. A  Cochrane  review of the efficacy of sacral nerve stimulation concluded that more research was needed, but can be helpful in selected people with FI, and reduce symptoms in selected people with constipation. [ 13 ]  It is possible to simulate the effect of SNS without surgery. This is trial usually lasts around 2–3 weeks, where a temporary percutaneous peripheral nerve electrode is placed in the lower back, and then connected to an external stimulator. This trial may not always accurately predict a successful outcome. If there is an improvement, a permanent electrode can be implanted on the sacrum and connected to an stimulator which is in turn implanted in the lower abdominal wall or in the buttock. Implanted stimulators usually last 8 years. The patients who may benefit from SNS include those with intact anal sphincters and those with a history of unsuccessful anal repair. [ 5 ]  Complications of the surgery are rare, including pain and infection, which may require implant removal in 5% of cases. The effects of SNS may include increased resting and squeeze anal tone, and improved rectal sensitivity. There is reported reduction of involuntary loss of bowel contents and increased ability to postpone defecation. A substantial percentage of patients regain full continence. Patient quality of life has also been shown to be improved after the procedure. [ 3 ]


In the 1950s described an operation using the  gracilis muscle  from the inner thigh and wrapping it around the anus to function as a new anal sphincter (neosphincter). Non dynamic graciloplasty was not particularly successful because the gracilis is mostly composed of type II, fast-twitch, fatiguable muscle fibres, whereas the sphincter ideally needs to be able to automatically contract for long periods. A neurostimulation device with an impulse generator can be implanted to adapt the muscle to prolonged contraction (dynamic graciloplasty). Over time, the muscle becomes mostly composed of type I, slow twitch, fatigue resistant fibres. The patient uses an external magnetic programming device to deactivate the electrical stimulation, relaxing the muscular contraction and enabling defecation at a voluntary time. [ 3 ] [ 5 ]  Dynamic graciloplasty may be indicated for patients with a completely destroyed anal sphincter or a torn sphincter with a large gap between both ends that is not amenable to repair. The procedure involves detachment of the gracilis from the leg, preserving both its blood supply and innervation. The muscle is then moved to wrap around the anal canal completely, and also attached to the  periosteum  of the inferior ramus of the  pubic bone . Various arrangements are described, depending upon the length of the gracilis. The implanted stimulator electrode is placed intramuscularly (within the muscle), very close to the gracilis nerve, and the impulse generator is placed subcutaneously (under the skin). [ 3 ] [ 5 ]  The success rate of the operation is between 40 and 60%, and varies with surgeon experience. The complication rate is high, (infections 28%, device problems 15%, and
leg pain 13%) but these are usually treatable without influence on the result. A second operation may be required for some complications. When dynamic graciloplasty is successful in curing FI, up to 50% of patients may develop signs and symptoms of  obstructed defecation . [ 3 ] [ 4 ] [ 5 ]


This is also termed artificial anal sphincter or neosphincter. [ 14 ]  The usual surgical approach is through the  perineum  or alternatively via the vagina. The artificial bowel sphincter involves the implantation of 3 components: (i) A fluid filled silicone elastomer cuff placed around the anus, (ii) a liquid filled, pressure-regulating balloon positioned in the peritoneal fat, and (iii) a manual pump connecting these components (placed in either the  labia majora  or the  scrotum ). When the cuff is inflated, the anal canal sealed. The fluid is transferred to the balloon by the manual pump, resulting in deflation of the cuff, opening of the anal canal and allowing for defecation. [ 3 ] [ 4 ] [ 5 ]  This procedure improves FI scores and quality of life, and continence is excellent when the procedure works (successful outcome in 85% patients with a functioning device). The procedure is less technically demanding than the graciloplasty, but there is the disadvantage of using foreign material, which can erode through the anal canal. As with graciloplasty, obstructed defecation may develop with a working device, and may be treated with enemas. Complications include infection, which may warrant temporary removal of the device. [ 3 ] [ 4 ] [ 5 ]  Graciloplasty and artificial anal sphincter both significantly improve continence, with artificial anal sphincter being superior, [ 15 ]  however both methods have high rates of complications. [ 15 ] [ 16 ]


This was originally described as a surgical management for  rectal prolapse . This operation essentially involves encircling the anal canal with implanted foreign material. Various materials have been used, including nylon, silk, fascia strips, silver wire, and
silastic bands. Anal encirclement effectively supplements the anal sphincter, narrowing the anal canal and its barrier function to stool, without altering voluntary control. Since complications are common, and can be serious (fecal impaction, infection, erosion of encirclement through anal canal), modern surgeons prefer to perform colostomy. [ 5 ]


This refers to temperature-controlled radiofrequency energy being delivered to the anal canal, and is marketed as the SECCA procedure. This procedure aims to create a controlled scarring and  stricturing  of the anal canal. [ 1 ]  In theory, it is thought that radiofrequency induced IAS injury may cause collagen deposition and fibrosis (scarring), resulting in the affected area tightening. [ 17 ]  Specialized surgical instrument called a radiofrequency handpiece is used. It has 4 needles which enter the IAS and heat up to 85 °C. This causes the water molecules in the tissue to vibrate with subsequent frictional heating. The hand piece is cooled by water and monitors the temperature of the tissues it is applied to for safety. It is thought that the improvement in FI occurs over time as  collagen  is deposited and the tissues undergo remodeling. [ 18 ]  The procedure is carried out under  local anesthesia  (with or without  conscious sedation ) on an  outpatient  basis. [ 19 ]  There appear to be relatively few serious complications. [ 18 ]
Initial studies of the SECCA procedure have shown promising improvements in quality of life and FI severity scores, however large  randomized control trials  and  systematic reviews  are currently lacking. [ 19 ] [ 20 ]


This procedure involves the surgical creation of a stoma (either an appendicostomy, cecostomy, or sigmoidostomy), which thereafter functions as an irrigation port. This antegrade colonic irrigation aims to introduce fluid to wash out the colon at regular intervals. The idea is to ensure regular emptying of the colon and rectum and hopefully, prevent involuntary loss of bowel content. [ 3 ]  The  Malone antegrade continence enema  (MACE) is where an appendicostomy is created, i.e. the  vermiform appendix  is stitched to the abdominal wall to form a stoma. ACE is often necessary in addition to others when FI is complicated by  neuropathy  and/or an incomplete IAS. Patients may have persistent leakage of fluid per rectum for several hours following the irrigation. [ 1 ]


Diversion may be a temporary measure in the management of FI, e.g. to allow healing of another surgical procedure, or it may be a definitive procedure.  Stoma creation is considered to be the last resort treatment, [ 4 ]  when all other attempts to improve symptoms have been unsuccessful, although they are associated with many problems such as odor associated with leakage of stool and flatus from the stoma.  The  stoma  may be  colostomy  (where the colon is ended in a stoma) or  ileostomy  (where the  ileum  is ended in a stoma).  Both may involve the creation of an  internal waste-holding reservoir  in a procedure developed by Dr.  Nils Kock  in the late 1960s. [ 21 ]


Diversion colitis  is inflammation of the section of gut through which stool no longer passes. This condition arises because normally the lining of the gut obtains some of its nutrients from the fecal stream.  This condition may cause a foul-smelling, mucous  rectal discharge  from the distal, unused colon. [ 5 ]


Transanal irrigation  is medical procedure in which water is used to evacuate feces from the  rectum  and  descending colon  via the  anus . [ 5 ] [ 1 ]


Transanal irrigation uses a large volume water  enema  system. [ 2 ]  It is carried out every day (or every 2 days) by the patient or carer as a long term management for bowel dysfunction, including  fecal incontinence  and/or  constipation  (especially  obstructed defecation ).


Although the procedure and general goals may be similar, transanal irrigation is different from  colon cleansing  (colon hydrotherapy), which is a term used in alternative medicine. Transanal irrigation is used for medical conditions which affect defecation, such as  spinal cord injury  or  multiple sclerosis . Colon cleansing is used outside of mainstream medical supervision, and may be used in the belief that the procedure removes toxins from the body.


The impact of transanal irrigation varies considerably. Some individuals experience complete control of incontinence, and other report little or no benefit. [ 5 ]  Evidence shows this treatment can be considered for children as well. [ 6 ] [ 7 ]  When diet and medication has proven ineffective, transanal irrigation may be used. [ 5 ] [ 8 ]


Transanal irrigation systems may use either a rectal balloon catheter or a cone-shaped colostomy tip. [ 9 ]


The catheter tip is inserted into the anal canal. Systems with balloon catheters require inflation of the balloon once the tip is in position. [ 9 ]  Cone shaped colostomy tip systems must be supported manually. [ 9 ]


Lukewarm tapwater (36-38°C) [ 4 ]  is used if it is drinkable. [ 9 ]   If tap water is not safe for drinking, a different source of clean water is needed. The irrigation bag is ideally placed or hung 1-1.5 m above the level of the toilet. The flow is switched on with a handheld valve. The flow rate of the water may be controlled by a manual pump or a battery pump. [ 9 ]


The volume of water used is normally about 1000 ml. [ 9 ]  Some sources recommend repeat irrigation with a higher volume up to 2300 ml. [ 9 ]


Transanal irrigation may be performed every day or every other day in order to simulate a normal defecation routine. [ 9 ]  Ideally, irrigation is performed at the same hour each day. [ 10 ]


The optimal volume and frequency may be determined by trail and error for each individual patient during the first few months of treatment. [ 9 ]


The time required for the procedure is in the range of 30–120 min. [ 9 ]


Some individuals take oral constipating medications or oral laxative medications in addition to transanal irrigation. [ 9 ]


It is unclear whether the mechanism of action of irrigation is by simple mechanical washing out of the bowel, or by triggering of colonic mass movements, or both. [ 9 ]


Disadvantages of the treatment may include:


Specific conditions for which transanal irrigatio has been used include:


A Cochrane review found evidence that transanal irrigation was more effective compared to conservative management in the management of spinal cord injury. There were more positive benefits for constipation scores, neurogenic bowel dysfunction scores, and fecal incontinence scores. Patients spent less time in total on bowel care and were more satisfied with the treatment. [ 12 ]


The treatment is generally considered safe. However, adverse effects are reported, including:


Bowel perforation  is when the wall of the bowel ruptures. It is a potentially lethal complication [ 9 ]  which requires emergency surgery. 49 bowel perforations caused by transanal irrigation were reported between 2005 and 2013. [ 19 ]  This rate was used to calculate a risk of 2-6 perforations per 1 million procedures. [ 19 ]  This risk of perforation is significantly lower compared to other common medical procedures such as flexible sigmoidoscopy (1 perforation per 40000 procedures), colonoscopy (1 per 1000) and barium enema (1 per 10000). [ 10 ]  However, patients may need to conduct transanal irrigation daily or near-daily for many years, which increases their lifetime risk. [ 9 ]  Perforation is more likely in the first weeks after starting treatment. [ 19 ]  People who have had a surgical anastomosis (for example, after low anterior resection,  stapled transanal rectal resection ,  ventral mesh rectopexy , or other types of surgery for  rectal prolapse ) are more at risk of bowel perforation during transanal irrigation. [ 10 ]


One study reported before and after changes in anorectal physiology tests in patients with idiopathic faecal incontinence or chronic idiopathic constipation. The patients had all used transanal irrigation for at least 30 months. In the chronic idiopathic constipation group there was no reduction in anal sphincter function after long term use of transanal irrigation. In the idiopathic faecal incontinence group anal resting and squeeze pressures were lower after long term use of transanal irrigation. The researchers suggested that this was due to age related changes in sphincter function and the deterioration of the disease over time rather than due to the use of transanal irrigation. In both groups rectal urge volume increased after long term use of transanal irrigation. The researchers suggested that patients get accustomed to larger rectal volumes, and without the irrigation their everyday sensation of urge from the presence of stool in the rectum is decreased. This may encourage patients to continue using the irrigation. However, rectal compliance (how well the rectum can stretch and accommodate increasing volumes without triggering discomfort or pain) and biomechanical properties of the rectal wall were unchanged. [ 3 ]


Management of ulcerative colitis  involves first treating the  acute  symptoms of the disease, then maintaining  remission .  Ulcerative colitis  is a form of  colitis , a  disease  of the  intestine , specifically the large intestine or  colon , that includes characteristic  ulcers , or open sores, in the colon. The main symptom of active disease is usually  diarrhea  mixed with blood, of gradual onset which often leads to  anaemia . Ulcerative colitis is, however, a  systemic disease  that affects many parts of the body outside the intestine.


Standard treatment for ulcerative colitis depends on  extent of involvement  and disease  severity . The goal is to induce  remission  initially with medications, followed by the administration of maintenance medications to prevent a relapse of the disease. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing a remission which involves relief of symptoms and mucosal healing of the lining of the colon and then longer-term treatment to maintain the remission.


Anaemia , caused by both chronic blood loss from the gastrointestinal tract and reduced absorption due to the up-regulation of  hepcidin  should also be treated, and this often requires the use of  parenteral iron . [ 1 ]


The following sections are sorted first by drug type and, second, by the type of ulcerative colitis:


Aminosalicylates  are the main  anti-inflammatory  drugs used to treat ulcerative colitis. Sometimes remission can be achieved, or at least maintained, with these drugs alone. If not, they are usually used in combination with the drugs listed in the ensuing sections.


The anti-inflammatory action in all these drugs is produced by 5-aminosalicylic acid (5-ASA), the active ingredient in Mesalazine. 5-ASA is produced from the other drugs in the intestine. The aminosalicylates used to treat ulcerative colitis include the following:


5-ASA is poorly-absorbed by the intestines, and hence provides topical relief within the intestine. It is therefore a non-systemic drug. 5-ASA is related to the systemic  non-steroidal anti-inflammatory drugs  (NSAIDs), such as  Aspirin  and  Ibuprofen .


The free radical induction theory, discussed below, proposes that 5-ASA is serving not just as an anti-inflammatory agent, but also as a free radical trap, destroying the hydroxyl and other radicals that may damage colonic epithelial barrier. [ 2 ]   5-ASA may also be an inhibitor of  TNF .


Possible side effects of 5-ASA include, nausea and vomiting, reduced sperm count and damage to red or white blood cells, or to the liver, kidneys, pancreas, nerves or hearing. Allergic reactions to sulfasalazine characterized by dizziness, fever and skin rash have been reported in a small percentage of patients. In some cases, sulfasalazine can exacerbate ulcerative colitis resulting in diarrhea, abdominal cramps and discomfort.


In the intestine sulfasalazine is converted to 5-ASA and sulfapyridine, which is responsible for some of its side-effects, and which should be monitored in patients taking sulfasalazine. Sulfapyridine levels above 50 μg/L are associated with the side-effects.


Patients on high dose sulfasalazine require  folic supplementation  (1 mg/day) (1000 μg/day) to maintain normal cell division. This may, however, be counter-productive for patients who are also taking methotrexate, which is a folic acid inhibitor. Folic acid might also be counter-productive for patients taking 6-MP and related drugs that inhibit all cell division.


It is often necessary to use  corticosteroids  in conjunction with 5-ASA drugs to bring about remission of ulcerative colitis. Thereafter it may be possible to maintain remission with 5-ASAs alone, though many patients require other, stronger immunosuppressive medications.  Corticosteroids should not be used for long-term therapy of UC, particularly without the concomitant use of an immunomodulator or anti-TNF. [ 3 ]


Corticosteroids reduce inflammation by blocking portions of the  leukocyte adhesion cascade  which results in inflammation.


Side effects of corticosteroids include  Cushing's syndrome , which most often exhibits itself as temporary facial puffiness, called "moon face". Cushing's syndrome can, however, involve  psychosis , including  manic  behavior. These drugs have been known to trigger  bipolar disorder . In prescribing these drugs it might be well to inquire as to any family history of bipolar disorder.


Corticosteroids should not be confused with  anabolic steroids , the controversial performance-building "steroids" that are banned in certain sports.


The following corticosteroids are used as immune system suppressants in treatment of ulcerative colitis:


Immunosuppressive drugs  inhibit the immune system generally. These include the  cytostatic drugs  that inhibit cell division, including the  cloning  of  white blood cells  that is a part of the immune response. Immunosuppressive drugs used with ulcerative colitis include:


Mercaptopurine is a cytostatic drug that is an  antimetabolite . The mercaptopurine molecule mimics  purine , which is necessary for the synthesis of  DNA . With mercaptopurine present, cells are not able to make DNA, and cell division is inhibited.


In administering mercaptopurine it is necessary to monitor the levels of mercaptopurine metabolites in the blood to establish the correct dosage for a patient. An initial concern is  hepatotoxicity .


Mercaptopurine inhibits the production of  white blood cells  generally. Because this makes the body more susceptible to infection, patients need to watch for infections.  Vaccinations  are critically important, particularly the yearly flu shot and periodic pneumonia immunizations.  Vaccine response is best if given prior to initiation of immunosuppressive medications, and patients on immunosuppressives should use caution when receiving vaccines containing live virus.


Frequent  blood cell counts  are also recommended during administration of mercaptopurine. The drug may be toxic to  bone marrow , where many blood components are made. If there is an abnormally large drop in white blood cell count, or any blood cell count, administration of the drug should be halted at least temporarily.


Methotrexate is another immunosuppressive drug. It works by inhibiting folic acid, which is necessary for DNA replication and, therefore, cell division.


TNF  is a protein that is released by activated white blood cells, triggering more inflammation, an immune system response and more damage to the mucosa of the colon because of the immune activation. Certain drugs inhibit TNF, hence reducing inflammation and immune system involvement. Infliximab was approved by the FDA for treating ulcerative colitis in March 2005. It is usually given as an intravenous infusions at weeks 0,2 and 6 and then every eight weeks thereafter. It is very useful for inducing and maintaining a remission of ulcerative colitis. Infliximab works better when used in combination with immunmodulators such as 6-mercaptopurine or azathioprine, but a corresponding increase in adverse events means that the decision to use one drug or two must be based on an individualized discussion between the patient and their doctor.


Proctitis  is an  inflammation  of the  anus  and the lining of the  rectum , usually involving the distal, or lower, 10–15 cm (3.9–5.9 in) of the colon, including the  rectum . Approximately 30% of ulcerative colitis patients initially present with proctitis.


Standard treatment for active disease includes Mesalazine suppositories and cortisone foam (Cortifoam). Mesalazine 1 g SUPP QHS or Cortifoam QHS/BID is continued until remission, with response seen usually within three weeks.


Maintenance therapy is with Mesalazine 1g QHS or Q3HS. Those with anal irritation or discomfort from the suppositories may switch to oral medications, such as sulfasalazine, Mesalazine, or Colazol, although they are not as effective as suppositories for proctitis. Maintenance therapy is not recommended for those with a first episode that responded to the Mesalazine. Steroid foam is not shown to prevent relapse.


Systemic steroids such as prednisone are not used unless proctitis fails to respond to the above treatments. [ 4 ]


Proctosigmoiditis and left-sided colitis  involves the lower colon, from the rectum up the left side of the patient.


Patients often respond to topical agents alone, such as Mesalazine, or hydrocortisone enemas. Again, the Mesalazine is preferred for maintenance therapy.


Oral anti-inflammatory drugs require four to six weeks to work.


Once remission is induced, maintenance levels can be used: sulfasalazine 2 g/day, mesalamine 1.2-2.4 g/day, or olsalazine 1 g/day. Patients on high dose sulfasalazine require  folic supplementation  (1 mg/day) because it inhibits folate absorption.


If oral Mesalazine is still not working, prednisone is often given, starting at 40–60 mg/day. Prednisone often takes effect within 10–14 days. The dose should then be tapered by about 5 mg/week until it can be stopped altogether.


Extensive or pancolitis . Patients usually require a combination of oral Mesalazine or sulfasalazine along with topical Mesalazine or steroid enemas. Oral prednisone (40–60 mg/day) should be given only in severe cases or if oral Mesalazine fails. Once remission is induced, maintenance therapy is with standard oral Mesalazine doses. Supplemental iron ( ferrous sulfate  or  ferrous gluconate ) may be given due to chronic blood loss.  Loperamide  may be given for symptomatic relief of chronic diarrhea, but should not be given in suspected toxic megacolon.


Severe or fulminant colitis . Patients need to be hospitalized immediately with subsequent bowel rest, nutrition, and IV steroids. Typical starting choices are hydrocortisone 100 mg IV q8h, prednisolone 30 mg IV q12h, or methylprednisolone 16–20 mg IV q8h. The last two are preferred due to less sodium retention and potassium wasting. 24-hour continuous infusion is preferred than the stated dosing. If the patient has not had any corticosteroids within the last 30 days, IV ACTH 120 units/day as continuous infusion is superior than the IV steroids mentioned above. In either case, if symptoms persist after 2–3 days, Mesalazine or hydrocortisone enemas daily or bid can be given. The use of antibiotics in those with severe colitis is not clear. However, there are those patients who have sub-optimal response to corticosteroids and continue to run a low grade fever with bandemia. Typically they can be treated with IV ciprofloxacin and metronidazole. However, in those with fulminant colitis or megacolon, with high fever, leukocytosis with high bandemia, and peritoneal signs, broad spectrum antibiotics should be given (i.e.,  ceftazidime ,  cefepime ,  imipeneum ,  meropenem , etc.). Abdominal x-ray should also be ordered. If intestinal dilation is seen, patients should be decompressed with NG tube and or rectal tube.


Refractory ulcerative colitis . Patients with toxic megacolon (colonic dilation > 6 cm and toxic appearing) who do not respond to steroid therapy within 72 hours should be consulted for colectomy. Those with less severe disease but do not respond to IV steroids within 7–10 days should be considered for colectomy or IV cyclosporine. IV cyclosporine at a rate of 2 mg/kg/day and if no response in 7–10 days, colectomy should be considered. If response is seen, oral cyclosporine at 8 mg/kg/day should be continued for 3–4 months while 6-MP or azathioprine is introduced. Those already on 6-MP or azathioprine should continue with these medications. A cholesterol level should be checked in patients taking cyclosporine as low cholesterol may predispose to seizures. Also, prophylaxis against PCP ( Pneumocystis carinii ) pneumonia is advised.


Unlike Crohn's disease, which cannot be cured/eliminated by surgically removing the diseased portions of the intestine and reconnecting the healthy ends, ulcerative colitis can generally be cured by surgical removal of the large intestine.  Surgical removal of the large intestine will not get rid of extra-intestinal symptoms. This procedure is necessary in the event of  exsanguinating   hemorrhage , frank perforation, or documented or strongly suspected  carcinoma . Surgery is also indicated for patients with severe colitis or toxic megacolon. Patients with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life. Depending on the type of surgery performed, the patient may still require periodic lower endoscopies to assess the pouch for dysplasia.


Ulcerative colitis is a disease that affects many parts of the body outside the intestinal tract. In rare cases the extra-intestinal manifestations of the disease may require removal of the colon. [ 5 ]


A  Cochrane  review of  controlled trials  using various probiotics found low-certainty evidence that probiotic supplements may increase the probability of clinical remission.  [ 6 ]  People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects.  [ 6 ] Although there was no clear evidence of greater remission when probiotic supplements were compared with  5‐aminosalicylic acid  treatment as a  monotherapy , the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy.   [ 6 ]


It is currently unclear whether probiotics help to prevent future relapse in people with stable disease activity, either as a monotherapy or  combination therapy .  [ 7 ]


There is no good evidence that dietary interventions have any impact on ulcerative colitis. [ 8 ]


The free radical induction theory suggests that the initial cause of ulcerative colitis may be a metabolic defect that allows a buildup of chemicals related to hydrogen peroxide beneath the membrane that protects the cells of the intestinal wall from the bacteria inside the intestine, resulting in destruction of the membrane. During remission the membrane is reestablished, but may be subject to new damage, resulting in a flare up of the disease. [ 2 ]  To the extent this may be true, it would be appropriate to take  antioxidants , dietary supplements that may support the body's defenses against oxidants like hydrogen peroxide. Antioxidants include:


Vitamin B6  and  iron  may be associated with increased hydrogen peroxide levels, and should not be taken in excess under this theory. [ 2 ]


Inflammatory bowel disease is less common in the developing world and it has been suggested that this may be because intestinal parasites are more common in underdeveloped countries. [ 15 ]  Some parasites are able to reduce the immune response of the intestine, an adaptation that helps the parasite colonize the intestine. A decrease in immune response could be helpful in inflammatory bowel disease. [ 15 ]


Helminthic therapy  using the  whipworm   Trichuris suis  was shown in a  randomized control trial  to produce benefit in patients with ulcerative colitis. This therapy tests the  hygiene hypothesis  which argues that the absence of  helminths  in the  colons  of patients in the western world may lead to  inflammation . Both  helminthic therapy  and  fecal bacteriotherapy  induce a characteristic  Th2  white cell response in the diseased areas, which is somewhat paradoxical given that ulcerative colitis immunology was thought to classically involve Th2 overproduction. [ 16 ]


In  medicine , the  urea-to-creatinine ratio  ( UCR [ 1 ] ), known in the United States as  BUN-to-creatinine ratio , is the  ratio  of the blood levels of  urea  ( BUN ) (mmol/L) and  creatinine  (Cr) (μmol/L). BUN only reflects the nitrogen content of urea (MW 28) and urea measurement reflects the whole of the molecule (MW 60), urea is just over twice BUN (60/28 = 2.14). In the United States, both quantities are given in mg/dL The ratio may be used to determine the cause of  acute kidney injury  or  dehydration .


The principle behind this ratio is the fact that both urea (BUN) and creatinine are freely filtered by the  glomerulus ; however, urea reabsorbed by the  renal tubules  can be regulated (increased or decreased) whereas creatinine reabsorption remains the same (minimal reabsorption).


Urea and creatinine are nitrogenous end products of metabolism. [ 2 ]  Urea is the primary metabolite derived from dietary protein and tissue protein turnover. Creatinine is the product of muscle creatine catabolism. Both are relatively small molecules (60 and 113 daltons, respectively) that distribute throughout total body water. In Europe, the whole urea molecule is assayed, whereas in the United States only the nitrogen component of urea (the blood or serum urea nitrogen, i.e., BUN or SUN) is measured. The BUN, then, is roughly one-half (7/15 or 0.466) of the blood urea. [ citation needed ]


The normal range of urea nitrogen in blood or serum is 5 to 20 mg/dl, or 1.8 to 7.1 mmol urea per liter. The range is wide because of normal variations due to protein intake, endogenous protein catabolism, state of hydration, hepatic urea synthesis, and renal urea excretion. A BUN of 15 mg/dl would represent significantly impaired function for a woman in the thirtieth week of gestation. Her higher glomerular filtration rate (GFR), expanded extracellular fluid volume, and anabolism in the developing fetus contribute to her relatively low BUN of 5 to 7 mg/dl. In contrast, the rugged rancher who eats in excess of 125 g protein each day may have a normal BUN of 20 mg/dl.


The normal serum creatinine (sCr) varies with the subject's body muscle mass and with the technique used to measure it. For the adult male, the normal range is 0.6 to 1.2 mg/dl, or 53 to 106 μmol/L by the kinetic or enzymatic method, and 0.8 to 1.5 mg/dl, or 70 to 133 μmol/L by the older manual Jaffé reaction. For the adult female, with her generally lower muscle mass, the normal range is 0.5 to 1.1 mg/dl, or 44 to 97 μmol/L by the enzymatic method.


Multiple methods for analysis of BUN and creatinine have evolved over the years. Most of those in current use are automated and give clinically reliable and reproducible results.


There are two general methods for the measurement of urea nitrogen. The diacetyl, or Fearon, reaction develops a yellow chromogen with urea, and this is quantified by photometry. It has been modified for use in autoanalyzers and generally gives relatively accurate results. It still has limited specificity, however, as illustrated by spurious elevations with sulfonylurea compounds, and by colorimetric interference from hemoglobin when whole blood is used.


In the more specific enzymatic methods, the enzyme urease converts urea to ammonia and carbonic acid. These products, which are proportional to the concentration of urea in the sample, are assayed in a variety of systems, some of which are automated. One system checks the decrease in absorbance at 340 nm when the ammonia reacts with alpha-ketoglutaric acid. The Astra system measures the rate of increase in conductivity of the solution in which urea is hydrolyzed.


Even though the test is now performed mostly on serum, the term BUN is still retained by convention. The specimen should not be collected in tubes containing sodium fluoride because the fluoride inhibits urease. Also chloral hydrate and guanethidine have been observed to increase BUN values.


The 1886 Jaffé reaction, in which creatinine is treated with an alkaline picrate solution to yield a red complex, is still the basis of most commonly used methods for measuring creatinine. This reaction is nonspecific and subject to interference from many noncreatinine chromogens, including acetone, acetoacetate, pyruvate, ascorbic acid, glucose, cephalosporins, barbiturates, and protein. It is also sensitive to pH and temperature changes. One or another of the many modifications designed to nullify these sources of error is used in most clinical laboratories today. For example, the recent kinetic-rate modification, which isolates the brief time interval during which only true creatinine contributes to total color formation, is the basis of the Astra modular system.


More specific, non-Jaffé assays have also been developed. One of these, an automated dry-slide enzymatic method, measures ammonia generated when creatinine is hydrolyzed by creatinine iminohydrolase. Its simplicity, precision, and speed highly recommend it for routine use in the clinical laboratory. Only 5-fluorocytosine interferes significantly with the test.


Creatinine must be determined in plasma or serum and not whole blood because erythrocytes contain considerable amounts of noncreatinine chromogens. To minimize the conversion of creatine to creatinine, specimens must be as fresh as possible and maintained at pH 7 during storage.


The amount of urea produced varies with substrate delivery to the liver and the adequacy of liver function. It is increased by a high-protein diet, by gastrointestinal bleeding (based on plasma protein level of 7.5 g/dl and a hemoglobin of 15 g/dl, 500 ml of whole blood is equivalent to 100 g protein), by catabolic processes such as fever or infection, and by antianabolic drugs such as tetracyclines (except doxycycline) or glucocorticoids. It is decreased by low-protein diet, malnutrition or starvation, and by impaired metabolic activity in the liver due to parenchymal liver disease or, rarely, to congenital deficiency of urea cycle enzymes. The normal subject on a 70 g protein diet produces about 12 g of urea each day.


This newly synthesized urea distributes throughout total body water. Some of it is recycled through the enterohepatic circulation. Usually, a small amount (less than 0.5 g/day) is lost through the gastrointestinal tract, lungs, and skin; during exercise, a substantial fraction may be excreted in sweat. The bulk of the urea, about 10 g each day, is excreted by the kidney in a process that begins with glomerular filtration. At high urine flow rates (greater than 2 ml/min), 40% of the filtered load is reabsorbed, and at flow rates lower than 2 ml/min, reabsorption may increase to 60%. Low flow, as in urinary tract obstruction, allows more time for reabsorption and is often associated with increases in antidiuretic hormone (ADH), which increases the permeability of the terminal collecting tubule to urea. During ADH-induced antidiuresis, urea secretion contributes to the intratubular concentration of urea. The subsequent buildup of urea in the inner medulla is critical to the process of urinary concentration. Reabsorption is also increased by volume contraction, reduced renal plasma flow as in congestive heart failure, and decreased glomerular filtration.


Creatinine formation begins with the transamidination from arginine to glycine to form glycocyamine or guanidoacetic acid (GAA). This reaction occurs primarily in the kidneys, but also in the mucosa of the small intestine and the pancreas. The GAA is transported to the liver where it is methylated by S-adenosyl methionine (SAM) to form creatine. Creatine enters the circulation, and 90% of it is taken up and stored by muscle tissue. [ 2 ]


Normal serum values


Serum ratios


The reference interval for normal BUN/creatinine serum ratio is 12 : 1 to 20 : 1. [ 4 ]


An elevated BUN:Cr due to a low or low-normal creatinine and a BUN within the reference range is unlikely to be of clinical significance.


The ratio is predictive of prerenal injury when BUN:Cr exceeds 20 [ 5 ]  or when urea:Cr exceeds 100. [ 6 ]   In prerenal injury, urea increases disproportionately to creatinine due to enhanced proximal tubular reabsorption that follows the enhanced transport of sodium and water.


The ratio is useful for the diagnosis of  bleeding  from the  gastrointestinal (GI) tract  in patients who do not present with overt vomiting of blood. [ 7 ]  In children, a BUN:Cr ratio of 30 or greater has a sensitivity of 68.8% and a specificity of 98% for upper gastrointestinal bleeding. [ 8 ]


A common assumption is that the ratio is elevated because of amino acid digestion, since blood (excluding water) consists largely of the  protein   hemoglobin  and is broken down by  digestive enzymes  of the upper GI tract into amino acids, which are then reabsorbed in the GI tract and  broken down  into urea.  However, elevated BUN:Cr ratios are not observed when other high protein loads (e.g., steak) are consumed. [ citation needed ]  Renal hypoperfusion secondary to the blood lost from the GI  bleed has been postulated to explain the elevated BUN:Cr ratio. However, other research has found that renal hypoperfusion cannot fully explain the elevation. [ 9 ]


Because of decreased  muscle  mass, elderly patients may have an elevated BUN:Cr at baseline. [ 10 ]


Hypercatabolic states, high-dose glucocorticoids, and resorption of large hematomas have all been cited as causes of a disproportionate rise in BUN relative to the creatinine. [ 11 ]


Ventral rectopexy  is a surgical procedure for external  rectal prolapse , internal rectal prolapse (rectal intussusception), and sometimes other conditions such as  rectocele ,  obstructed defecation syndrome , or  solitary rectal ulcer syndrome . The  rectum  is fixed into the desired position, usually using a biological or synthetic  mesh  which is attached to the  sacral promontory . The effect of the procedure is correction of the abnormal descended position of the posterior compartment of the pelvis (i.e., the rectum), reinforcement of the anterior (front) surface of the rectum, and elevation of the  pelvic floor . [ 3 ]  In females, the rectal-vaginal septum is reinforced, and there is the opportunity to simultaneously correct any prolapse of the middle compartment (i.e., the  uterus ). [ 4 ]  In such cases, ventral rectopexy may be combined with  sacrocolpopexy . [ 5 ] [ 3 ]  The surgery is usually performed  laparoscopically  (via small openings made in the abdomen).


There are over 300 different variations of surgical procedures described for rectal prolapse, and this area has seen rapid development. [ 3 ]  However, there is no clear consensus regarding the best method. [ 6 ]  Surgical treatment for rectal prolapse may be via the perineal or abdominal (transabdominal / peritoneal) approach. [ 5 ] [ 6 ]  Generally speaking, perineal procedures have less complications but higher rates of recurrence compared to abdominal procedures. [ 7 ]  Ventral rectopexy falls into the abdominal procedure category, and can be considered as a type of abdominal rectopexy.


Abdominal rectopexy encompasses several procedures which involve mobilization and fixation of the rectum, with or without resection, via abdominal approach. Some of types of abdominal rectopexy are now rarely or never performed. For example, the Ripstein rectopexy (anterior fixation of mesh below the sacral promontory) and the Wells procedure (involving detachment of the lateral ligaments of the rectum) have been abandoned. [ 8 ]  In general, abdominal rectopexy procedures have been associated with post-operative problems with defecation such as new or worsened constipation, obstructed defecation or fecal incontinence. [ 9 ] [ 2 ]  This does not seem to be a significant problem with ventral rectopexy, [ 2 ]  which represents the most recent development of abdominal rectopexy. In men, mobilization of the rectum may risk the development of  erectile dysfunction . [ 9 ]


Another way of categorizing surgery for prolapse of pelvic organs is suspensive or resective (involving removal of sections of the bowel wall). Ventral rectopexy alone is a syspensive type surgery, a category which also includes  colposacropexy . [ 10 ]  Resection rectopexy additionally involves removal of a section of the  sigmoid colon  ( sigmoidectomy ). It is thought to have decreased post operative problems of constipation, because the redundant colon is removed and therefore cannot "kink". However, there is no evidence that this improves the outcomes, and the necessary creation of an  anastomosis  (surgically created joining between two ends of bowel when a section of bowel is removed) increases the risk of severe complications. [ 8 ]


Ventral rectopexy with an  autologous graft  ( fascia lata ), [ 9 ]  and then with a synthetic mesh for external rectal prolapse was first reported in 1971. [ 11 ]  The Orr-Loygue procedure (lateral mesh rectopexy) was described in 1984. [ 12 ] [ 5 ]  The Orr-Loygue procedure involved anterior and posterior mobilization of the rectum to the level of the levator ani muscle and removal of the pouch of Douglas. Mesh was sutured to the lateral surfaces (sides) of the rectum. [ 1 ]


The Orr-Loygue procedure was modified by D'Hoore in 2004. [ 13 ]  In ventral rectopexy, there is no posterior dissection and mobilization of the rectum apart from to expose the sacral promontory. With no posterior (dorsal) or lateral dissection, damage to the autonomic nerves is minimized. As a result, there are less problems with post-operative constipation. There is no excision of the pouch of Douglas, and the mesh is placed directly onto the anterior (ventral) surface of the rectum. This procedure aims to suspend the middle and lower sections of the rectum. This modified procedure is now known as the anterior rectopexy or ventral rectopexy. [ 1 ]  D'Hoore also used a  laparoscopic  approach (laparoscopic ventral mesh rectopexy, LVMR). [ 14 ]


After 2002, the minimally invasive trans-anal approach known as  Stapled Trans-Anal Rectal Resection  (STARR) became popular for treating  obstructed defecation syndrome . However, over time, there has been a general trend away from STARR towards abdominal rectopexy for surgical treatment of obstructed defecation syndrome. [ 15 ]


Ventral mesh rectopexy has become the one of the most popular options for rectal prolapse. [ 16 ] [ 7 ]  Ventral rectopexy also provides the opportunity to simultaneously correct any prolapse of the middle compartment of the pelvis, [ 4 ]  and is sometimes combined with  sacrocolpopexy . [ 5 ]


There has been some controversy connected with transvaginal placement of mesh in the treatment of  pelvic organ prolapse  and  stress urinary incontinence . This is because there is a risk of erosion (tissue breakdown around the mesh) and sepsis (infection). [ 4 ]  In 2008 and 2016 the  US Food and Drug Administration  published guidance about potential serious complications caused by such meshes and upgraded their risk classification of such meshes from Class II (moderate risk) to Class III (high risk). Procedures involving transvaginal mesh have since decreased by 40–60% in the USA. [ 14 ]  In 2011, manufacturers of permanent transvaginal meshes withdrew the products from the market. [ 17 ]  In Europe, the  Scientific Committee on Emerging and Newly Identified Health Risks  (SCENIHR) stated in 2015 that implantation of any mesh via the vaginal route should be done only in complicated cases where a primary repair has failed. [ 14 ]  A  Cochrane review  in 2016 stated that the risks were higher with such meshes compared to native tissue repair (using the patient's own tissues instead of mesh). [ 17 ]  Transvaginal meshes have higher risk of repeat surgery, injury to the bladder, and stress urinary incontinence which appears after the surgery. [ 17 ]  They concluded that transvaginal meshes have limited benefit in the primary surgical management of pelvic organ prolapse and stress urinary incontinence. [ 17 ] [ needs update ]  The review was updated in 2024 with the same conclusions but based on newly available evidence. [ 18 ]


In response to the controversy connected with transvaginal meshes, the Pelvic Floor Society on behalf of the Association of Coloproctology of Great Britain and Ireland issued a position statement regarding the use of mesh in ventral rectopexy in 2020. They stated that meshes in ventral rectopexy are not the same because the mesh is inserted between the rectum and the vagina and not directly into the vagina as with transvaginal meshes. [ 14 ]  They also stated that according to current evidence ventral mesh rectopexy is the best available treatment to restore normal rectal function, and that the estimated overall risk of complications is about 2.5% based on the worst-case scenario. [ 14 ]


The definitive indication for ventral rectopexy is:


Relative indications are:


Absolute contraindications are:


Relative contraindications are:


There are 3 options for surgical approach: open abdominal surgery, laparoscopic approach or  robotic surgery . The laparoscopic approach is safer than open surgery, [ 4 ]  and there is less risk of complications after the procedure. [ 23 ]  There is also less blood loss, less pain after the procedure, shorter average length of stay in hospital and faster recovery. [ 8 ] [ 23 ]  Rarely, the procedure must be converted into an open abdominal surgery. [ 7 ]


The procedure is still almost always carried out via laparoscopic approach. [ 14 ]  However, increasingly some surgeons use robotic surgery to conduct the procedure. [ 5 ]  Some surgeons claim that the use of robotic surgery makes ventral rectopexy less technically demanding, because it requires careful dissection and suture placement in a tight, narrow space. [ 1 ]  This is especially true in patients with a narrow pelvis. [ 16 ]  Laparoscopic ventral rectopexy is also difficult in patients who are obese. [ 8 ]


Robotic approach has the benefit of three-dimensional visualization, precise dissection and the possibility of refined, articulated movements suitable for a narrow conical space such as the pelvis. [ 16 ]  There is less trauma to the tissues and less blood loss compared to conventional laparoscopy. [ 8 ]  In the case of ventral rectopexy, which is considered a difficult procedure requiring a lot of training (100 cases), robotic surgery is reported to speed up the learning curve for surgeons (20 cases). [ 8 ]  Longer operation times are usually reported with robotic surgery, but operation time is less With surgeons who are experienced in using the robotic technique. [ 8 ]  The laparoscopic approach is cheaper than robotic surgery, [ 16 ]  but when considering the reduced hospital stay, robotic surgery may be cheaper overall. [ 8 ]


The choice of synthetic material used to perform the rectopexy may also vary and can include nylon, Teflon, Marlex, Ivalon, Gore‐Tex, Vicryl or Dexon. There is debate regarding the best mesh material, and whether a biologic or synthetic mesh is superior. One systematic review found no significant difference between biologic or synthetic mesh with regards to the rates of mesh erosion or recurrence of prolapse. [ 21 ]  However, a later systematic review reported lower rate of mesh erosion for biologic mesh (0.22%) compared to synthetic mesh (1.87%). [ 23 ]


Usually one strip of mesh is placed, but sometimes two are used. [ 7 ]  The meshes are 15, 17 or 20 cm long. [ 7 ]  Tackers (Protack), titanium screw tacks, or sutures (absorbably or non-absorbable) are used to fix the mesh to the sacral promontory. [ 7 ]  Absorbable or non-absorbable sutures (Ethibond, prolypropylene), or 4mm titanium staples are used to fix the mesh to anterior rectal wall. [ 7 ]


After the procedure, patients are advised to avoid sex and lifting heavy weights, and to use laxatives for 6 weeks. [ 5 ]  Continuing pelvic floor physical therapy may be beneficial in those cases where people had symptoms of obstructed defecation or incontinence before the procedure. [ 5 ]


According to one publication, risk of a complication occurring is 14%. [ 5 ]  Another systematic review reported an average complication rate of 4.8%. [ 7 ]  Complications involving the urinary tract are most common and mesh related complications are less common. [ 5 ]


Recurrence of the prolapse after ventral rectopexy is possible. Recurrence rates are reported as between 1.4 and 9.7% of cases. Recurrence occurs sooner and the overall rate is higher when ventral rectopexy is performed on a prolapse which has already recurred in the past (25% of cases after 5 years). Risk factors for recurrence after ventral rectopexy include old age, male gender, higher  body mass index , higher Cleveland Clinic incontinence score, prolonged  pudendal nerve terminal motor latency , weak pelvic floor, [ 5 ] [ 7 ]   benign joint hypermobility syndrome , [ 4 ]  and excessive perineal descent associated with chronic straining. [ 4 ]  Mesh of 20 cm length has lower risk of recurrence than mesh of 15–17 cm. [ 5 ]  Recurrence may occur as either full thickness prolapse or mucosal prolapse. [ 7 ]


Recurrence may occur if the mesh slips from the sacral promontory. This may happen because of inadequate fixation and adherence of the mesh to the anterior rectal wall or to the sacral promontory, or incorrectly placed staples to the upper sacrum. [ 5 ] [ 7 ]  Another technical reason for relapse is inadequate dissection on the anterior aspect of the rectum. [ 7 ]  Recurrence can be a challenging situation for surgeons, [ 7 ]  and in this case the patient is re-evaluated for 6 months to identify the reason for the recurrence. [ 5 ]  A further surgical procedure to re-fix the mesh may be required. [ 5 ]


Overall risk of complications associated with the mesh have been reported as 2.5%. [ 14 ]  Such complications include detachment and migration of the mesh. This complication is reported at a rate of 4.6% of cases. [ 5 ]  The mesh can erode into the vagina (1.3% of cases), or into the rectum.  The risk of mesh complications appears to be low regardless of what mesh material is used. [ 21 ]  However, biologic mesh may have a lower risk of complications compared to synthetic mesh. [ 23 ]  When suturing synthetic mesh to the rectum, the use of absorbable sutures leads to lower risk of complications compared to non-resorbable sutures. [ 5 ]   When mesh erosion into the vagina occurs, a further surgical procedure is required to remove the tissue from the mesh and to close the vaginal wall over the defect. [ 5 ]  Most mesh-related complications can be treated successfully. [ 5 ]


At the site where the mesh is attached (lumbosacral region), vertebral  discitis  may occur. This is a rare but serious complication. In one case, the discitis may have been caused by the use of titanium screws. Signs and symptoms of discitis include chronic back pain and infection. Discitis is treated with intravenous antibiotics and possible removal of the mesh. [ 5 ]


Urinary-related complications include  urinary tract infection ,  urinary retention , damage to structures like the  ureter ,  bladder  or  vas deferens . [ 5 ]


Other possible complications are infection or hernia at the port site,  ileus  and small bowel injury. [ 7 ]


The average improvement in fecal incontinence is reported as 62.5 [ 7 ]  to 79.3%, [ 5 ]  and the average improvement in constipation from 76.6% [ 7 ]  to 71%. [ 5 ]  However, these conditions may not fully resolve after the procedure. [ 5 ]  Ventral rectopexy may be more effective as an initial surgical repair of a prolapse rather than treatment for a recurrent prolapse which was previously operated upon. [ 5 ]


One systematic review comparing laparoscopic ventral mesh rectopexy and robotic ventral mesh rectopexy concluded that robotic approach resulted in a longer operation time. [ 16 ]  However, this may be related to lack of operator experience with the robotic platform, and it has been suggested that a surgeon who is experienced with the robotic approach can perform the operation as fast or faster than a surgeon who is experienced with the laparoscopic approach. The robotic approach resulted in a shorter stay in hospital for patients, which balanced the increased cost of the robotic surgery itself. This may be because robotic surgery is more precise and leads to less bleeding and pain after the procedure. One study showed lower scores for obstructed defecation after robotic approach. In general, both approaches showed improvement in function and quality of life, but some studies reported robotic approach as giving slightly more improvement in quality of life. Both approaches resulted in similar long term outcome and recurrence rates. The review authors concluded that robotic ventral mesh rectopexy is safe and results in at least the same outcomes as laparoscopic approach. [ 16 ]


The most commonly used material for synthetic mesh is polypropylene. This material has a lower risk of mesh exposure compared to polyester. [ 19 ]  The two most common biologic mesh products are Permacol, which is cross-linked collagen, and Biodesign, which is non-cross linked. It is not known if one type of biologic mesh is better. [ 19 ]


In 2020 another systematic review compared the use of synthetic mesh and biologic mesh in ventral mesh rectopexy for external rectal prolapse or symptomatic internal rectal prolapse. [ 19 ]  The review included 32 studies containing a total of 4001 cases where synthetic mesh was used and 762 where biologic mesh was used. The rate of mesh-related complications ranged from 0 to 2.4% for synthetic mesh, with a pooled incidence rate of 1%. The rate of mesh-related complications ranged from 0 and 0.7% for biologic mesh. The rate of recurrence ranged from 1.1 to 18.8% for synthetic mesh. The rate of recurrence ranged from 0 to 15.4% for biologic mesh. The reviewers stated that the risk of mesh related complications are low for both synthetic and biologic mesh, and there may a small reduction in mesh-related complications with biologic mesh. However, due to lack of sufficient high quality data for biologic mesh, they were unable to make definitive conclusions. [ 19 ]


One systematic review compared laparoscopic suture rectopexy with laparoscopic mesh rectopexy in the treatment of full-thickness rectal prolapse (external rectal prolapse, complete rectal prolapse). Compared to suture rectopexy, mesh rectopexy had lower rate of recurrence and longer operation time. There were no differences in degree of improvement of constipation, incontinence, bleeding during the surgery, length of stay in hospital, and overall rate of complications after the surgery. [ 24 ]


A  wale mark ,  red wale sign  or  wale sign  is an endoscopic sign suggestive of recent hemorrhage, or propensity to bleed, seen in individuals with  esophageal varices  at the time of  endoscopy .  The mark has the appearance of a longitudinal red streak located on an esophageal varix.  It derives its name from the visual similarity to patterns seen in the  textile   corduroy . [ 1 ]


Similar lesions that are suggestive of recent or impending bleeding from esophageal varices include the  cherry-red  spot, which is circular and red in colour.  Bleeding risk of esophageal varices can be ascertained at the time of endoscopy by evaluating for the presence of these markers. [ 2 ]


Aceglutamide  (brand name  Neuramina ), or  aceglutamide aluminium  (brand name  Glumal ), also known as  acetylglutamine , is a  psychostimulant ,  nootropic , and  antiulcer agent  that is marketed in  Spain  and  Japan . [ 1 ] [ 2 ] [ 3 ] [ 4 ]  It is an  acetylated  form of the  amino acid   L -glutamine , the  precursor  of  glutamate  in the body and  brain . [ 5 ]  Aceglutamide functions as a  prodrug  to glutamine with improved  potency  and  stability . [ 5 ]


Aceglutamide is used as a psychostimulant and nootropic, while aceglutamide aluminium is used in the treatment of ulcers. [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Aceglutamide can also be used as a liquid-stable source of glutamine to prevent damage from protein energy malnutrition. [ 10 ] [ 11 ] [ 12 ]  The drug has shown  neuroprotective  effects in an  animal model  of  cerebral ischemia . [ 5 ]


Acetoxolone  (also known as acetylglycyrrhetic acid, acetylglycyrrhetinic acid, glycyrrhetinyl acetate and glycyrrhetic acid acetate) is a drug used for  peptic ulcer  and  gastroesophageal reflux disease . [ 1 ]   It is an  acetyl  derivative of  glycyrrhetinic acid . It is found in  Echinopora  lamellosa. [ 1 ]


Alicaforsen  (trade name  Camligo ) is an  antisense  oligonucleotide therapeutic that targets the  messenger RNA  for the production of human  ICAM-1  receptor [ 1 ]   and is being developed for the treatment of acute disease flares in moderate to severe  Inflammatory Bowel Disease  (IBD).


Alicaforsen inhibits ICAM-1 production, which is an important adhesion molecule involved in leukocyte migration and trafficking to the site of inflammation. Hitherto, alicaforsen has been granted orphan drug designation and is prescribed as an unlicensed medicine in accordance with international regulation, for the treatment of  pouchitis  and left-sided  ulcerative colitis . Given the positive results from an open-label trial and one case series in patients with chronic refractory pouchitis,  US FDA  has agreed to a rolling submission for a license application for the treatment of pouchitis.


It was discovered by  Ionis Pharmaceuticals  (formerly Isis Pharmaceuticals) and in 2017  Atlantic Healthcare plc took over the development for chronic antibiotic refractory  pouchitis  in an  enema  formulation. [ 2 ]


ICAM-1 promotes the  extravasation  and activation of  leukocytes  (white blood cells), which is part of the  inflammation  process. [ 3 ]   Alicaforsen inhibits the activity of  ICAM-1  protein by degrading  mRNA  coding for it via an  RNase-H  based mechanism. [ 3 ]


It appears to have better efficacy as a  topical medication  than via  systemic administration  which is typical of antisense drugs. [ 3 ]


In a Phase III randomised clinical trial with 299 patients with steroid dependent Crohn's disease, clinical response was correlated with drug exposure, with significant efficacy versus placebo being observed in the subgroup with greatest area under the curve, hence pharmacodynamic modelling suggests that alicaforsen (ISIS 2302) may be an effective therapy at adequate dose levels. [ 4 ]


In another placebo-controlled study with 331 subjects with active Crohn's Disease, alicaforsen failed to demonstrate efficacy in any of its primary outcome measures. However there was a suggestion of a therapeutic response in a sub-population with elevated serum CRP (C-reactive Protein) levels >2mg/dl. The differential response highlights the confounding symptoms of a large subset of subjects whose needs are apparently not being met by the current clinical trial design. There is a need for more specific biomarkers that clearly can identify disease severity and subtypes of Crohn's disease and can be used to monitor disease response objectively. [ 5 ]


Alicaforsen is a 20 unit phosphorothioate modified antisense  oligonucleotide . [ 6 ]


Alicaforsen was discovered and initially developed by Isis Pharmaceuticals, [ 7 ]  which changed its name to  Ionis Pharmaceuticals  in 2015.


Isis partnered on development of alicaforsen with  Boehringer Ingelheim  starting in 1995; that deal ended in 1999, after each of IV and subcutaneously delivered alicaforsen failed in phase III trials for  Crohn's disease  and development of those formulations in that indication was terminated; development for  rheumatoid arthritis  was terminated the same year and development in kidney transplant apparently ceased as well at that time. [ 7 ]


The company reformulated alicaforsen as an  enema  and three small trials were published between 2004 and 2006, an open label trial in chronic  pouchitis  and two randomized trials in  ulcerative colitis  (UC); in the UC trials the drug missed its primary endpoint of improvements at 6 weeks, but showed a better effect in the longer term (between 18 and 30 weeks). [ 3 ]


A post hoc meta-analysis of individual data of 200 patients from four phase 2 studies evaluating nightly alicaforsen 240 mg enema for six weeks showed that alicaforsen is effective in patients with active, distal, moderate to severe UC. The efficacy of alicaforsen was durable in these sub-groups, with significantly improved duration of clinical response with no maintenance therapy, suggesting a disease-modifying effect. This analysis suggests that alicaforsen enema could offer an effective, potentially durable response in moderate/severe distal active UC. [ 8 ]


Alicaforsen was licensed to Atlantic Healthcare in 2007. [ 9 ]


The use of the enema formulation of alicaforsen to treat  pouchitis  was granted  orphan drug  status in the US in 2008 [ 10 ]  and received the same in Europe in 2009. [ 11 ]   The enema formulation of alicaforsen for  pouchitis  received  FDA Fast Track  designation. [ 12 ]  In a subsequent multicentre Phase 3 clinical trial in 138 subjects with Active, Chronic, Antibiotic Refractory Primary Idiopathic  Pouchitis , showed a clinically relevant 34% remission in stool frequency with 8% delta vs placebo. However the co-primary endpoints (an adaptation of the Mayo Score of improvement in endoscopic remission and bowel frequency) were not met, perhaps due to the high discontinuation rate of 35% that compromised the sample size available for statistical analysis. Disallowing background maintenance therapies contributed to this high dropout rate in this challenging, heterogenous patient group. Further the appropriateness of endoscopy as a primary end point is questionable.


Atlantic Healthcare has supplied over 350 courses of alicaforsen enema treatment on a named patient / compassionate use programme. Clinical outcomes published in case series have confirmed durable disease remission in patients with Ulcerative Colitis with no treatment related SAEs. [ 13 ]


•    UC case series publications confirming prolonged duration of action:


Ø     Digestive Diseases Journal  (Nov 2017); 10/12 patients with left-sided UC/proctitis responded to treatment, with a median durable response of 18 weeks


Ø     Gastrodagarna Congress, Sweden  (May 2016); all 7 distal UC patients that completed treatment responded, 57% remained in remission for 5-20 months


Ø     Irish Society of Gastroenterology  (Nov 2014); reported remission achieved in 57% of patients with UC with a durable response  1


No drug-related SAEs have been reported in any usage of alicaforsen enema


Alka-Seltzer  is an  effervescent   antacid  and pain reliever owned by  Bayer  since 1978. First marketed by the  Dr. Miles Medicine Company  of  Elkhart, Indiana ,  United States , Alka-Seltzer contains three active ingredients:  aspirin  (acetylsalicylic acid or ASA),  sodium bicarbonate , and  anhydrous   citric acid . [ 1 ]  The aspirin is a pain reliever and  anti-inflammatory , the sodium bicarbonate is an antacid, and the citric acid reacts with the sodium bicarbonate and water to form  effervescence . [ 2 ]


It was developed by head chemist Maurice Treneer. [ 3 ] [ 4 ]  Alka-Seltzer is marketed for relief of minor aches, pains,  inflammation ,  fever ,  headache ,  heartburn ,  stomach ache ,  indigestion ,  acid reflux , and  hangovers  while  neutralizing  excess  stomach acid . [ 4 ]  It was launched in 1931. [ 5 ]


Its sister product, Alka-Seltzer Plus, treats cold and flu symptoms. A wide variety of formulae, many using  acetaminophen  (paracetamol) instead of aspirin, are available under the sister brand. [ 6 ]


Alka-Seltzer is a combination of  sodium bicarbonate ,  aspirin , and  anhydrous   citric acid  used for the relief of heartburn, acid indigestion, and stomach aches. [ 7 ]


Alka-Seltzer is sold in foil packets, each containing two tablets. Prior to 1984, it was also available stacked in cylindrical glass bottles. It is available in many different flavors.


It was once marketed as a cure-all; at one time, its ads even suggested taking it for "the blahs". Subsequent promotion has taken into consideration that aspirin is a drug that is not tolerated by everyone, and the product is no longer advertised in this fashion.


Alka-Seltzer marketed as an antacid no longer contains aspirin (ASA).  [ 8 ]  The original effervescent formula has aspirin as its main active ingredient, and is marketed for pain relief.


Though important to the overall effect of the medication, the aspirin ( acetylsalicylic acid ) is not required to produce the  effervescent  action of Alka-Seltzer; the effervescence is produced by the baking soda ( sodium bicarbonate ) and  citric acid  reacting to form sodium citrate and carbon dioxide gas. [ citation needed ]


The product has been extensively advertised since its launch in the United States. It was originally marketed by Mikey Wiseman, a company scientist of Dr. Miles Medicine Company, who also helped direct its development.


Print advertising was used immediately, and in 1932 the radio show  Alka-Seltzer Comedy Star of Hollywood  began, with  National Barn Dance  following in 1933, along with many more. The radio sponsorships continued into the 1950s, with the  Alka-Seltzer Time  show airing from 1949 to 1957.


In his 1976 revival, American actor and radio performer  Richard Beals  proclaimed Alka-Seltzer's virtues and sang the "Plop, plop, fizz, fizz, oh what a relief it is" song in his iconic high, squeaky voice. In the early 1960s, a commercial showing two tablets dropping into a glass of water instead of the usual one caused sales to double. [ citation needed ]


Alka-Seltzer TV ads from the 1960s and 1970s in the US were among the most popular of the 20th century, ranking number 13, according to  Advertising Age . To increase sales in a relatively flat business, Bayer  revived several of the vintage spots. [ citation needed ]


During the race for space in the early 1960s before the Moon landing, there was a commercial with Speedy in a space suit and a jingle with the lyrics "On Man's first trip through space, I only hope that I'm aboard, securely strapped in place. They'll track our ship with radar and telescopes and soon, imagine seeing Speedy Alka-Seltzer on the moon!" [ citation needed ]


George Raft  starred in the 1969 Alka-Seltzer commercial "The Unfinished Lunch". It consisted of Raft incarcerated in a prison lunchroom. He takes a bite of the prison food and recoils. Suddenly he bangs his cup on the steel table. It ripples throughout the room. He starts intoning "Alka-Seltzer, Alka-Seltzer..." Soon, the other hundreds of inmates do the same. The commercial became so popular that several weeks later, Raft appeared as a guest on  The Tonight Show Starring Johnny Carson . Raft told Carson that it took more than 7 hours to tape the 30-second commercial. Raft was enraged by the end of the day, thus making his inmate portrayal that much more convincing for the final editing. The film crew gave Raft his crumpled tin cup, which he showed to Carson and the audience. [ citation needed ]


An animated mid-1960s commercial, animated by  R. O. Blechman , shows a man and his own stomach sitting opposite each other in chairs, having an argument moderated by their therapist in a voiceover. The stomach (voiced by  Gene Wilder ) accuses the man of purposely trying to irritate it. The man accuses his stomach of complaining too much about the foods he likes. The therapist suggests Alka-Seltzer and that the two must take care of each other. The closing words are of the stomach saying to the man: "Well, I'll try — if you will." [ citation needed ]


Alka-Seltzer had a series of commercials during the mid-1960s that used a song called " No Matter What Shape (Your Stomach's In) ". A different version was recorded by  The T-Bones  and was released as a single, which became a hit in 1966. The ads featured only the midsections (no faces) of people of all shapes and sizes. A clip of the ad can be seen briefly in the 1988 motion picture  The In Crowd , immediately before the movie's first live broadcast of the fictitious "Perry Parker's Dance Party."


In an Alka-Seltzer commercial from 1969, an actor named "Jack" (played by  Jack Somack ) in a commercial for the fictional product "Magadini's Meatballs" has to eat a meatball and then say "Mamma mia, that's-a spicy meat-a ball-a!" in an ersatz Italian accent. Take after take is ruined by some comedic trial or another (comedian  Ronny Graham  dropping the clapperboard). By the commercial's end, Jack has eaten so many meatballs that it's "Alka-Seltzer to the rescue." With his stomach settled, Jack does a perfect take, except that the oven door falls off. The director (off-camera) sighs and says, "OK, let's break for lunch." [ 9 ]


A 1970 commercial shows a newlywed couple in the bedroom after the woman (played by  Alice Playten ) has finished serving her husband (played by  Terry Kiser ) a giant dumpling; the implication is that her cooking skills are severely lacking, despite her husband's lament, "I can't believe I ate that whole thing!", the commercial's  catchphrase . She lies on the bed in delusional triumph. She offers her beleaguered husband a heart-shaped meatloaf; he disappears to take some Alka-Seltzer. When she hears the fizzy noise coming from the bathroom, he quickly covers the glass of dissolving Alka-Seltzer as she wonders aloud if it is raining. Just when he has recovered his well-being, he hears her misreading recipes for dinner the next night: "Marshmallowed meatballs," "medium salad snails," and "pouched (actually poached) oysters". He returns to the bathroom for more Alka-Seltzer. [ 10 ]  The catchphrase, Howie Cohen told the  Los Angeles Times , was inspired when he ate too much of the food at a  London  commercial shoot because "I am a nice Jewish kid from the Bronx, so I ate everything," and when he told his wife "I can't believe I ate the whole thing", she said, "There's your next Alka-Seltzer commercial." [ 11 ]


A 1971 commercial featured another catch-phrase from Cohen (along with Bob Pasqualina), "Try it, you'll like it!" It was remade with  Kathy Griffin  in 2006. [ 12 ]  In 1972, an actor (Milt Moss) spent the commercial moaning, "I can't believe I ate that who-o-o-o-o-ole thing" while his wife (Lynn Whinic) made sarcastic comments and finally advised him to take some Alka-Seltzer. [ 13 ]  In 2005, this ad was also remade, featuring  Peter Boyle  and  Doris Roberts  from the 1996–2005 TV sitcom  Everybody Loves Raymond . [ 14 ]


In 2009, the brand was featured in television commercials supporting the  United States Ski Team  that included alpine skier  Lindsey Vonn  and Nordic combined skier  Bill Demong . Miniature figures of the Speedy mascot were shown with each. Alka-Seltzer products are sold in nighttime [ 15 ]  and daytime, or nondrowsy, [ 16 ]  formulas. The non-drowsy claims have recently been questioned. [ 17 ]


In 1951, the "Speedy" character was introduced. The character was conceived by creative directors Bob Watkins and Chuck Tennant of the Wade Advertising agency and designed by illustrator  Wally Wood . Originally named Sparky, the name was changed to Speedy by sales manager Perry L. Shupert to align with that year's promotional theme, "Speedy Relief". Speedy appeared in over 200 TV commercials between 1954 and 1964. [ 18 ]  His body was one Alka-Seltzer tablet, while he wore another as a hat.


Buster Keaton  appeared along with the animated Speedy Alka-Seltzer figure in a series of 1950s commercials based on the product slogan, "Relief is just a swallow away." Speedy Alka-Seltzer was voiced by  Dick Beals .


Paul Margulies  (father of actress  Julianna Margulies ) created the famous "Plop, plop, fizz, fizz" ad campaign when he worked as a  Madison Avenue  ad executive. The ubiquitous jingle was composed by Tom Dawes, a former member of  The Cyrkle . The slogan was altered to "Plink, plink, fizz" in the United Kingdom. [ 19 ]


Speedy was revived for a "Plop, plop, fizz, fizz" song spot in 1976.


Sammy Davis Jr. , recorded two versions of the "Plop Plop Fizz Fizz" jingle in 1978, one of which (the "big band" version) was featured on a television commercial. Both the big band and rock versions had additional lyrics (with at least one verse unique to each song) written by Tom Dawes, former lead singer of  The Cyrkle  who wrote the original jingle.


Speedy was again revived in 2008 when Alka-Seltzer began a series of new commercials featuring him (using a  CGI  character created by animation director  David Hulin  to recreate the stop-motion puppetry of the 1950s and 1960s); in these ads, he was voiced by  Debi Derryberry . [ 20 ]


Alverine  is a drug used for  functional gastrointestinal disorders . Alverine is a  smooth muscle  relaxant. Smooth muscle is a type of muscle that is not under voluntary control; it is the muscle present in places such as the  gut  and  uterus .


The side effects of Alverine include: [ 1 ] [ 2 ]


It was reported that alverine may induce toxic  hepatitis . [ 3 ] [ 4 ]


Alverine acts directly on the muscle in the gut, causing it to relax. Alverine is a 5HT1A antagonist, which reduces rectal hypersensitivity. [ 5 ]  This prevents the  muscle spasms  which occur in the gut in conditions such as  irritable bowel syndrome  and  diverticular disease . [ 6 ]  Diverticular disease is a condition in which small pouches form in the gut lining. These pouches can trap particles of food and become inflamed and painful. In irritable bowel syndrome, the normal activity of the gut muscle is lost. The muscle spasms result in symptoms such as  abdominal pain  and  bloating ,  constipation  or  diarrhoea . By relaxing the gut muscle, alverine citrate relieves the symptoms of this condition. Alverine also relaxes the smooth muscle in the womb (uterus). It is therefore also used to treat painful menstruation, which is caused by muscle spasms in the uterus ( dysmenorrhea ).


Alverine capsules [ 7 ]  are now available in the market. There are two strengths of capsule - 60 mg and 120 mg. The common dosage for adults and children over 12 years is 60–120 mg taken one, two or three a day, either before or after meals. Alverine is not suitable for those aged under 12 years. Women who are pregnant or breast-feeding should follow the instruction of doctors for the drug.


A combination of alverine citrate and  simeticone  (ACS) for irritable bowel syndrome therapy were compared with placebo in a phase IV  clinical trial . [ 8 ]  At week 4, the alverine citrate and simeticone group had lower VAS scores for abdominal pain/discomfort (median: 40 mm vs. 50 mm, P = 0.047) and higher responder rate (46.8% vs. 34.3%, OR = 1.3; P = 0.01) as compared with the  placebo  group. [ 9 ]


The drug was firstly authorized for marketing on 03/06/2014. The marketing authorisation holder is Dr. Reddy's Laboratories (UK) Ltd. [ 10 ]


An  aminosalicylate  is a class of medications that is often used to treat  ulcerative colitis [ 1 ]  and  Crohn's disease . The class includes among others: [ 1 ]


Side effects may include  abdominal pain ,  diarrhea ,  headaches , and nausea. [ 1 ]


Anticachexia  (AN-tee-kuh-KEK-see-uh)  is a drug or effect that works against  cachexia  (loss of body weight and muscle mass).


This  pharmacology -related article is a  stub . You can help Wikipedia by  expanding it .


Antisialagogues  are  drugs  or substances that decrease the flow rate of  saliva  and their effect is opposite to that of  sialagogues . [ 1 ]  Their origin may be both natural and synthetic.


Anticholinergics  generally have antisialagogue effects, and most produce some level of  sedation , both being advantageous in  surgical procedures . [ 2 ]


Classic antisialagogues [ 1 ]  include:


An  antispasmodic  (synonym:  spasmolytic ) is a  pharmaceutical drug  or other agent that suppresses muscle  spasms . [ 1 ]


One type of antispasmodics is used for  smooth muscle  relaxation, especially in tubular organs of the  gastrointestinal tract . The effect is to prevent spasms of the  stomach ,  intestine  or  urinary bladder .
Both  dicyclomine  and  hyoscyamine  are antispasmodic due to their  anticholinergic  action. [ medical citation needed ]  Both of these drugs have side effects common to anticholinergics and can worsen  gastroesophageal reflux disease  (GERD). [ 2 ]


Papaverine  is an  opium   alkaloid  used to treat  visceral  spasms, particularly those of the intestines. [ 3 ]   Mebeverine  is a papaverine analog and spasmolytic with a strong and selective action on the smooth muscles of the gastrointestinal tract, particularly of the colon. Despite being anticholinergic, it does not have the systemic anticholinergic side effects seen in other such drugs. [ 4 ]


Peppermint oil  has been traditionally used as an antispasmodic, and a review of studies on the topic found that it "could be efficacious for symptom relief in  IBS " [ 5 ]  (as an antispasmodic) although more carefully controlled studies are needed. A later study showed it is an effective antispasmodic when test-applied topically to the intestine during  endoscopy . [ 6 ]


Bamboo shoots have been used for gastrointestinal and antispasmodic symptoms. [ medical citation needed ]


Anisotropine ,  atropine ,  clidinium bromide  are also the most commonly used modern antispasmodics. [ citation needed ]


Pharmacotherapy may be used for  acute   musculoskeletal  conditions when  physical therapy  is unavailable or has not been fully successful. Another class of antispasmodics for such treatment includes  cyclobenzaprine ,  carisoprodol ,  diazepam ,  orphenadrine , and  tizanidine . [ 7 ]   Meprobamate  is another effective antispasmodic which was first introduced for clinical usage in 1955 mainly as an  anxiolytic  and soon afterward became a blockbuster psychotropic drug. While clinical usage of meprobamate has largely become obsolete since the development of  benzodiazepines  due to its liability for developing physical   dependence  and severe toxicity during instances of acute   overdose , it is still manufactured and available by prescription. Carisoprodol is similar to meprobamate as they both belong to the  carbamate   drug class  and meprobamate is a clinically significant  active metabolite  of carisoprodol, although carisoprodol itself possesses additional antispasmodic properties which are distinct from its metabolites. Effectiveness has not been clearly shown for  metaxalone ,  methocarbamol ,  chlorzoxazone ,  baclofen , or  dantrolene . [ 7 ]  Applicable conditions include acute back [ 8 ]  or neck pain, or pain after an injury. Long-term use of muscle relaxants in such cases is poorly supported. [ 8 ]


Spasm may also be seen in movement disorders featuring  spasticity  in neurologic conditions such as  cerebral palsy ,  multiple sclerosis , and  spinal cord disease . Medications are commonly used for spastic movement disorders, but research has not shown functional benefit for some drugs. [ 9 ] [ 10 ]  Some studies have shown that medications have been effective in decreasing spasticity, but that this has not been accompanied by functional benefits. [ 9 ]  Medications such as  baclofen ,  tizanidine , and  dantrolene  have been used. [ 7 ]


Aramchol  is an investigational drug being developed by  Galmed Pharmaceuticals  as a first-in-class, potentially disease modifying treatment for nonalcoholic  steatohepatitis , or NASH, a more advanced condition of  non-alcoholic fatty liver disease . [ 1 ] [ 2 ] [ 3 ] [ 4 ]


Aramchol, a conjugate of  cholic acid  and  arachidic acid , is a member of a synthetic fatty-acid/bile-acid conjugate (FABAC). FABACs are composed of endogenous compounds, orally administrated with potentially good safety and tolerability parameters. [ 5 ]


Aramchol affects liver fat metabolism and has been shown in a Phase IIa clinical study to significantly reduce liver fat content as well as improve metabolic parameters associated with fatty liver disease. Furthermore, it has been shown to be safe for use, and with no severe adverse effects. [ 6 ] [ 7 ]


Aramchol was initially intended to combine a cholesterol solubilizing moiety (a saturated fatty acid) with a bile acid (cholic acid) acting as a vehicle to enable secretion into bile and entry into the enterohepatic circulation to solubilise bile stones. [ 8 ]  However, early in the development, it was observed that Aramchol reduced liver fat infiltration in animals fed a high fat, lithogenic diet. [ 9 ]  This effect was confirmed in other animal models and the development plan was modified according to these findings, as fatty liver is an unmet need. [ citation needed ]


Aramchol has been shown to work by two parallel pathways, leading to synergistic effects [ citation needed ]


Aramchol inhibits the activity of  stearoyl coenzyme A desaturase 1  (SCD1) in the liver. This is likely a direct effect since the mRNA of this and other lipogenic genes or the activities of nuclear receptors are not affected. The physiologic effects of SCD1 inhibition are: decreased synthesis of fatty acids, resulting in a decrease in storage triglycerides and other esters of fatty acids. This reduces liver fat (including triglycerides and free fatty acids), and results in an improvement in insulin resistance. [ 10 ]  Aramchol’s mechanism of action, inhibition of the SCD1 enzyme, has been confirmed in human liver microsomes2 and in animal studies by showing a reduction of the SCD1 activity marker, the fatty acid ratio 16:1/16:0, following Aramchol treatment. These studies showed that the SCD1 inhibition effect of Aramchol is partial (can reach to 70 to 83%). Unlike other SCD1 inhibitors, it was shown that Aramchol’s effects are non-atherogenic. [ 8 ]  There are at present no known inhibitors of SCD1 with the established safety and efficacy profile of Aramachol. [ citation needed ]


Aramchol activates cholesterol efflux by stimulating (2 to 4-fold) the ABCA1 transporter, a universal cholesterol export pump present in all cells. [ 11 ] [ 12 ]  In animal models, this led to a significant reduction of blood and body cholesterol and an increase in fecal sterol output, mostly neutral sterols. [ 11 ]


Aramchol is the first small molecule that was shown to induce ABCA1-dependent cholesterol efflux without affecting transcriptional control. [ 11 ]


Axelopran  ( INN ,  USAN ) (developmental code name  TD-1211 ) is a  drug  which is under development by  Theravance Biopharma  and licensed to  Glycyx  for all indications. It acts as a  peripherally acting μ-opioid receptor antagonist  and also acts on  κ- , and  δ-opioid receptors , with similar  affinity  for the μ- and κ-opioid receptors and about an order of magnitude lower affinity for the δ-opioid receptor. Recent data suggests that μ-opioid antagonists have a direct effect on  overall survival  in patients with advanced cancer. [ 1 ]


A μ-opioid agonist (e.g., morphine) have been shown to have multiple pro-tumor effects in vivo and in vitro, which can be blocked with μ-opioid antagonists including promoting  angiogenesis , [ 2 ] [ 3 ]  accelerating tumor cell proliferation, [ 4 ] [ 5 ]  and modifying the response to  chemotherapeutics .  An extensive body of literature has shown diverse and profound immunosuppressive effects of μ-opioid activation in vivo and in vitro. [ 6 ]


Recent data for axelopran in three different pre-clinical models of cancer shows that a μ-opioid antagonist isolates distinct effects of the endogenous opioid system on tumor growth and works in combination with  checkpoint inhibitors . The study of axelopran in  melanoma  in a  zebrafish  embryo model with an immature immune system and no  microbiome  tested axelopran direct effects on tumor growth and  metastasis . The study of  breast cancer  in chicken eggs with a functional immune system and no microbiome tested the direct effect of axelopran on tumor weight, tumor immune infiltration, metastasis and angiogenesis. The study of axelopran in MC-38 syngeneic  colorectal cancer  in mice in combination with murine  anti-PD-1  antibody tested the effect of a μ-opioid blockade on tumor volume and survival in a full in vivo model with both fully functional immune system and mature gut function and enteric microbiome.


All three pre-clinical studies showed a significant impact of axelopran on their respective endpoints, suggesting that μ-opioid blockade is useful across different tumor types and has multiple mechanisms of action, including direct suppression of tumor cell proliferation, angiogenesis and metastasis, and immune surveillance. Furthermore, axelopran and murine anti-PD-1 antibody were synergistic in slowing tumor growth and increasing survival in the syngeneic mouse model.


Axelopran has potent μ-opioid receptor antagonist activity on the  gastrointestinal tract   in vivo , and thus it produces a dose-dependent inhibition of opioid-induced delaying in gastric emptying in mice and rats following  subcutaneous  or  oral  administration. [ 7 ] [ 8 ]


Benexate  (BEX) is an anti-ulcer agent used in the treatment of acid-related disorders. It is unique in its inability to form salts that are both non-bitter and soluble. [ 1 ] [ 2 ]


Benexate is approved from treatment of  gastric ulcer  in Japan. [ 3 ]


The  mechanism of action  of benexate involves promotion of  prostaglandin  synthesis,  protein secretion , and blood flow stimulation in the gastrointestinal tract. [ 4 ]


Bevenopran  ( INN ,  USAN ) (former developmental code names  CB-5945 ,  ADL-5945 ,  MK-2402 ,  OpRA III ) is a  peripherally acting μ-opioid receptor antagonist  that also acts on  δ-opioid receptors  and was under development by  Cubist Pharmaceuticals  for the treatment of chronic  opioid -induced  constipation . [ 1 ] [ 2 ] [ 3 ]  It reached  phase III   clinical trials  for this indication before being discontinued. [ 4 ] [ 5 ]


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Bismuth subgallate , with a chemical formula C 7 H 5 BiO 6 , is commonly used to treat malodor by deodorizing  flatulence  and  stools . In the United States, it (bismuth subgallate) is the active ingredient in  Devrom  (internal deodorant), an over-the-counter FDA-approved medicine.  Also, it has been used to treat  Helicobacter pylori  infection and is used in wound therapy.  As an internal deodorant, it is commonly used by individuals who have had  gastrointestinal stoma  surgery, bariatric surgery, fecal incontinence, and irritable bowel syndrome. [ 1 ]


Also, a double blind study in 1974 reported its effectiveness as a flatulence/stool deodorant in ileostomy patients. [ 2 ]


It can cause darkening of the tongue and stools, which is temporary. [ 3 ]


In 1974, a reversible  encephalopathy  was noted and examined in four colon cancer patients taking bismuth subgallate after  abdominoperineal resection . [ 4 ]


Bismuth subgallate is contraindicated in case of  hypersensitivity  to the substance, and should be used with caution in people with  liver disease  or  kidney disease . [ 3 ]  It is grouped in  pregnancy category C [ 3 ]  (risk not ruled out: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks). During  lactation , very little bismuth subgallate passes over to the child. [ 3 ]


Crystal structure determination of bismuth subgallate revealed it is a  coordination polymer  with the formula [Bi(C 6 H 2 (O) 3 COOH)(H 2 O)] n 2nH 2 O. [ 5 ]  The phenolate oxygen atoms of the gallate ligand chelate to bismuth cations and form chains. The material is nanoporous and the open-channels can be filled with small gas molecules such as carbon dioxide. [ 5 ]


Bismuth subsalicylate , sold generically as  pink bismuth  and under brand names including  Pepto-Bismol ,  Pepti-Calm  and  BisBacter , is a medication used to treat temporary discomfort of the  stomach  and  gastrointestinal tract . This includes an  upset stomach ,  heartburn  or other similar symptoms.


Bismuth subsalicylate has the empirical chemical formula C 7 H 5 BiO 4 , [ 1 ]  and is a  colloidal  substance obtained by  hydrolysis  of  bismuth   salicylate  (Bi(C 6 H 4 (OH)CO 2 ) 3 ).


As a derivative of  salicylic acid , bismuth subsalicylate displays  anti-inflammatory [ 2 ]  and  bactericidal  action. [ 3 ]  It also acts as an  antacid .


Bismuth subsalicylate is used as an antacid and  antidiarrheal , and to treat some other gastrointestinal symptoms, such as nausea. The means by which this occurs is still not well documented. It is thought to be some combination of the following: [ 4 ]


In vitro  and  in vivo  data have shown that bismuth subsalicylate hydrolyzes in the gut to  bismuth oxychloride  and  salicylic acid  and less commonly  bismuth hydroxide . In the stomach, this is likely an acid-catalyzed hydrolysis. The salicylic acid is absorbed and therapeutical concentrations of salicylic acid can be found in blood after bismuth subsalicylate administration. Bismuth oxychloride and bismuth hydroxide are both believed to have bactericidal effects, as is salicylic acid for  enterotoxigenic  E. coli , a common cause of " traveler's diarrhea ". [ 5 ]


Organobismuth compounds have historically been used in growth media for selective isolation of microorganisms. Such salts have been shown to inhibit proliferation of  Helicobacter pylori , other enteric bacteria, and some fungi. [ 6 ]


There are some  adverse effects . It can cause a  black tongue  and black  stools  in some users of the drug when it combines with trace amounts of  sulfur  in saliva and the colon to form  bismuth sulfide . [ 7 ]  Bismuth sulfide is a highly insoluble black salt, and the discoloration seen is temporary and harmless.


Long-term use (more than six weeks) may lead to accumulation and toxicity. [ 8 ]  High daily intake over a period of months can possibly cause severe fatigue, weakness and neurological symptoms that reverse with discontinuation. [ 9 ]  Some of the risks of  salicylism  can apply to the use of bismuth subsalicylate. [ 10 ] [ 11 ] [ 12 ]


Children should not take medication with bismuth subsalicylate while recovering from  influenza  or  chicken pox , as epidemiologic evidence points to an association between the use of  salicylate -containing medications during certain viral infections and the onset of  Reye syndrome . [ 13 ]  For the same reason, it is typically recommended that nursing mothers not use medication containing bismuth subsalicylate because small amounts of the medication are excreted in human breast milk, and these pose a theoretical risk of Reye syndrome to nursing children. [ 14 ]


Salicylates are very toxic to cats, and thus bismuth subsalicylate should not be administered to cats. [ 15 ]


The  British National Formulary  does not recommend bismuth-containing antacids (unless  chelated ), cautioning that absorbed bismuth can be neurotoxic, causing encephalopathy, and that such antacids tend to be constipating. [ 16 ]


There is an increased risk of  bleeding  when using bismuth subsalicylate and anticoagulation therapy, like  Coumadin (Warfarin) . [ 17 ] [ 18 ] [ 19 ]


Bismuth salts were in use in Europe by the late 1700s. The combination of bismuth subsalicylate and zinc salts for astringency with  salol  (phenyl salicylate) appears to have begun in the US in the early 20th century as a remedy for life-threatening diarrhea in infants with  cholera . At first sold directly to physicians, it was first marketed as  Bismosal  in 1918. [ 20 ]


Pepto-Bismol was first sold in 1900 [ 20 ]  by a doctor in New York. It was originally sold as a remedy for infant diarrhea by  Norwich Pharmacal Company  under the name "Bismosal: Mixture Cholera Infantum". [ 20 ]  It was renamed Pepto-Bismol in 1919. Norwich Eaton Pharmaceuticals was acquired by Procter and Gamble in 1982. [ 21 ]


As of 1946 and 1959, Canadian advertisements placed by Norwich show the product as Pepto-Besmal both in graphic and text. [ 22 ] [ 23 ]


Pepto-Bismol is an  over-the-counter drug  currently produced by the  Procter & Gamble  company in the United States, Canada and the United Kingdom. Pepto-Bismol is made in chewable tablets [ 24 ]  and swallowable caplets, [ 25 ]  but it is best known for its original formula, which is a thick liquid. This original formula is a medium pink in color, with a  teaberry  ( methyl salicylate ) flavor. [ 26 ]


Generic bismuth subsalicylate and other branded versions of the drug are widely available in pill and liquid form.


Despite its common usage and commercial significance, the exact structure of the pharmaceutical long remained undetermined, but was revealed, through the use of advanced  electron crystallography  techniques, to be a layered coordination polymer with the formula BiO(C 7 H 5 O 3 ). [ 27 ]  In the structure, both the carboxylate and phenol groups of the salicylate coordinate towards the bismuth cations. The determination of bismuth subsalicylate had long been hindered due to the small particle size as well as defects within the structure, arising from variations in the stacking arrangement of the bismuth subsalicylate layers, which could be observed as part of the structural investigation. [ 28 ]


Bromo-Seltzer  is a brand of  antacid  formulated to  relieve pain  occurring together with  heartburn ,  upset stomach , or  acid indigestion . It originally contained  sodium bromide  and  acetanilide , both toxic substances which were eventually removed. Its current formulation contains the pain reliever  aspirin  and two reactive chemicals –  sodium bicarbonate  and  citric acid  – which creates effervescence when mixed with water. Sodium bicarbonate is an antacid.