Lubiprostone

Lubiprostone, a drug used for treating obstipation, has been claimed to be an activator of C1C-2. This is based on a single paper showing activation by lubiprostone of currents thought to represent C1C-2. These currents, however, differ starkly from typical C1C-2 currents. Furthermore, C1C-2 is located in basolateral membranes of the intestine. This localization is incompatible with the hypothesis that its activation increases intestinal chloride and fluid secretion. Thus, the claim that lubiprostone is a Cl- channel activator must be subject to considerable doubt. 

Lubiprostone (Amitiza), a bicyclic acid oral agent, is approved for treatment of chronic idiopathic constipation in adults. It has not been studied in children. Lubiprostone acts locally on intestinal chloride channels and increases intestinal fluid secretion, resulting in increased intestinal motility and thereby increasing the passage of stool.6... 

Lubiprostone is contraindicated in patients with a history of mechanical gastrointestinal obstruction. Safety has not been established in pregnant women animal studies indicated the potential to cause fetal loss. Women who could become pregnant should have a negative pregnancy test result prior to beginning therapy with lubiprostone. 

Gastrointestinal adverse events reported with lubiprostone include nausea, diarrhea, abdominal distention, abdominal pain, flatulence, vomiting, loose stools, and dyspepsia. Nausea is a prominent adverse effect and may be minimized when lubiprostone is taken with food. 

The recommended dose of lubiprostone is 24 meg orally twice daily with food. Early studies evaluated lubiprostone use for no longer than 4 weeks. Patients should be assessed periodically for the need to continue therapy. 

Lubiprostone is a chloride channel activator that acts locally on the gut to accelerate genitourinary transit time and delay gastric emptying. It is approved for chronic idiopathic constipation in adults. The dose is 24 mg capsule twice daily with food. Lubiprostone may cause headache, diarrhea, and nausea. 

The field of gastrointestinal drugs saw the entry of Amitiza (lubiprostone), the first selective and locally acting CIC-2 chloride channel activator, for the... 

Hyoscyamine, Atropine, Scopolamine, Phenobarbital (Donnatal, oth s) Infliximab (Remicade) Lubiprostone (Amitiza) Mesalamine (Asacol, Lialda, Pentasa, Rowasa) Metoclopramide (Reglan, Clopra, Octamide)... 

Lubiprostone (Amitiza) [Laxative] Uses Chronic idiopathic constipation in adults Action Selective Cl channel activator Dose Adults. 24 meg PO bid w/ food Contra Mechanical GI obst Caution [C, /-] Severe D, severe renal or mod-severe hepatic impair Disp Gel, caps meg SE N, HA, D, GI distention, abd pain EMS Monitor for signs of electrolyte disturbances and h5rpovolemia d/t D OD May cause severe D, hypovolemia, and abd pain/cramps give IV fluids Lutropin Alfa (Luveris) [Hormone] Uses Inf ility Action Recombinant LH Dose 75 Units SQ w/ 75—150 Units FSH, 2 s arate inj max 14 d Caution [X, /M] Contra Primary ovarian failure, uncontrolled thyroid/adrenal dysfxn, intracranial lesion, AUB, hormone-dqjendent GU tumor, ovarian cyst, PRG Disp Inj SE HA, N, ovarian h5rpCTstimulation synd, breast pain, ovarian cysts T risk of multiple births EMS None OD Unlikely to cause life-threatening Sxs... 

Lubiprostone is a novel agent, currently in clinical phase III for the treatment of constipation. This 16,16-difluoro-15-ketoprostaglandine potently activates intestinal Ch channels without altering Na+ and K+ ones. The difluoromethylk-etone is in equilibrium with the bicyclic hemiketal form, and the latter is predominant in the absence of water (Fig. 71) [166],... 

L.A. Sorbera, J. Castaner, N.E. Mealy, Lubiprostone. Treatment of constipation, treatment of irritable bowel syndrome, treatment of postoperative ileus, CIC-2 channel activator, Drugs Fut. 29 (2004) 336-342. 

C-11 and carbonyl group at C-15 to give lubiprostone 8 because of the electron-withdrawing effect of the fluorine atoms. The compound is mainly formed as bicyclic hemiacetal 8 as stable crystals or crystalline powder. 

Lubiprostone has used as a novel PG compound for an oral treatment of constipation with a unique action directed to the target tissue, although it has low systemic availability following oral administration. It activates a locally acting chloride channel, which is a normal constituent of the apical membrane of the human intestine, and enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentration in the serum. In fasted rats administered doses of 1, 10, or lOOpg/kg of the compound, dose-dependent increases in the concentration of chloride ions in the bowel were detected, indicating that the compound opens chloride channels and promotes chloride ion transport in vivo [45]. 

The standard pharmacokinetic parameters of the compound such as a half-life or bioavailability cannot be reliably calculated, because the concentrations in plasma are below lOpg/mL. As analogously expected from the results on the shift in keto-alcohol equilibrium of 16,16-difluoro-PGE2, it is rapidly metabolized by C-15 reduction mediated by the ubiquitously expressed carbonyl reductase. The metabolism followed by jS-oxidation and co-oxidation forms a mixture of a and fi epimers at the 15-hydroxy moiety as a sole measurable metabolite [46], In 2006, the US Food and Drug Administration approved the drug application for an oral treatment of chronic idiopathic constipation in adults, estimating that 4-5 million Americans are affected. Lubiprostone has also completed a phase II trial in constipation-predominant irritable bowel syndrome, and has been further evaluated for other bowel dysfunctions. 

Lubiprostone, a 16,16-difluoro-15-ketoprostaglandin, an agonist of chloride channels, and AFP-168, a deoxy-15,15-difluoro Pp2a, are currently under clinical development (Figure 4.37) (cf. Chapter 8). ... 

Lubiprostone is a prostanoic acid derivative labeled for use in chronic constipation and irritable bowel syndrome (IBS) with predominant constipation. It acts by stimulating... 

As discussed previously, lubiprostone is a prostanoic acid derivative that stimulates the type 2 chloride channel (CIC-2) in the small intestine and is used in the treatment of chronic constipation. Lubiprostone recently was approved for the treatment of women with IBS with predominant constipation. Its efficacy for men with IBS is unproven. 

The approved dose for IBS is 8 meg twice daily (compared with 24 meg twice daily for chronic constipation). Lubiprostone has not been compared with other less expensive laxatives (eg, milk of magnesia). Lubiprostone is listed as category C for pregnancy and should be avoided in women of childbearing age. 

Chloride channel activator Lubiprostone, prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content... 

Chloride channel activator Lubiprostone (see above) useful in constipation-predominant IBS in women ... 

Johanson JF et al Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-active type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008 103 170. [PMID 17916109]... 

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