oxadiazoles and Diarrhea

To assess the efficacy and safety of Aβ-targeting agents for mild to moderate Alzheimer's disease.. The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses.. Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-Aβ drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81;. From current evidence, anti-Aβ interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from Aβ clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small.. PROSPERO registration number CRD42019126272.

Topics: Acitretin; Alanine; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal, Humanized; Anxiety; Azepines; Clioquinol; Copper; Cyclic S-Oxides; Depression; Diarrhea; Exanthema; Fatigue; Flurbiprofen; Humans; Immunoglobulins, Intravenous; Inositol; Mental Status and Dementia Tests; Minimal Clinically Important Difference; Orotic Acid; Oxadiazoles; Severity of Illness Index; Sulfonamides; Syncope; Thiadiazines; Treatment Outcome; Vomiting

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.

Topics: Administration, Oral; Adolescent; Adult; Cholera; Cystic Fibrosis Transmembrane Conductance Regulator; Diarrhea; Double-Blind Method; Female; Humans; Hydroxyquinolines; Male; Oxadiazoles; Vibrio cholerae; Young Adult

The novel capsid-binding antiviral pleconaril inhibits in vitro replication of most rhinoviruses and enteroviruses. Oral pleconaril treatment was studied in 2 parallel randomized, double-blind, placebo-controlled trials. Among 1363 picornavirus-infected participants (65%) in the studies combined, the median time to alleviation of illness was 1 day shorter for pleconaril recipients than for placebo recipients (P<.001). Cold symptom scores and frequency of picornavirus cultured from nasal mucus specimens were lower among pleconaril recipients by day 2 of treatment. No treatment effects were seen in those without picornavirus infection. Pleconaril was associated with a higher incidence of nausea (6% vs. 4%) and diarrhea (9% vs. 7%) and with small increases in mean serum cholesterol levels and platelet counts, compared with baseline measurements. A subsequent 6-week prophylaxis study found that pleconaril induces cytochrome P-450 3A enzymes, which metabolize a variety of drugs, including ethinyl estradiol. Early pleconaril treatment was well tolerated and significantly reduced the duration and severity of colds due to picornaviruses in adults.

Topics: Administration, Oral; Adult; Antiviral Agents; Common Cold; Diarrhea; Double-Blind Method; Female; Humans; Male; Nausea; Oxadiazoles; Oxazoles; Picornaviridae; Picornaviridae Infections; Prospective Studies; Treatment Outcome

SC-27166 is the result of continuing efforts to discover selective and orally active antidiarrheal agents. SC-27166, which is chemically unrelated to opiates or neuroleptics, possesses potent constipating and antidiarrheal activity in several animal models. Tolerance to the constipating actions of SC-27166 did not develop in mice. On the other hand, gut tolerance rapidly developed to morphine sulfate and loperamide. The basic mechanism of the antidiarrheal action of SC-27166 is a consequence of increased intestinal circular muscle contractile activity. Supportive pharmacological studies indicated that SC-27166 has equivocal analgesia in mice which is manifested at near toxic dose levels. SC-27166 was also evaluated for potential dependence liability in morphine abstinence-induced jumping in mice. The abstinence-induced jumping was suppressed to a far lesser extent by SC-27166 than by either loperamide or diphenoxylate at equal doses. SC-27166 was also devoid of anticbholinergic activity. When compared with the reference standards morphine and diphenoxylate, these pharmacological studies indicated that SC-27166 has a high degree of separation of undesirable central nervous system actions from its antidiarrheal properties and may have important therapeutic potential.

Topics: Analgesics; Animals; Antidiarrheals; Behavior, Animal; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Constipation; Diarrhea; Diphenoxylate; Diuresis; Dogs; Female; Gastrointestinal Motility; Haplorhini; Humans; Macaca mulatta; Male; Mice; Morphine; Naloxone; Oxadiazoles; Parasympatholytics; Rats; Substance Withdrawal Syndrome

Topics: Child; Diarrhea; Diarrhea, Infantile; Furazolidone; Humans; Infant; Infant, Newborn; Intestines; Oxadiazoles; Pediatrics; Toxicology