chiniofon and Diarrhea

Topics: Antidiarrheals; Child, Preschool; Diarrhea; Drug Labeling; Humans; Hydroxyquinolines; Legislation, Drug; Risk Factors

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

Topics: Antidiarrheals; Chlorine; Clinical Trials as Topic; Diarrhea; Humans; Hydroxyquinolines; Placebos; Travel

Topics: Adult; Aged; Clinical Trials as Topic; Constipation; Diarrhea; Drug Combinations; Drug Evaluation; Dyspepsia; Fatigue; Feeding and Eating Disorders; Female; Flatulence; Heartburn; Humans; Hydroxyquinolines; Malabsorption Syndromes; Male; Middle Aged; Nausea; Pain; Pancreatin; Papaverine; Vomiting

Topics: Adult; Clioquinol; Diarrhea; Evoked Potentials, Visual; Female; Humans; Hydroxyquinolines; Male; Middle Aged; Myelitis; Optic Neuritis; Syndrome

Twenty coccidia-free Holstein bull calves were allotted to groups to study effects of treatment with lasalocid and decoquinate on subsequent resistance to coccidiosis (Eimeria spp infections). Calves fed medicated rations of either drug at dosages of 50 mg/kg of feed (approx 1.2 mg/kg of body weight) had significantly fewer oocysts (P less than 0.01) than did nontreated controls regardless of other procedures used. Treated calves premunized with 2,000 oocysts/day for 5 days and later challenge inoculated with 200,000 oocysts did not develop diarrhea, unless the drugs were withdrawn from feed. Animals premunized (2,000 oocysts/day for 5 days) in absence of drug were no more resistant to the challenge inoculation than nonpremunized animals. These results indicated that lasalocid and decoquinate were efficacious coccidiostats and protected calves as long as they were administered. Cessation of drug treatment usually resulted in appearance of oocysts in feces and diarrhea. Premunization alone cannot be expected to prevent coccidiosis when animals are exposed to large numbers of oocysts.

Topics: Animal Feed; Animals; Cattle; Cattle Diseases; Coccidiosis; Decoquinate; Diarrhea; Feces; Hydroxyquinolines; Immunization; Lasalocid; Male

Rotavirus particles are unique in their configuration. They have a double-shelled protein capsid, inside which are the viral RNA fragments and a viral polymerase. The outer shell is involved in the infectivity of the virus particle; without it the particle is not infective. At the cellular level during the infection process, this outer shell is made permeable by an unknown mechanism. This makes the RNA polymerase within the particle accessible to precursors of new RNA. Transcription begins, and progeny virus RNA and protein soon accumulate in the cell. In vitro studies show that chelators such as EDTA and EGTA may be used to make the virion permeable, allowing the measurement of viral RNA polymerase activity. These chelators remove divalent cations such as Ca++ from the virus particle, thereby altering the outer shell of the virus [2]. We were interested in measuring the effect on rotavirus of chelators that have been used to treat diarrheal disease, such as clioquinol, an 8-hydroxyquinoline derivative and the principal ingredient of Entero-Vioform (Ciba Pharmaceutical Co, Summit, NJ). Seven of 10 three-day-old Icr white mice simultaneously inoculated with EDIM and administered a single dose of clioquinol developed diarrhea 48 hr after inoculation, although none had displayed diarrhea at 24 hr. These mice, therefore, developed diarrhea 24 hr later than six of eight untreated animals (P = 0.004 at 24 hr by Fisher's exact test). Moreover, no animals receiving doses of clioquinol every 12 hr had developed diarrhea by 48 hr after inoculation (P = 0.006 at 24 hr and P = 0.0001 at 48 hr, compared to untreated mice).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Clioquinol; Diarrhea; Hydroxyquinolines; Mice; Mice, Inbred ICR; Rotavirus Infections

Topics: Aeromonas; Antimalarials; Diarrhea; Enterobacteriaceae; Escherichia coli; Humans; Hydroxyquinolines; Oxyquinoline; Sulfamethoxazole; Trimethoprim; Vibrio; Vibrio cholerae; Yersinia

Topics: Adult; Chloroquinolinols; Clioquinol; Diarrhea; Drug Labeling; Female; Humans; Hydroxyquinolines; Jurisprudence; Optic Atrophy; United States

Topics: Animals; Anti-Infective Agents; Chloroquinolinols; Diarrhea; Female; Horse Diseases; Horses; Hydroxyquinolines; Male