Loperamide (ADL 2-1294), an opioid antihyperalgesic agent with peripheral selectivity.
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The antihyperalgesic properties of the opiate antidiarrheal agent loperamide (ADL 2-1294) were investigated in a variety of inflammatory pain models in rodents. Loperamide exhibited potent affinity and selectivity for the cloned micro (Ki = 3 nM) compared with the delta (Ki = 48 nM) and kappa (Ki = 1156 nM) human opioid receptors. Loperamide potently stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding (EC50 = 56 nM), and inhibited forskolin-stimulated cAMP accumulation (IC50 = 25 nM) in Chinese hamster ovary cells transfected with the human mu opioid receptor. The injection of 0.3 mg of loperamide into the intra-articular space of the inflamed rat knee joint resulted in potent antinociception to knee compression that was antagonized by naloxone, whereas injection into the contralateral knee joint or via the i.m. route failed to inhibit compression-induced changes in blood pressure. Loperamide potently inhibited late-phase formalin-induced flinching after intrapaw injection (A50 = 6 microgram) but was ineffective against early-phase flinching or after injection into the paw contralateral to the formalin-treated paw. Local injection of loperamide also produced antinociception against Freund's adjuvant- (ED50 = 21 microgram) or tape stripping- (ED50 = 71 microgram) induced hyperalgesia as demonstrated by increased paw pressure thresholds in the inflamed paw. In all animal models examined, the potency of loperamide after local administration was comparable to or better than that of morphine. Loperamide has potential therapeutic use as a peripherally selective opiate antihyperalgesic agent that lacks many of the side effects generally associated with administration of centrally acting opiates. (+info)
The impact of face-to-face educational outreach on diarrhoea treatment in pharmacies.
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Private pharmacies are an important source of health care in developing countries. A number of studies have documented deficiencies in treatment, but little has been done to improve practices. We conducted two controlled trials to determine the efficacy of face-to-face educational outreach in improving communication and product sales for cases of diarrhoea in children in 194 private pharmacies in two developing countries. A training guide was developed to enable a national diarrhoea control programme to identify problems and their causes in pharmacies, using quantitative and qualitative research methods. The guide also facilitates the design, implementation, and evaluation of an educational intervention, which includes brief one-on-one meetings between diarrhoea programme educators and pharmacists/owners, followed by one small group training session with all counter attendants working in the pharmacies. We evaluated the short-term impact of this intervention using a before-and-after comparison group design in Kenya, and a randomized controlled design in Indonesia, with the pharmacy as unit of analysis in both countries (n = 107 pharmacies in Kenya; n = 87 in Indonesia). Using trained surrogate patients posing as mothers of a child under five with diarrhoea, we measured sales of oral rehydration salts (ORS); sales of antidiarrhoeal agents; and history-taking and advice to continue fluids and food. We also measured knowledge about dehydration and drugs to treat diarrhoea among Kenyan pharmacy employees after training. Major discrepancies were found at baseline between reported and observed behaviour. For example, 66% of pharmacy attendants in Kenya, and 53% in Indonesia, reported selling ORS for the previous case of child diarrhoea, but in only 33% and 5% of surrogate patient visits was ORS actually sold for such cases. After training, there was a significant increase in knowledge about diarrhoea and its treatment among counter attendants in Kenya, where these changes were measured. Sales of ORS in intervention pharmacies increased by an average of 30% in Kenya (almost a two-fold increase) and 21% in Indonesia compared to controls (p < 0.05); antidiarrhoeal sales declined by an average of 15% in Kenya and 20% in Indonesia compared to controls (p < 0.05). There was a trend toward increased communication in both countries, and in Kenya we observed significant increases in discussion of dehydration during pharmacy visits (p < 0.05). We conclude that face-to-face training of pharmacy attendants which targets deficits in knowledge and specific problem behaviours can result in significant short-term improvements in product sales and communication with customers. The positive effects and cost-effectiveness of such programmes need to be tested over a longer period for other health problems and in other countries. (+info)
Prevention and treatment of traveler's diarrhea.
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Common pathogens in traveler's diarrhea include enterotoxigenic Escherichia coli, Campylobacter, Shigella, Salmonella, Yersinia and many other species. Viruses and protozoa are the cause in many cases. Fortunately, traveler's diarrhea can usually be avoided by carefully selecting foods and beverages. Although drug prophylaxis is now discouraged, treatment with loperamide (in the absence of dysentery) and a fluoroquinolone, such as ciprofloxacin (500 mg twice daily for one to three days), is usually safe and effective in adults with traveler's diarrhea. Trimethoprim-sulfamethoxazole and doxycycline are alternatives, but resistance increasingly limits their usefulness. Antibiotic treatment is best reserved for cases that fail to quickly respond to loperamide. Antibiotic resistance is now widespread. Nonabsorbable antibiotics, immunoprophylaxis with vaccines and biotherapeutic microbes that inhibit pathogen infection may eventually supplant antibiotic treatment. In the meantime, azithromycin and new fluoroquinolones show promise as possible replacements for the older agents. Ultimately, the best solution is improvements in sanitary engineering and the development of safe water supplies. (+info)
Effect of the 5-hydroxytryptamine3 (5-HT3)-receptor antagonist KB-R6933 on experimental diarrhea models.
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The effects of a 5-hydroxytryptamine3 (5-HT3)-receptor antagonist KB-R6933 (6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-benzimidazole dimaleate) on experimental diarrhea and on intestinal fluid secretion stimulated by cholera toxin were examined and compared with those of ramosetron and loperamide. KB-R6933 and ramosetron (0.03-1 mg/kg, p.o.) inhibited the diarrhea induced by 5-HT, but not that by castor oil or prostaglandin E2 (PGE2), in mice. Loperamide significantly inhibited the diarrhea induced by 5-HT, castor oil and PGE2. All drugs tested inhibited the diarrhea induced by restraint stress and the intestinal fluid secretion stimulated by cholera toxin in rats. The results suggest the possibility that KB-R6933 may have clinical efficacy in the treatment of diarrhea. (+info)
Oral rehydration therapy plus loperamide versus loperamide alone in the treatment of traveler's diarrhea.
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Eighty United States students in Mexico received either loperamide (an initial dose of 4 mg, followed by 2 mg after passage of each unformed stool, up to 8 mg/d; 40 patients) or loperamide (at the same dosage schedule) plus an oral rehydration therapy (ORT) preparation (500 mL initially, followed by 250 mL after each subsequently passed unformed stool, up to 1,000 mL per 24 hours; 40 patients). The ORT preparation was a modification of the World Health Organization-recommended solution, adjusted to a sodium concentration of 60 mEq/L. All treatments were given for 48 hours. The study demonstrated equivalent clinical responses with regard to diminishment of diarrhea or subjective findings such as abdominal pain/cramps, headache, dry mouth, dizziness, or thirst. Stool number (by form) and specific gravity of urine postenrollment were similar in the groups. Administration of loperamide plus ORT for the management of traveler's diarrhea, in cases in which subjects were encouraged to drink ad libitum, offered no benefit over administration of loperamide alone. (+info)
Enteroaggregative Escherichia coli as a cause of traveler's diarrhea: clinical response to ciprofloxacin.
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The purpose of this study was to determine the role of enteroaggregative Escherichia coli (EAEC) in the development of traveler's diarrhea and the clinical response of patients with EAEC diarrhea following treatment with ciprofloxacin. Sixty-four travelers with diarrhea and no other recognized enteropathogen were enrolled in treatment studies in Jamaica and Mexico from July 1997 to July 1998. EAEC was isolated from 29 travelers (45.3%). There was a significant reduction in the duration of posttreatment diarrhea in the 16 patients treated with ciprofloxacin, as compared with that in the 13 patients who received placebo (mean of 35.3 versus 55.5 hours; P = .049). There was a nonsignificant reduction in the mean number of unformed stools passed during the 72 hours after enrollment in the ciprofloxacin-treated group (5.6), as compared with that in the placebo group (7.5) (P = .128). This study provides additional evidence that EAEC should be considered as a cause of antibiotic-responsive traveler's diarrhea. (+info)
Racecadotril demonstrates intestinal antisecretory activity in vivo.
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BACKGROUND: Racecadotril (acetorphan), a potent enkephalinase inhibitor, protects endogenous enkephalins from degradation. Racecadotril exhibits experimental and clinical antidiarrhoeal activity without any effect on intestinal motility, suggesting selective antisecretory activity. The antisecretory effect of racecadotril was directly assessed in the present study. METHODS: A 1 m, jejunal, Thiry-Vella loop was created in six mongrel dogs, and water and ionic fluxes were evaluated during infusion (2 mL/min) of Tyrode solution labelled with 14C-polyethylene glycol. Fluxes were determined both in the basal state and 5-6 h after commencement of a 2-h infusion of cholera toxin (0.4 microgram/mL). Racecadotril (10 mg/kg) or vehicle was given orally with and without prior intravenous administration of naloxone (0.1 mg/kg) or phentolamine (0.2 mg/kg). RESULTS: Basal absorption remained unchanged following racecadotril administration; however, racecadotril significantly decreased (P = 0.01) cholera toxin-induced water, sodium, and potassium hypersecretion, from 0.73 +/- 0.15 to 0.37 +/- 0.13 mL/min; from 125.0 +/- 16.1 to 14.7 +/- 9.5 microMol/min; and from 3.41 +/- 0.66 to 1.66 +/- 0.61 microMol/min, respectively. This antisecretory activity of racecadotril was suppressed by naloxone but not by phentolamine. CONCLUSIONS: This study directly demonstrates the antisecretory activity of racecadotril in relation to the protection of endogenous enkephalins. (+info)
Effects of racecadotril and loperamide on bacterial proliferation and on the central nervous system of the newborn gnotobiotic piglet.
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METHODS: The effects of 4 days of oral administration of different doses of two drugs, an enkephalinase inhibitor (the antisecretory agent, racecadotril) and a mu-receptor agonist (loperamide), on intestinal growth of a bacterial nonpathogenic strain (Escherichia coli E 404) and on the central nervous system (CNS) were compared in newborn gnotobiotic piglets. RESULTS: The E. coli content of the proximal jejunum (segment S1) and the E. coli ratio of stomach:segment S1 were similar in the racecadotril (20 mg/kg b.d., n = 5) and control groups. In contrast, in the loperamide group (1 mg/kg b.d., n = 4), the E. coli content of segment S1 and the E. coli ratio stomach:S1 were both significantly higher than with racecadotril or control (P = 0.04 and 0.005, respectively, for E. coli content; P = 0.05 and 0.03, respectively, for stomach:S1). There were no clinical signs of neurotoxicity and no deaths with racecadotril given orally at a high dose of 130 mg/kg b.d. (n = 5)--nearly 60 times the paediatric dosage. In contrast, an equivalent high dose of loperamide (5 mg/kg b.d.) resulted in death in three out of four piglets. CONCLUSIONS: In contrast to loperamide, racecadotril did not induce bacterial overgrowth and did not produce central neurotoxicity. (+info)