Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro

OBJECTIVE: The potent CYP1A2 inhibitor fluvoxamine has recently been shown also to be an effective inhibitor of the CYP2C19-mediated metabolism of the antimalarial drug proguanil in vivo. The purpose of the present study was to confirm this interaction in vitro. METHODS: A high-performance liquid chromatography (HPLC) method was developed to assay 4-chlorophenylbiguanide (4-CPBG) and cycloguanil formed from proguanil by microsomes prepared from human liver. The limit of detection was 0.08 nmol mg-'. h-I. RESULTS: The formation of 4-CPBG and cycloguanil could be described by one-enzyme kinetics, indicating that the formation of the two metabolites is almost exclusively catalysed by a single enzyme, i.e. CYP2C19 within the concentration range used, or that the contribution of an alternative low-affinity enzyme, probably CYP3A4, is very low. This notion was confirmed by the lack of potent inhibition by four CYP3A4 inhibitors: ketoconazole, bromocriptine, midazolam and dihydroergotamine. Fluvoxamine was a very effective inhibitor of the oxidation of proguanil, displaying Ki values of 0.69 micromol x l(-1) for the inhibition of cycloguanil formation and 4.7 micromol x l(-1) for the inhibition of 4-CPBG formation. As expected, the CYP2C19 substrate omeprazole inhibited the formation of both metabolites with an IC50 of 10 micromol x l(-1). Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with Ki values of 7.3-16 micromol x l(-1), suggesting that the two compounds are moderate inhibitors of CYP2C19. CONCLUSIONS: Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine, clomipramine, amitriptyline and diazepam. The combination of fluvoxamine and proguanil can not be recommended.     

Occupational medicine in general practice. A study of the extent and nature of occupational injuries in the county of Ringkj?bing

The purpose of this investigation was to estimate the occurrence and type of work-related incidents in primary health care in the county of Ringkoebing, Denmark, with 270,000 inhabitants. Symptom-related general practitioner (GP)-consultations among 17-66 year-old residents were registered among 114 GP's during four days over one year. In each occasion the GP evaluated the question of work-relatedness versus none-work-relatedness. Of 3017 registered consultations, 479 were work-related (15.9%). There were 376 disease cases and 103 injury cases. Musculoskeletal diseases constituted the dominating diagnostic category, as well as being the category with the highest proportion of work-relatedness, corresponding to 35% of all musculoskeletal consultations. Notification as a work injury case was performed for 19% of all work-related cases. This investigation represents the hitherto most extensive Danish material of the distribution of work-related incidents within the broad spectrum of the GP's practice.     

Favourable effect of olive oil in patients with non-insulin-dependent diabetes. The effect on blood pressure, blood glucose and lipid levels of a high-fat diet rich in monounsaturated fat compared with a carbohydrate-rich diet

The aim of the study was to elucidate the role of the neuropeptide galanin in the regulation of somatotropic and gonadotropic function in normal women. Thirteen normally ovulating (aged 28 to 40 years), non-obese (body mass index, 18.4 to 27.1 kg/m2) women with infertility due to a tubal or male factor were studied. Each woman underwent three tests: (1) bolus intravenous (IV) injection of growth hormone (GH)-releasing hormone (GHRH) (1-29)NH2 1 microgram/kg plus gonadotropin-releasing hormone (GnRH) 100 micrograms at time 0; (2) IV infusion of porcine galanin 500 micrograms in 100 mL saline from -10 minutes; and (3) bolus IV injection of GHRH(1-29)NH2 1 microgram/kg plus GnRH 100 micrograms at time 0 plus IV infusion of porcine galanin 500 micrograms in 100 mL saline from -10 to +30 minutes. All results are expressed as the mean +/- SEM. GH peak after GHRH was 14 +/- 5 micrograms/L; porcine galanin significantly increased serum GH (GH peak, 7.3 +/- 1.2) with respect to baseline levels. No significant differences were observed between either GH peak or GH absolute values after galanin as compared with GHRH alone. Porcine galanin significantly enhanced GH response to GHRH (peak, 31.4 +/- 4.4 micrograms/L) with respect to either GHRH or galanin alone. Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) peaks after GnRH were 16.5 +/- 5.3 and 17.4 +/- 4 IU/L, respectively. Porcine galanin did not cause significant increases in serum LH and FSH levels with respect to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Outcome of lithium prophylaxis: a prospective follow-up of affective disorder patients assigned to high and low serum lithium levels

Recently, the availability of 5-hydroxytryptamine-3 antagonists has provided better protection from chemotherapy-induced emesis. These drugs, in combination with dexamethasone, are more expensive but more cost-effective than the alternative antiemetic regimens in the prevention of acute emesis induced by high single dose and low and repeated doses of cisplatin and, probably, of acute emesis induced by moderately emetogenic chemotherapy. In the prevention of emesis induced by oral cyclophosphamide-methotrexate-fluorouracil and in the prevention of delayed emesis induced by cisplatin and moderately emetogenic chemotherapy, the most cost-effective choices are represented, respectively, by a combination of intravenous dexamethasone on day 1 and 8 plus 14-day oral metoclopramide (a combination of oral dexamethasone plus metoclopramide and oral dexamethasone alone). In all cases, the 5-hydroxytryptamine-3 antagonists should be used only in patients in whom the most cost-effective antiemetic regimens either fail or are not tolerated.     

Is the Chinese number-naming system transparent? Evidence from Chinese-English bilingual children.

Chinese-speaking children have been shown to have an advantage over English-speaking children in a variety of mathematical areas, including counting. One possible explanation for the advantage in counting is that the Chinese number-naming system is relatively transparent, compared to English, in that number names typically are directly indicative of base-10 structure (e.g., 12 is named "ten-two" rather than "twelve"). To determine whether the transparency of the Chinese number-naming system influences counting in bilingual children, we tested 25 Chinese-English bilingual children between the ages of 3 and 5 years, both in English and in Chinese. Children were asked to count as high as they could (abstract counting) and also to count objects in small, medium, and large arrays (object counting). No evidence was found for transparency or for transfer from one language to the other. Instead, relative proficiency in the two languages influenced counting skill. These results are discussed in terms of linguistic and cultural variables that might account for cross-linguistic differences in counting. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An ester bond linking a fragment of a serine proteinase to its serpin inhibitor

Most known members of the serpin superfamily are serine proteinase inhibitors. Serpins are therefore important regulators of blood coagulation, complement activation, fibrinolysis, and turnover of extracellular matrix. Serpins form SDS-resistant complexes of 1:1 stoichiometry with their target proteinases by reaction of their P1-P1' peptide bond with the active site of the proteinases. The nature of the interactions responsible for the high stability of the complexes is a controversial issue. We subjected the complex between the serine proteinase urokinase-type plasminogen activator (uPA) and the serpin plasminogen activator inhibitor-1 (PAI-1) to proteolytic digestion under nondenaturing conditions. The complex could be degraded to a fragment containing two disulfide-linked peptides from uPA, one of which included the active site Ser, while PAI-1 was left undegraded. By further proteolytic digestion after denaturation and reduction, it was also possible to degrade the PAI-1 moiety, and we isolated a fragment containing 10 amino acids from uPA, encompassing the active site Ser, and 6 amino acids from PAI-1, including the P1 Arg. Characterization of the fragment gave results fully in agreement with the hypothesis that it contained an ester bond between the hydroxyl group of the active site Ser and the carboxyl group of the P1 Arg. These data for the first time provide direct evidence that serine proteinases are entrapped at an acyl intermediate stage in serine proteinase-serpin complexes.     

Fathers of persons with mental illness: a preliminary study of coping capacity and service needs

The effects of a single dose of caffeine on specific information processing operations were examined by using a visual selective attention task in which subjects were asked to select between a left and right hand response on the basis of two different target letters. The target was presented on a predefined position in the visual field and was either presented alone or with flanker letters, calling for the correct, the incorrect or no specific response. A dose of 3 mg/kg body weight caffeine or lactose, dissolved in a cup of decaffeinated coffee, was administered double blind and deceptively to overnight abstinence coffee drinkers. Behavioural measures were supplemented by psychophysiological measures. The present results replicated the basic findings obtained in this paradigm. The results indicated that the time to localise the target decreased and response preparation started earlier after caffeine than after placebo. These caffeine effects did not interact with the time subjects spent on the task or with the reaction time distribution, which might be due to a high level of practice.