Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

Interventions to Increase Multivitamin Use Among Women in the Interconception Period: An IMPLICIT Network Study

Maternal and Child Health Journal - Each year, 3% of infants in the Unites States (US) are born with congenital anomalies, including 3000 with neural tube defects. Multivitamins (MVIs) including...     

Intrathecal IgM response in disseminated cerebrospinal metastasis from malignant melanoma

Summary Neurological complications are a major cause of morbidity and mortality in patients with disseminated malignant melanoma. We have studied and correlated clinical and cerebrospinal fluid (CSF) findings in 20 patients with central nervous system metastases from malignant melanoma including 8 patients with metastatic meningeal melanomatosis (MMM) and 12 patients with solid cerebral metastases (SCM). The putative CSF tumor markers, fibronectin and ₂-microglobulin, were elevated significantly in MMM but not in SCM patients. A prominent increase in the IgM index, which reflects intrathecal B-cell stimulation, and a rise of IgG index, interleukin-6, and tumor necrosis factor- in MMM patients provide preliminary evidence for a local intrathecal immune response triggered by melanoma cell invasion of the subarachnoid space.     

Reported disease and psychological well-being in Swiss adults

Summary In Switzerland, and in many other countries as well, the distribution of morbidity and perceived health in the general population and their determining factors have not been systematically studied so far. This article reports an exploratory study of prevalence of two complex health indicators, longstanding disease (Disease) and psychological well-being (Well-being) and of their environmental, person-specific and behavioural determinants. Data from a health survey conducted in five cantons and three language regions as part of the Swiss Intercantonal Health Indicators Project were used. Whereas distributions of prevalence of Disease according to gender, age, level of education and place of living confirm results of other studies, unexpected prevalence patterns were found for Well-being, especially with regard to gender differences. Multivariate analyses by general linear models (independent sub-samples of the study population were used to develop and validate models) showed different sets of environmental, person-specific and behavioural factors to explain inter-individual differences of Disease and Well-being, both in the total validation sample and in sub-samples of women and men. The results are discussed with regard to implications for socioepidemiological health research.

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Zusammenfassung Wie in zahlreichen anderen Ländern so sind bisher in der Schweiz die Verteilung und die Determinanten von Morbidität und wahrgenommener Gesundheit in der Gesamtbevölkerung nicht systematisch untersucht worden. Die vorliegende Arbeit berichtet über eine explorative Studie über die Prävalenz zweier komplexer Gesundheitsindikatoren, länger andauernde Krankheit (Disease) und psychisches Wohlbefinden (Well-being), und über deren jeweilige umweltbedingte, personale und verhaltensbezogene Einflußfaktoren. Grundlage dafür waren Daten, die in einer Bevölkerungsbefragung in 5 Kantonen und 3 Sprachregionen im Rahmen des Interkantonalen Gesundheitsindikatorenprojekts (IGIPPROMES) erhoben wurden. Während die Verteilung der Prävalenz von Krankheit nach Geschlecht, Alter, Bildungsstatus und Wohnortgrösse den Ergebnissen anderer Studien entspricht, ergaben sich bei der Prävalenz von Wohlbefinden unerwartete Verteilungsmuster, insbesondere Unterschiede zwischen Frauen und Männern. Eine Analyse interindividueller Unterschiede von Krankheit und Wohlbefinden mit Hilfe eines allgemeinen linearen Modells (Modellentwicklung und Validierung an unabhängigen Teilstichproben) zeigte, dass diese durch jeweils spezifische Konstellationen von Umwelt-, Personen- und Verhaltensfaktoren erklärt werden können, sowohl in der gesamten Validierungsstichprobe als auch in den Teilstichproben für Frauen und Männer. Die Ergebnisse der Studie werden in Hinblick auf die Weiterentwicklung der sozialepidemiologischen Gesundheitsforschung diskutiert.

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Résumé En Suisse, comme dans beaucoup d'autres pays, la morbidité et le bien-être psychologique de la population générale n'ont presque pas été étudiés jusqu'à présent. Dans ce rapport, les résultats d'une étude exploratoire sur deux indicateurs complexes de santé, maladie chronique (Disease) et bien-être psychologique (Well-being) et sur les facteurs de l'environnement, de la personnalité et du comportement qui influencent ces deux indicateurs sont présentés. Cette étude faisait part du projet intercantonal sur les indicateurs de santé (IGIP-PROMES) et se base sur les données tirées d'une enquête auprès des populations de cinq cantons et trois régions linguistique de la Suisse. Tandis que la prévalence de l'indicateur «maladie» par sexe, age, degré de formation et dimension du lieu de résidence était conforme aux résultats d'autres études, des distributions inattendues de la prévalence de «bien-être psychologique», notamment des différences entre hommes et femmes ont été trouvées. Une analyse des différences entre individue de «maladie» et «bien-être» au moyen d'un modèle linéaire généralisi — le développement et l'évaluation duquel ont été faits à l'aide de deux échantillons d'occasion indépendents — a montré que des constellations spécifiques constituées de facteurs de l'environnement, de la personnalité et du comportement, peuvent expliquer ces différences, soit dans l'échantillon d'évaluation totale, soit dans les échantillons partiels de femmes et d'hommes. Ces résultats sont discutés par rapport à l'évolution de la recherche socio-épidémiologique.

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Paper presented at a symposium on The Public Health Perspective of Social and Preventive Medicine, in celebration of the 20th anniversary of the Department of Social and Preventive Medicine, University of Berne, 25 June 1992 in Berne.     

Dental referral of drug addicts

Reasons for drug addicts' non-compliance to dental referral were investigated. Sixty-eight out of 83 addicts referred to the dentist were interviewed. Eighty-one percent intended to go, but only 42% did show up for their first appointment. Mean dental anxiety score (SDAI) was 23.6. An active referral of a non-anxious patient who visited the dentist in the past if in pain appeared least likely to fail. Dental care as an integral part of care for drug addicts is advocated.     

Dynamic interaction between Isp45 and mitochondrial hsp70 in the protein import system of the yeast mitochondrial inner membrane.

The protein import system of the yeast mitochondrial inner membrane includes at least three membrane proteins that presumably form a transmembrane channel as well as several chaperone proteins that mediate the import and refolding of precursor proteins. We show that one of the membrane proteins, Isp45, spans the mitochondrial inner membrane yet is extracted from this membrane at high pH. Solubilization of mitochondria with a nonionic detergent releases Isp45 as a complex with the chaperones mitochondrial hsp70 (mhsp70) and GrpEp. Both chaperones reversibly dissociate from Isp45 upon addition of ATP or adenosine 5'-[gamma-thio]triphosphate, suggesting that dissociation requires the binding of ATP. Control experiments indicate that the interaction between mhsp70 and Isp45 occurs in the intact mitochondria. We propose that Isp45 lines the inside of a proteinaceous channel across the inner membrane and that it is the membrane anchor for an ATP-driven "import motor" composed of mhsp70 and GrpEp. This arrangement is reminiscent of the protein transport systems of the yeast endoplasmic reticulum and the bacterial plasma membrane.