Pharmacokinetics of Dexamethasone and Valspodar,a P-glycoprotein (mdr1) Modulator: Implications for Coadministration

Study Objective . To assess the potential for a drug-drug interaction between valspodar, a P-glycoprotein (mdr1) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens. Design . Randomized, open-label, three-period crossover study. Setting . Clinical pharmacology research center. Subjects . Eighteen healthy men volunteers (age 25.8 ± 3.5 yrs, weight 71.6 ± 10.3 kg). Interventions . Subjects received single fasting oral doses of valspodar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2- to 3-week washout phases between administrations. Measurements and Main Results . Lack of a pharmacokinetic drug-drug interaction with respect to valspodar was conclusively demonstrated for both C_max,b (2.3 ± 0.4 vs 2.4 ± 0.5 μg/ml) and AUC_b (19.8 ± 4.8 vs 19.6 ± 4.9 μg·hr/ml) inasmuch as bioequivalence criteria were satisfied when comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (C_max 88 ± 23 vs 91 ± 20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400 ± 87 vs 494 ± 90 ng·hr/ml). Regression analysis of valspodar C_max,b and AUC_b during coadministration versus the extent of the interaction (percentage increase in dexamethasone AUC) did not reveal a concentration-effect relationship (p=0.7299 and 0.9718, respectively). Conclusion . Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clinical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in dexamethasone's AUC is unlikely to be relevant. Thus no alterations in valspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple-dose experience in patients would be desirable to confirm these conclusions.     

Skin wrinkling: can food make a difference?

OBJECTIVES: This study addressed whether food and nutrient intakes were correlated with skin wrinkling in a sun-exposed site. METHODS: 177 Greek-born subjects living in Melbourne (GRM), 69 Greek subjects living in rural Greece (GRG), 48 Anglo-Celtic Australian (ACA) elderly living in Melbourne and 159 Swedish subjects living in Sweden (SWE) participating in the International Union of Nutritional Sciences IUNS "Food Habits in Later Life" study had their dietary intakes measured and their skin assessed. Food and nutrient intakes were assessed using a validated semi-quantitative food frequency questionnaire (FFQ). Skin wrinkling was measured using a cutaneous microtopographic method. RESULTS: SWE elderly had the least skin wrinkling in a sun-exposed site, followed by GRM, GRG and ACA. Correlation analyses on the pooled data and using the major food groups suggested that there may be less actinic skin damage with a higher intake of vegetables (r(s)=-0.31, p<0.0001), olive oil (r(s)=-0.29, p<0.0001), fish (r(s)=-0.24, p<0.0001) and legumes (r(s)=-0.16, p<0.0001), and lower intakes of butter (r(s)=0.46, p<0.0001) and margarine (r(s)=0.24, p<0.001), milk products (r(s)=0.16, p<0.01) and sugar products (r(s)=0.12, p<0.01). Similar findings were obtained using regression analyses, except fish was no longer significant; 32% of the variance for actinic skin damage was predicted by six out of the ten major food groups. In particular, a high intake of vegetables, legumes and olive oil appeared to be protective against cutaneous actinic damage (collectively explaining 20% of the variance); a high intake of meat, dairy and butter appeared to be adverse (explaining <5% of the variance). Prunes, apples and tea explained 34% of variance amongst ACA. CONCLUSION: This study illustrates that skin wrinkling in a sun-exposed site in older people of various ethnic backgrounds may be influenced by the types of foods consumed.     

Can skin wrinkling in a site that has received limited sun exposure be used as a marker of health status and biological age?

OBJECTIVES: to determine if skin wrinkling in a site that had received limited sun exposure may be a marker of health status and biological age. DESIGN: population-based, cross-sectional study. PARTICIPANTS: we evaluated the health status of representative samples of elderly Greek-born people living in Melbourne, Greeks living in rural Greece, Anglo-Celtic Australians living in Melbourne and Swedes living in Sweden. We carried out microtopographic assessment of their skin and measured plasma dehydroepiandrosterone concentrations. METHODS: we derived activities of daily living, well-being, memory and general health status scores from a cross-cultural questionnaire. We measured skin wrinkling using cutaneous microtopographic methods and plasma dehydroepiandrosterone by enzyme immuno-assay. RESULTS: skin wrinkling was positively correlated with age (r(s)=0.27, P<0.0001) and negatively with body mass index (r(s)=-0.19, P<0.0001). Therefore, all analyses were controlled for these variables. Plasma dehydroepiandrosterone was higher in smokers than non-smokers (2.86 vs 2.08; P<0.001) and men had significantly higher plasma dehydroepiandrosterone than women (2.74 vs 1.69; P<0.0001). In the pooled data, skin wrinkling was negatively associated with general health score (r(s)=-0.13, P<0.01) and activities of daily living score (r(s)=-0.14, P<0.05) after controlling for age, body mass index and smoking. These associations were more pronounced in women. Finally, those with the least skin wrinkling had the highest dehydroepiandrosterone level (r(s)=-0.12, P=0.06) after adjusting for age, smoking and sex. CONCLUSION: skin wrinkling in a site with limited sun exposure might be used as a marker of health status and, to some extent, biological age--particularly for women.     

Use of a control chart to monitor diarrhoea admissions: a quality improvement exercise in West Kalimantan Provincial Hospital, Pontianak, Indonesia.

Data on the number of admissions for diarrhoea each week to the West Kalimantan Provincial Hospital, Pontianak, Indonesia over a 5 year period, 1992-1996, were collected. After cleaning and exclusion of extreme values, transformation was then performed to ensure that the data were free of special cause variation and normally distributed. A control chart was then constructed to provide an 'early warning' system for hospital authorities in order to facilitate the management of the epidemic and to improve patient care.     

Inhibition of drug metabolism by the antimalarial drugs chloroquine and primaquine in the rat

The effect of the antimalarial drugs chloroquine (CQ) and primaquine (PQ) on rat liver microsomal drug metabolism has been studied in vitro and in vivo. After acute administration, PQ increased pentobarbitone sleeping time in a dose-related manner [control, 94.0 ± 9.4 min; 10mg/kg, 137.0 ± 2.4 min; 20mg/kg, 197.0 ± 7.5 min; 50 mg/kg, 269.0 ± 2.9 min (means ± S.E.M.)], prolonged zoxazolamine paralysis time (control, 140.0 ± 10.0 min; 50 mg/kg, 341.5 ± 25.6 min) and decreased antipyrine blood clearance from 2.17 ± 0.19 to 0.86 ± 0.12 ml/min. CQ showed no effect on pentobarbitone sleeping time or zoxazolamine paralysis time, but decreased antipyrine clearance from 2.17 ± 0.19 to 1.11 ± 0.18 ml/min. Both drugs inhibited aminopyrine N-demethylase activity, although the concentration required to produce 50% inhibition was much greater for CQ (10 mM) than for PQ (approximately 0.1 mM). Lineweaver-Burk plots showed that CQ inhibited competitively whereas PQ inhibition was apparently non-competitive. Ethoxyresorufin O-deethylase activity decreased by about 40 and 50% in the presence of CQ and PQ respectively (250 nM, equimolar with substrate). There was no evidence of induction following chronic administration of CQ and PQ (50 mg/kg/day for 4 days). There was an apparent decrease in cytochrome P-450 content and aminopyrine N-demethylase activity was decreased. These results demonstrate that PQ and CQ inhibit hepatic drug metabolism both in vitro and in vivo and that PQ appears to be the more potent inhibitor.     

Assessment of DNA damage by comet assay and fast halo assay in buccal epithelial cells of Indian women chronically exposed to biomass smoke

Genotoxicity of indoor air pollution from biomass burning was evaluated in buccal epithelial cells (BECs) of 85 pre-menopausal Indian women who were engaged in cooking with biomass (wood, dung, crop residues) and 76 age-matched control women who were cooking with cleaner fuel liquefied petroleum gas (LPG). DNA damage was evaluated by comet assay and fast halo assay (FHA). The concentrations of particulate matter with aerodynamic diameters of less than 10 and 2.5 μm (PM(10) and PM(2.5), respectively) in indoor air were measured by real-time aerosol monitor. Generation of reactive oxygen species (ROS) was measured by flow cytometry and the level of superoxide dismutase (SOD) by spectrophotometry. Compared with control, BEC of biomass users illustrated 2.6-times higher comet tail % DNA (32.2 vs. 12.4, p < 0.001), 2.7-times greater comet tail length (37.8 μm vs. 14.2 μm, p < 0.001) and 2.2-times more olive tail moment (7.1 vs. 3.2, p < 0.001), suggesting marked increase in DNA damage. FHA also showed 5-times more mean nuclear diffusion factor (9.2 vs. 1.8, p < 0.0001) in BEC of biomass users, confirming sharp rise in DNA single strand breaks. Airway cells of biomass-using women showed 51% rise in ROS generation but 28% reduction in SOD, suggesting oxidative stress in the airways. Indoor air of biomass-using households had 3-times more PM(10) and PM(2.5) than LPG-using families, and DNA damage showed positive association with PM(10) and PM(2.5) levels controlling education, kitchen location and family income as potential confounders. In summary, chronic inhalation of biomass smoke elicits oxidative stress and extensive DNA damage in BEC.     

‘Diabetes is a gift from god’ a qualitative study coping with diabetes distress by Indonesian outpatients

Quality of Life Research - More than two-thirds of patients diagnosed with type 2 diabetes mellitus (T2DM) in Indonesia encounter medical-related problems connected to routine self-management of...     

Expression of Insulin-like Growth Factor-I in Uterus is Ovarian Steroid Dependent： An in situ Immunohistochemical Study in Rat

Objective To study the immunohistochemical localization of insulin-like growth factor-I (IGF-I) in rats’uteri to determine if expression of the growth factor is ovarian steroid dependent. Method The study was carried out in presence and absence of ovary in situ of non pregnant females and during early gestation (day 1 to day 5.5). Cyclic females were tested to observe the effect of native steroids on IGF-I expression. Adult females were ovariectomized (OVX) and injected (s.c) with estradiol-17β in a dose of 0.1μg/ml per day for three consecutive days at interval of 24h prior to the collection of uterine horns. During the early pregnancy, studies were carried out on day 3.5 and day 5.5 of geatation respectively to determine the steroids’effects during pre- and post-implantation period. Tamoxifen was administered (s.c) in a dose of 250μg/ml per day from day 1 to day 3 of gestation while, the prostaglandin F 2α (PGF 2α ) was administered (s.c) from day 3 of gestation onward for three consecutive days at interval of 24h in a dose of 150μg/ml per day. Expression of IGF-I was immunohistochemically localised using IGF-I antibody in paraffin embedded sections. Results IGF-I was expressed in rat uterus during estrus phase as well as during pre and post-implantation period. The ovariectomized females’uteri lost the expression of IGF-I. Exogenous administration of tamoxifen and PGF 2α reduce the expression of the growth factor. Conclusion Expression of IGF-I in rat uterus during cyclic stage and early gestation depends upon the availability of circulating estrogen and progesterone. Uterine expression of IGF-I can be modulated by manipulating circulating ovarian steroid either during cyclic stage or during gestation.     

Functional neuroanatomy and neuropathology of the human hypothalamus

The human hypothalamus is involved in a wide range of functions in the developing, adult and aging subject and is responsible for a large number of symptoms of neuroendocrine, neurological and psychiatric diseases. In the present review some prominent hypothalamic nuclei are discussed in relation to normal development, sexual differentiation, aging and a number of neuropathological conditions.The suprachiasmatic nucleus, the clock of the brain, shows seasonal and circadian variations in its vasopressin neurons. During normal aging, but even more so in Alzheimer's disease, the number of these neurons decreases. In homosexual men this nucleus is larger than in heterosexual men.The difference between the sexually dimorphic nuclei of men and women arises between the ages of 2–4 to puberty. In adult men this nucleus is twice as large as in adult women. In the process of aging, a sex-dependent decrease in cell number occurs. The vasopressin and oxytocin cells of the supraoptic and paraventricular nucleus are present in adult numbers as early as mid-gestation. Lower oxytocin neuron numbers are found in Prader-Willi syndrome, AIDS and Parkinson's disease. Familial hypothalamic diabetes insipidus is based upon a point mutation in the vasopressin-neurophysin-glycopeptide gene.Parvicellular corticotropin-releasing hormone-containing neurons in the paraventricular nucleus increase in number and are activated during the course of aging.In post-menopausal women, the infundibular or arcuate nucleus contains hypertrophie neurons containing oestrogen receptors. These neurons may be involved in the initiation of menopausal flushes.The nucleus tuberalis lateralis may be involved in feeding behaviour and metabolism. In Huntington's disease the majority of its neurons is lost; in Alzheimer's disease it shows very strong cytoskeletal alterations.Tuberomammillary nucleus neurons contain, e.g., histamine or galanine, and project to the cortex. Strong cytoskeletal changes, as well as plaques and tangles are found in this nucleus in Alzheimer's disease.The various hypothalamic nuclei are probably involved in many functions and symptoms of which only a minority has been revealed.