Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy

Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (Cmin) and total drug exposure over 24 hr (AUC24) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the Cmin and AUC24 below which the risk of virologic failure increased. The relation between Cmin and AUC24 with virologic failure (never a plasma viral load [pVL] < 50 copies/ml or a rebound to two consecutive pVL > 50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a Cmin < 3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC24. The risk of virologic failure with EFV (n = 312) was significantly increased at a Cmin < 1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC24 < 40 mg x hr x L1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between Cmin and AUC24 with virologic failure statistically nonsignificant. The sensitivity of the Cmin values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the Cmin value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV).     

Oral administration of the growth hormone secretagogue NN703 in adult patients with growth hormone deficiency

OBJECTIVE: Little is known of the usefulness of GH secretagogues (GHSs) in GH-deficient (GHD) adults. The objective of this study was to determine the number of responders to treatment with NN703 in GHD adults. DESIGN: A multicentre, randomized, double-blind, and placebo-controlled study. PATIENTS: Ninety-seven GHD adults were included. MEASUREMENTS: The GH response before and after 1 week of oral treatment with NN703 (n = 83) or placebo (n = 14) was determined. The first and last dose of NN703 was 3 mg/kg, whereas the dose of NN703 was 1.5 mg/kg/day during the 6 days between the first and last doses. Furthermore, all 97 patients received 1 micro g/kg GH-releasing hormone (GHRH) 3 weeks after the last dose of NN703. RESULTS: Serum GH peak and area under curve (AUC) values after the first NN703 administration were greater than those after placebo administration (P < 0.05). However, after correction for the lower body mass index (BMI) in the NN703 group, this difference lost statistical significance. After 1 week of therapy, GH peak and AUC values were similar following the final doses of NN703 and placebo. Serum peak and AUC values of other anterior pituitary hormones were similar between the NN703 and placebo groups both after the first and last administration of study drug. Nine of the 83 patients (11%) responded with a serum peak GH concentration >or= 5 micro g/l after the first and/or last NN703 administration, whereas no patient responded after placebo administration. Serum IGF-I was unaffected by 1-week NN703 treatment, whereas serum IGFBP-3 was increased (P < 0.05 vs. placebo) also after correction for BMI. Mean serum peak GH concentration after GHRH administration was 2.1 micro g/l (+/-0.3, SEM), which was higher than that after the first NN703 administration (1.32 +/- 0.3, P < 0.05). CONCLUSION: NN703 administration was generally well tolerated. Eleven per cent of the GHD adult patients responded with a peak GH response >or= 5 micro g/l after the first and/or last administration of oral NN703. Although a majority of GHD adults will not respond to NN703, the present results suggest that oral NN703 treatment could be useful in some adult patients with moderately severe GHD. These patients may be identified by a test dose of GHS.     

Synergistic effects of butyrate on platelet responses to arachidonate, A23187, PGE1, and forskolin

With eukaryotic cells, butyrate is known to induce a series of morphological and biochemical changes that mimic cellular differentiation. With platelets, we have found that butyrate (10 mmol/L) caused an approximately threefold increase in sensitivity to calcium ionophore A23187 and arachidonate. Maximum aggregation was observed at agonist concentrations of 3 mumol/L and 170 mumol/L, respectively, as compared with required concentrations of 10 mumol/L and 400 mumol/L in the absence of butyrate. Similar effects were seen with isobutyric acid, and about one-half the effect was shown with valerate and caproate, but lower homologues showed no synergistic effect. No ultrastructural changes were observed in platelets incubated with butyrate, and the aggregation effects were reversible and returned to normal on removal of butyrate. Membrane fluidity was unchanged by butyrate as measured by changes in the fluorescence depolarization of diphenylhexatriene. Butyrate caused a 60% to 70% increase in the uptake of 3H-arachidonate. Butyrate also potentiated the inhibition of platelet function by prostaglandin E1 and forskolin and uptake of 3H- forskolin was increased approximately 20%. In contrast, platelet response to other agonists (ADP, epinephrine, collagen, thrombin, and platelet-activating factor) was essentially unaffected by butyrate. These results suggest that butyrate may increase the uptake of certain hydophobic agonists and antagonists by platelets. Similar mechanisms for uptake of endogenous effectors may explain the response of eukaryotic cells to butyrate in culture.     

Antimicrobial resistance of bacterial pathogens associated with diarrheal patients in Indonesia

The antimicrobial susceptibility patterns for 2,812 bacterial pathogens isolated from diarrheal patients admitted to hospitals in several provinces in the cities of Jakarta, Padang, Medan, Denpasar, Pontianak, Makassar, and Batam, Indonesia were analyzed from 1995 to 2001 to determine their changing trends in response to eight antibiotics: ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol, tetracycline, cephalothin, ceftriaxone, norfloxacin, and ciprofloxacin. Vibrio cholerae O1 (37.1%) was the pathogen most frequently detected, followed by Shigella spp. (27.3%), Salmonella spp. (17.7%), V. parahaemolyticus (7.3%), Salmonella typhi (3.9%), Campylobacter jejuni (3.6%), V. cholerae non-O1 (2.4%), and Salmonella paratyphi A (0.7%). Of the 767 Shigella spp. isolated, 82.8% were S. flexneri, 15.0% were S. sonnei, and 2.2% were S. dysenteriae (2.2%). The re-emergence of Shigella dysenteriae was noted in 1998, after an absence of 15 years. Shigella spp. were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline. Salmonella typhi and Salmonella paratyphi A were susceptible to all antibiotics tested, while Salmonella spp. showed various resistance patterns according to species grouping. A small number of V. cholerae O1 were resistant to ampicillin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline; however, they were still sensitive to ceftriaxon, norfloxacin, and ciprofloxacin. Similar results were shown for V. cholerae non-O1. Campylobacter jejuni showed an increased frequency of resistance to ceftriaxone, norfloxacin, and ciprofloxacin, but was susceptible to erythromycin. This study shows that except for C. jejuni and V. parahaemolyticus, which appeared to be resistant to ciprofloxacin, the majority of the enteric pathogens tested were still susceptible to fluoroquinolones.     

A soluble activity from adherent marrow cells cooperates with IL 3 in stimulating growth of pluripotential hematopoietic precursors

Marrow cells from 5-fluorouracil (5-FU)-treated mice formed few or no mixed erythroid colonies when plated in semisolid medium with interleukin 3 (IL 3) and erythropoietin (Ep) alone. When conditioned medium (CM) from plastic-adherent marrow or thymus cells was also included, however, growth of mixed erythroid colonies was strongly stimulated. Both IL 3 and the accessory activity (AA) had to be present at the initiation of the cultures for growth to occur. AA was also produced by a cloned immortalized line (95/1.7) of fibroblastoid marrow cells that lacked macrophage-specific cell surface markers. Colony- stimulating factor-1 (CSF-1) was also released, but not granulocyte colony-stimulating activity. When 95/1.7 CM was analyzed by gel filtration, AA eluted with an apparent size of 35 kd and separated completely from the CSF-1. Biologic assays failed to detect IL 1 or IL 3 activity in 95/1.7 CM. Growth of mixed erythroid colonies from 5-FU- treated marrow is thus stimulated by adherent marrow cell-derived factors that appear distinct not only from the known CSFs including IL 3, but also from IL 1.     

Serum vascular endothelial growth factor concentrations and ovarian stromal blood flow are increased in women with polycystic ovaries

The aim of this study was to determine basal serum vascular endothelial growth factor (VEGF) concentrations and Doppler blood flow changes within the ovarian stroma of women with polycystic ovaries (PCO) and women with normal ovaries. Pulsed and colour Doppler blood flows within the ovarian stroma were recorded, and serum VEGF concentrations measured, in the early follicular phase (days 2-3 of a menstrual cycle) in 60 women undergoing ovarian stimulation for in-vitro fertilization. 36 women had normal ovaries, 14 women had PCO as seen on pelvic ultrasound examination and 10 had polycystic ovarian syndrome (PCOS). Mean+/-SD serum VEGF concentrations were significantly higher (P < 0.001) in women with PCO and PCOS (3.4+/-0.7 and 3.2+/-0.66 ng/ml respectively) compared with women with normal ovaries (2.3+/-0.5 ng/ml). Mean peak systolic blood flow velocity (PSV) and time-averaged maximum flow velocity (TAMXV) were significantly higher (P < 0.001) in women with PCO and PCOS compared with women with normal ovaries. The mean PSV were 15+/-4 and 16+/-4 cm/s in women with PCO and PCOS respectively, compared with 9+/-2 cm/s in women with normal ovaries. The TAMXV were 9+/-3 and 11+/-3 cm/s in women with PCO and PCOS respectively compared with women with normal ovaries (5.8+/-1.5 cm/s). Serum VEGF concentrations were positively correlated with PSV (r=0.44, P=0.001) and TAMXV (r=0.45, P < 0.000) in all three groups of women. Higher serum concentrations of VEGF in women with PCO and PCOS may relate to the increased vascularity that underlies the increased blood flow demonstrated by Doppler blood flow velocity measurements in these women. The results may explain the higher risk of ovarian hyperstimulation syndrome in programmes of ovarian stimulation in patients with PCO compared with those with normal ovaries.      

美国口腔医学院的社区教学模式

高昂的医疗费用和不够便利的就医条件是阻碍美国人,特别是少数民族和劣势群体,获得口腔医疗护理的重要原因,其根源在于传统口腔教学僵化的教学方式和昂贵的学习费用.近年来,美国各界为改变口腔医疗的状况,进行了多种尝试,旨在降低口腔医学学习成本,并培养乐于奉献、积极投身社区医疗的口腔医师.该文分析了美同口腔医疗面临的问题及其原因,并以亚利桑那大学齿科与口腔健康学院的教学改革为例,介绍美国口腔医学教学如何与社区医疗相结合.     

地龙(蚯蚓)体内磷脂的组成和血小板活化因子的生物合成

首次发现低等动物地龙(Eisenia foetida,亦称蝗蚓)体内含有血小板活化因子(PAF),含量随季节变化,平均达10.7±6.1pmol/g湿重(或1.1±0.5μmol/mol磷脂)。磷脂成分中,PAF前体物质1-O-烷基-2-酰基(长链)-sn-甘油-3-磷酸胆碱占磷脂酰胆碱的比例高达61.4%。并证实地龙体内含有与哺乳类动物相同的两种PAF合成酶蛋白。当针刺、切断等伤害性刺激时,PAF水平显著升高。此结果提示PAF是一种初始的活性介质,在地龙这类低等动物体内也参与机体的病理、生理应急反应。本研究为阐明中药地龙的降血压等药理作用机理提供新线索。