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Photodynamic effectiveness and vasoconstriction in hairless mouse skin after topical 5-aminolevulinic acid and single- or two-fold illumination

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PHOTOCHEMISTRY AND PHOTOBIOLOGY 1999年第6期70卷 921-929页

作者： van der Veen, N Hebeda, KM de Bruijn, HS Star, WM Univ Rotterdam Hosp Daniel den Hoed Canc Ctr Dept Radiat Oncol Subdiv Clin Phys Rotterdam Netherlands Univ Nijmegen St Radboud Hosp Dept Pathol NL-6500 HB Nijmegen Netherlands

Several options were investigated to increase the efficacy of photodynamic therapy (PDT) using protoporphyrin IX (PpIX) induced by topically applied 5-aminolevulinic acid (ALA). Hairless mice with normal skin or UVB-light-induced skin changes were used as a model. In the first part of the study animals were illuminated immediately (t = 4) or 6 h (t = 10, PpIX fluorescence maximum) after the end of a 3 h ALA application. A total incident light fluence of 100 J/cm(2) (514.5 nm) was delivered at a fluence rate of 100 or 50 mW/cm(2). The PDT-induced damage to normal skin was more severe after treatment at t = 10 than at t = 4, Illumination at 50 mW/cm(2) caused significantly more visible damage than the same light fluence given at 100 mW/cm2. For UVB-illuminated skin, different intervals or fluence rates made no significant difference in the severity of damage, although some qualitative differences occurred. In situ fluence rate measurements during PDT indicated vasoconstriction almost immediately after the start of the illumination, A fluorescein exclusion assay after PDT demonstrated vasoconstriction that was more pronounced in UVB-treated skin than in normal skin. The second part of the study examined the effect of two illuminations. The first illumination bleaches the PpIX fluorescence. At the start of the second illumination, new PpIX had been formed. Light of 514.5 nm was delivered at 100 mW/cm(2) to a total incident light fluence of 200 J/cm(2) at t = 4 (single illumination) or 100 J/cm(2) at t = 4 plus 100 J/cm(2) at t = 10. There was no visual difference in skin damage between 100 and 200 J/cm(2) single illumination. Two-fold illumination (100 + 100 J/cm(2)) caused significantly more skin damage, indicating a potentially successful option for increasing the efficacy of topical ALA-PDT.

关键词：投药局部氨基酮戊酸/药理学疾病模型动物用药计划表小鼠近交HRS 光化学疗法/方法光敏感药/药理学皮肤/解剖学和组织学皮肤/血液供给紫外线血管收缩/药物作用动物女(雌)性小鼠

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Management and dosing of warfarin therapy

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AMERICAN JOURNAL OF MEDICINE 2000年第6期109卷 481-488页

作者： Gage, BF Fihn, SD White, RH Washington Univ Sch Med Div Gen Med Sci St Louis MO 63110 USA Univ Washington Div Gen Internal Med Seattle WA 98195 USA VA Puget Sound Hlth Care Syst Seattle WA USA Univ Calif Davis Div Gen Med Sacramento CA 95817 USA

When initiating warfarin therapy, clinicians should avoid loading doses-that can raise the International Normalized Ratio (INR) excessively;instead, warfarin should be initiated with a 5-mg dose (or 2 to 4 mg in the very elderly). With a 5-mg initial dose, the INR will not rise appreciably in the first 24 hours, except in rare patients who will ultimately require a very small daily dose (0.5 to 2.0 mg). Adjusting a steady-slate warfarin dose depends on the measured INR values and clinical factors: the dose does not need to be adjusted for a single INR that is slightly out of range, and most changes should alter the total weekly dose by 5% to 20%. The INR should be monitored frequently (eg, 2 to 4 times per week) immediately after initiation of warfarin;subsequently, the interval between INR tests can be lengthened gradually (up to a maximum of 4 to 6 weeks) in patients with Stable INR values. Patients who have an elevated INR will need more frequent testing and may also require vitamin K1. For example, a nonbleeding patient with an INR of 9 can be given low-dose vitamin K1 (eg, 2.5 mg phytonadione, by mouth). Patients who have an excessive INR with clinically important bleeding require clotting factors leg, fresh-frozen plasma) as well as vitamin K1. Am J Med. 2000;109:481-488. (C) 2000 by Excerpta Medica, Inc.

关键词：用药计划表药物监测出血/化学诱导出血/预防和控制国际标准化比监测便携式华法林/投药和剂量华法林/血液华法林/药理学人类

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Predictors of medical events and of their competitive interactions in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2)

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AMERICAN HEART JOURNAL 2001年第6期142卷 989-997页

作者： Funck-Brentano, C Lancar, R Hansen, S Hohnloser, SH Vanoli, E Hop St Antoine Dept Pharmacol F-75571 Paris 12 France St Antoine Fac Med INSERM Paris France Eksjoe Hosp Dept Med Eksjo Sweden Goethe Univ Frankfurt Dept Cardiol D-6000 Frankfurt Germany Pavia Univ Hosp Dept Cardiol Inst Rech & Cura Carettere Sci San Matteo Pavia Italy

Aims Predictive factors for medical events and interactions between events were not reported in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2). We examined the interactions among death, permanent treatment withdrawals, nonlethal cardiovascular hospitalizations and their own occurrence in a given patient, the treatment received, and baseline variables during CIBIS-2. Methods and Results A Cox model for censored data was used to analyze the relations among baseline variables, medical events, and their interactions with treatment. We used competitive risk analysis to examine the interactions between successive events in a given patient during follow-up. No baseline variable predicted the reduction of mortality with bisoprolol. Withdrawal from bisoprolol therapy was more frequent in patients whose baseline heart rate was in the lower tertile of the distribution (P = .0002) but otherwise was not different between patients randomized to bisoprolol and to placebo. Event history analysis revealed that bisoprolol reduced mortality (P = .0006) and hospitalizations for nonlethal cardiovascular events (P = .003) in patients in whom treatment was not permanently withdrawn. Analysis of survival curves in patients who permanently discontinued treatment showed that bisoprolol did not reduce mortality compared with placebo in this population (relative risk 1.03, 95% Cl 0.67-1.59;P = .88). Recurrent nonlethal events were reduced by bisoprolol. Conclusion In CIBIS-2, medical events were significantly influenced by treatment withdrawal. Patients who derive benefit from bisoprolol therapy are those in whom treatment is not permanently withdrawn.

关键词：肾上腺素能β受体拮抗剂/投药和剂量比索洛尔/投药和剂量用药计划表随访研究住院/统计学和数值数据多元分析病人依从预后比例危险度模型危险性评估存活率治疗结果老年人女(雌)性人类男(雄)性中年人

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Two inbred strains of rats, Fischer 344 and Lewis, showed differential behavior and brain expression of corticosterone receptor mRNA induced by methamphetamine

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NEUROBIOLOGICAL MECHANISMS OF DRUGS OF ABUSE: COCAINE, IBOGAINE, AND SUBSTITUTED AMPHETAMINES 2000年第1期914卷 33-45页

作者： Numachi, Y Yoshida, S Toda, S Matsuoka, H Sato, M Tohoku Univ Grad Sch Med Dept Psychiat Sendai Miyagi 9808574 Japan Univ Michigan Mental Hlth Res Inst Ann Arbor MI 48109 USA

Recently, a role of the hypothalamo-pituitary-adrenocortical (HPA) axis in facilitating the behavioral and neurochemical effects of psychostimulants has been proposed. Two inbred strains of rats, Fischer 344/N (F344) and Lewis/N (LEW), have markedly different HPA axes as well as behavioral responses to psychostimulants: F344 rats show hyperresponsive BPA axis and no significant sensitization to cocaine, whereas LEW rats display blunted response in HPA axis and develop cocaine-induced locomotor sensitization. Corticosterone exerts its biological effects via intracellular receptors, termed type I (mineralocorticoid receptor: MR) and type II (glucocorticoid receptor: GR). The present study examines the development of stereotypy sensitization and the brain expression of mRNAs for MR, GR, and heat shock protein 90 (HSP90) in methamphetamine (MAP)-treated F344 and LEW rats. Animals received i.p. injections with chronic saline (SAL: once daily for 21 days), chronic saline and acute MAP (AM: saline for 20 days and 4 mg/kg MAP on the 21st day), or chronic MAP (CM: 4 mg/kg MAP for 21 days) and were sacrificed three hours after the last injections. Striatum, hippocampus, and cerebellum were quickly dissected on ice and total RNA was isolated for northern analyses. LEW rats developed stereotypy sensitization significantly earlier than F344 rats. AM significantly decreased GR and MR mRNA expression in hippocampus of LEW, compared to SAL. CM significantly increased GR and MR mRNA expression in striatum of F344 compared to SAL and AM, while it decreased GR mRNA in striatum of LEW and MR mRNA in hippocampus, compared to SAL. AM significantly increased HSP90 mRNA in all brain regions examined, without the hippocampus in LEW. CM significantly increased the expression of HSP90 mRNA in the striatum and cerebellum of F344, but significantly decreased in the striatum and hippocampus of LEW. These contrasting differences between F344 and LEW, in their susceptibility to stereotypy sensitiz

关键词：行为动物/药物作用印迹法 RNA/方法体温/药物作用脑/解剖学和组织学脑/药物作用脑/代谢中枢神经系统刺激剂/投药和剂量用药计划表基因表达/药物作用 HSP90热休克蛋白质类/遗传学 HSP90热休克蛋白质类/代谢甲基苯丙胺/投药和剂量大鼠近交F344 大鼠近交Lew 受体糖皮质激素/遗传学受体糖皮质激素/代谢受体盐皮质激素/遗传学受体盐皮质激素/代谢受体类固醇/遗传学受体类固醇/代谢种特异性刻板行为/药物作用时间因素动物男(雄)性大鼠

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Management of endemic outbreaks of scabies with allethrin, permethrin, and ivermectin

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INTERNATIONAL JOURNAL OF DERMATOLOGY 2000年第6期39卷 463-470页

作者： Paasch, U Haustein, UF Univ Leipzig Dept Dermatol D-7010 Leipzig Germany

Background At three residences for the elderly, recurrent scabies infestations became out of control. Due to the failure of repeated, nonsynchronized therapeutic efforts with conventional external anti-scabies treatments, an eradication program had to be developed. We describe a protocol for the management of outbreaks of scabies. Methods According to the clinical examination and microscopically identified mites, all individuals of the population (IOP: patients, staff, and family members) were divided into two groups: (a) healthy and infested IOP;and (b) cases with crusted scabies. The first group was treated simultaneously once with external scabicides (allethrin or permethrin). All others were hospitalized and treated either with systemic ivermectin or with the latter in combination with permethrin. Results In 252 IOP living in three residences for the elderly, clinical signs of scabies were reported in 91.5%, 78.5%, and 15.4% of the patients (age 55-97 years;mean, 80.5 years), 54.1%, 32.9%, and 16.6% of staff members, and in 7%, 3%, and 0% of family members. The infested IOP showed crusted scabies (index cases) in 5.3%, 5.0%, and 1.7%, common scabies in 43.1%, 36.7%, and 7.1%, and postscabiotic dermatitis in 10.3%, 7.6%, and 3.5%. In 99.2% of the synchronously treated IOP in group (a) (n = 240), the conventional treatment with permethrin cream 5% or allethrin spray was effective. Group (b) (n = 12) received ivermectin (12 mg) once (n = 5) or twice (n = 7) after an interval of 8 days. One index case received permethrin three times. Conclusions Outbreaks of scabies in populations of elderly people require special management for disease control. Synchronous treatment with external permethrin cream 5% or allethrin spray, including all IOP once, and close control offers a time-saving, cheap, and reliable method. Crusted scabies should be treated by oral administration of ivermectin once or twice after an interval of 8 days. Additional applications of permethrin and me

关键词：丙烯除虫菊素/投药和剂量丙烯除虫菊素/化学疾病暴发流行/预防和控制用药计划表德国/流行病学老人疗养院杀虫药/投药和剂量杀虫药/化学伊维菌素/投药和剂量伊维菌素/化学医护疗养所扑灭司林除虫菊酯类/投药和剂量除虫菊酯类/化学疥疮/流行病学疥疮/病理学疥疮/预防和控制头皮皮肤病/流行病学头皮皮肤病/病理学头皮皮肤病/预防和控制构效关系老年人老年人 80以上女(雌)性人类男(雄)性中年人

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AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients

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ANTIVIRAL THERAPY 2001年第2期6卷 127-134页

作者： Gartland, M Glaxo Wellcome Res & Dev Ltd HIV & Ols Therapeut Dev Grp Greenford Middx England

The objective of our randomized, multicentre, double-blind, placebo-controlled study was to investigate the safety, tolerability, and antiretroviral and immunological effect of double and triple combination therapy regimens. A total of 105 antiretroviral therapy-naive patients were randomized to receive either zidovudine (300 mg twice per day) plus lamivudine (150 mg twice per day) plus nelfinavir placebo (three times per day) (n=52), or zidovudine/lamivudine (dose as before) plus nelfinavir (750 mg three times per day) (n=53) for 28 weeks. After this time, patients were allowed to switch to open-label zidovudine/lamivudine/nelfinavir. The overall log,, reduction from baseline in plasma HIV-1 RNA was significantly greater in the zidovudine/lamivudine/nelfinavir group than the zidovudine/lamivudine group (P=0.001;median treatment difference, -1.01 log(10) copies/ml;95% confidence interval -1.23 to -0.79), as measured by the average area under the curve minus baseline over 28 weeks. Increases from baseline in CD4 cell counts were statistically significantly greater in the zidovudine/lamivudine/nelfinavir group (101.5 cells/ml) than the zidovudine/lamivudine group (47.0 cells/ml;P=0.027) at week 28. Of note, the addition of nelfinavir from weeks 28-52 led to an increase in the proportion of subjects with plasma HIV-1 RNA <400 copies/ml from 17% (9/52 patients on zidovudine/lamivudine) to 50% (13/26 patients who switched to zidovudine/lamivudine/nelfinavir). Incidence of drug-related adverse events was similar in the two groups, except for nausea (more common in zidovudine/lamivudine group;40 versus 17%) and diarrhoea (more common in zidovudine/lamivudine/nelfinavir group;45 versus 14%). In conclusion, our study confirms the efficacy of triple combination therapy with two nucleoside analogues and a protease inhibitor compared with double-nucleoside therapy. Interestingly, the addition of nelfinavir to zidovudine/lamivudine, even after 6 months of double nucleoside thera

关键词：投药口服抗HIV药/投药和剂量抗HIV药/治疗应用临床方案腹泻/化学诱导双盲法用药计划表药物疗法联合 HIV感染/药物疗法 HIV感染/免疫学 HIV感染/病毒学 HIV-1/分离和提纯 HIV-1/生理学拉米夫定/投药和剂量拉米夫定/治疗应用恶心/化学诱导奈芬纳韦/投药和剂量奈芬纳韦/治疗应用病人依从 RNA 病毒/血液齐多夫定/投药和剂量齐多夫定/治疗应用成年人人类男(雄)性

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MANAGEMENT AND RESULTS OF LOCALIZED EWINGS SARCOMA

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CANCER 1979年第3期43卷 1001-1006页

作者： CHAN, RC SUTOW, WW LINDBERG, RD SAMUELS, ML MURRAY, JA JOHNSTON, DA The University of Texas System Cancer Center M. D. Anderson Hospital and Tumor Institute Houston TX

Seventy-six patients with localized Ewing's sarcoma who received primary treatment at M. D. Anderson Hospital from 1948 through December 1975 were reviewed. Patients have been divided into four groups according to the different treatment regimens they received: Group I, moderate dose radiotherapy alone; Group II, high dose radiotherapy alone; Group III, radiotherapy plus vincristine and cytoxan; and Group IV, radiotherapy plus vincristine, Adriamycin, cytoxan and actinomycin. The problem of local recurrence appears to be solved with combined chemotherapy and radiation therapy with only one of 36 patients having a recurrence at the primary site in Groups III and IV. Multimodal therapy is the preferred treatment to obtain control of the primary lesion by radiation therapy while preserving good function. However, the major cause of failure remains distant metastases, 19 of 36 (53%) in Groups III and IV. In addition, 4 of 10 patients who have survived over 5 years have developed osteogenic sarcoma. Cancer 43:1001–1006, 1979.

关键词：抗肿瘤药/投药和剂量骨肿瘤/药物疗法骨肿瘤/死亡率骨肿瘤/放射疗法钴放射性同位素环磷酰胺/投药和剂量更生霉素/投药和剂量多柔比星/投药和剂量用药计划表药物疗法联合放射疗法高能肉瘤 Ewing/药物疗法肉瘤 Ewing/死亡率肉瘤 Ewing/放射疗法长春新碱/投药和剂量人类

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A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 662-669页

作者： Äbelö, A Eriksson, UG Karlsson, MO Larsson, H Gabrielsson, J AstraZeneca R&D Molndal Drug Metab & Pharmacokinet & Bioanalyt Chem S-43183 Molndal Sweden AstraZeneca R&D Molndal Expt Med S-43183 Molndal Sweden AstraZeneca R&D Molndal Gastrointestinal Pharmacol S-43183 Molndal Sweden Univ Uppsala Ctr Biomed Dept Pharm Div Biopharmaceut & Pharmacokinet S-75123 Uppsala Sweden AstraZeneca R&D Drug Metab & Pharmacokinet Sodertalje Sweden

A turnover model for irreversible inhibition of gastric acid secretion by omeprazole in gastric fistula dogs was developed using data from studies with both short- and long-term measurement periods. In the short- term experiments, after stimulation of acid secretion with histamine, the dogs were infused i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profiles and schedule dependence in the inhibitory effect of omeprazole was observed. In the long-term experiments, dogs were given single intraduodenal doses, which inhibited the acid secretion for several days. Combining the short- term and long-term data allowed the observation of a biphasic recovery of acid secretion that was described by the turnover model. Second order association rate constants (k(ome)) for the covalent binding of omeprazole to H+,K+-ATPase were estimated to 11 and 3.0 l/mu mol/h for the i.v. and intraduodenal experiments, respectively. The apparent turnover rate constant of the enzyme (k(out)) was 0.013 h(-1) and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as k(out) over k(ome), was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, respectively. Allometric scaling of the model resulted in trustworthy predictions for observations previously done in humans. The model predicted a good correlation between maximal inhibitory effect and exposure (area under the plasma concentration curve). The time dependence in this relation was also predicted by the model.

关键词：抗溃疡病药/药代动力学抗溃疡病药/药理学体液分布用药计划表胃酸/分泌 H(+)K(+)交换ATP酶/代谢模型生物学奥美拉唑/代谢奥美拉唑/药代动力学奥美拉唑/药理学试验预期值动物狗人类

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Pharmacodynamic profile of short-term readministration of abciximab in healthy subjects

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AMERICAN HEART JOURNAL 2002年第1期143卷 87-94页

作者： Freedman, J Mascelli, MA Pezzullo, JC Barnathan, ES Frederick, B Jordan, RE Albernethy, DR Centocor Inc Malvern PA 19355 USA Georgetown Univ Sch Med Washington DC USA Natl Inst Aging Baltimore MD USA

Objective The purpose of the study was to establish a rebolus regimen for abciximab that restores pharmacologic glycoprotein (GP) IIb/IIIa receptor blockade within a short time frame (up to 48 hours) after completion of an initial treatment. Methods and Results The study was a single-center, nonrandomized, open-label dose escalation trial in healthy volunteers (n = 30). Each subject received a 0.25 mg/kg bolus and a 0.125 mug/kg per minute infusion of abciximab, followed by incremental bolus doses of the agent at 15-minute intervals up to 48 hours (10 per group) after completion of the infusion, (maximal cumulative rebolus dose of 0.25 mg/kg). Pharmacodynamic measurements (GP IIb/IIIa receptor blockade, turbidimetric and whole blood platelet aggregation with use of a rapid platelet function assay [RPFA]) were obtained at periodic intervals during and after administration of the abciximab bolus and infusion. At the time of the first rebolus, pharmacodynamic measurements were attained immediately before administration of each rebolus and 15 minutes after the last rebolus dose. In subjects who received reboluses 12 hours after infusion, a cumulative dose of 0.05 mg/kg restored >80% blockade of GP IIb/IIIa receptors and >80% inhibition of turbidimetric (5 and 20 mumol/L adenosine diphosphate) and RPFA aggregation in 10 of 10 subjects. At 24 hours after treatment, a cumulative abciximab bolus dose of 0.1 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. At 48 hours after treatment, a cumulative bolus dose of 0.15 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. Conclusions A fraction of the bolus of abciximab restored pharmacologic (>80%) GP IIb/IIIa receptor blockade when readministered at various postinfusion time points. These observations suggest that in the setting where acute readministration of abciximab is required less than a full bolus dose of the agent is warranted.

关键词：抗体单克隆/投药和剂量抗体单克隆/药代动力学用药计划表免疫球蛋白Fab片段/投药和剂量血小板聚集/药物作用血小板糖蛋白GPⅡb-Ⅲa复合物/拮抗剂和抑制剂时间因素成年人老年人人类男(雄)性中年人

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Effect of acute and chronic administration of methamphetamine on calcium-calmodulin dependent protein kinase II activity in the rat brain

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NEUROBIOLOGICAL MECHANISMS OF DRUGS OF ABUSE: COCAINE, IBOGAINE, AND SUBSTITUTED AMPHETAMINES 2000年第1期914卷 263-274页

作者： Akiyama, K Suemaru, J Okayama Univ Sch Med Dept Neuropsychiat Okayama 7008558 Japan

Several lines of evidence have implicated Ca2+/calmodulin (CaM)dependent protein kinase II (CaM-kinase II), a multifunctional protein kinase, in the regulation of signal transduction after chronic administration of psychostimulants. CaM-Kinase II activities were decreased in discrete brain regions after a single methamphetamine (METH) injection to rats. Pretreatment with either SCH 23390 (a dopamine D1 receptor antagonist) or MK-801 (an N-methyl-D-aspartate receptor antagonist) prevented the acute METH-induced decrease in CaM-kinase II activity in the parietal cortex, nucleus accumbens, and substantia nigra/ventral tegmental area (SN/VTA). Striatal CaM-kinase H activity was significantly lower than that of the chronic saline-treated controls after a one-week, but not a four-week, abstinence from chronic administration of METH. A METH challenge after a four-week abstinence period decreased CaM-kinase II activity in rats chronically injected with METH to a greater extent than in rats chronically injected with saline. Western blot analysis revealed that protein amount of CaM-kinase H was not altered after a single METH injection or after chronic METH injections, as compared with saline-treated controls. However, amounts of phosphorylated (Thr(286)) CaM-kinase II in the parietal cortex, striatum, and SN/VTA were significantly decreased at 3 h after an acute METH injection compared with saline-treated controls. It is suggested that dephosphorylation of CaM-kinase II may contribute to the decreased enzyme activities induced by acute METH administration, and that chronic treatment with METH leads to an enhanced capacity of METH to decrease CaM-kinase II activity after an extended withdrawal period.

关键词：方差分析苯丙氮|艹卓|类/药理学印迹法蛋白质/方法脑/解剖学和组织学脑/药物作用脑/酶学脑化学/药物作用钙-钙调素依赖性蛋白激酶2型钙-钙调素依赖性蛋白激酶类/代谢中枢神经系统刺激剂/投药和剂量地卓西平马来酸盐/药理学多巴胺拮抗剂/药理学用药计划表药物相互作用兴奋性氨基酸拮抗剂/药理学甲基苯丙胺/投药和剂量大鼠 Sprague-Dawley 时间因素动物男(雄)性大鼠

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