Elderly medical patients treated with prophylactic dosages of enoxaparin: influence of renal function on anti-Xa activity level

BACKGROUND: The safety and optimal use of prophylactic treatment with low-molecular-weight heparins in elderly patients with impaired renal function remain undefined. METHODS: The primary aim of this study was to analyse, in 'real life', the influence of renal function, as assessed by creatinine clearance (CL(CR)), on the level of anti-Xa activity in medical hospitalised elderly patients receiving prophylactic dosages of enoxaparin. Consecutive hospitalised acutely ill medical patients aged >or=75 years receiving daily dosages of enoxaparin 4000 IU for up to 10 days were prospectively enrolled in two centres. Peak anti-Xa activity was measured at the beginning and during the course of therapy. RESULTS: One hundred and twenty-five patients (31 men, 94 women), mean age 87.5 +/- 6.3 years, mean bodyweight 56.4 +/- 11.9 kg and mean CL(CR) 39.8 +/- 16.1 mL/min, were enrolled in the study. The mean maximum anti-Xa activity (day 1 to day 10) [anti-Xa(max1-10)] was 0.64 +/- 0.23 IU/mL (range 0.24-1.50 IU/mL). Weak negative correlations were found between CL(CR) and anti-Xa(max) and between bodyweight and anti-Xa(max). Mean anti-Xa(max) was slightly but significantly higher in patients with CL(CR) of 20-30 mL/min compared with patients with CL(CR) of 31-40, 41-50 or 51-80 mL/min (0.72 versus 0.61, 0.61 and 0.60 IU/mL, respectively), and in patients weighing <50 kg compared with patients weighing 50-60 kg or >60 kg (0.74 vs 0.64 and 0.52 IU/mL, respectively). Serious bleeding occurred in five patients, but anti-Xa(max) values in these patients were not different to those in patients without bleeding (p = 0.77). Individual anti-Xa(max) at the beginning or during the course of treatment was measured in the subgroup of 58 patients in whom anti-Xa activity was measured at least once during the study. The mean anti-Xa(max) value was slightly but significantly higher during the course of the therapy than at the beginning of the study (0.63 +/- 0.26 IU/mL vs 0.56 +/- 0.23 IU/mL, p = 0.012). CONCLUSION: Only CL(CR) <30 mL/min and bodyweight <50 kg were associated with significantly higher anti-Xa(max) values. The clinical relevance of these increases remains questionable. No conclusions about the safety of enoxaparin in elderly medical patients can be drawn from these findings.     

Comparison of VO2max in obese and non-obese young Indian population

Incidence of obesity in early life is increasing nowadays because of faulty food habits and lack of exercise. This study was aimed to find out whether obesity affects cardiorespiratory efficiency of young adults. As VO2max is the most accepted indicator of cardiorespiratory efficiency it was compared in 30 obese and 30 non-obese subjects aged around 18-20 years. VO2mx was estimated by Queen's college step test. Various other parameters measured and calculated are weight, height, BMI, skin fold thickness, percentage body fat, lean body mass, fat mass. The results showed that cardiorespiratory efficiency (absolute VO2max & VO2max/kg lean body mass) was not affected (P > 0.05) in obese group in both sexes. Ability to do exhausting work (VO2max/kg body weight) was less in obese group (P = 0.001) compared to non-obese group & in obese males (P < 0.01) as compared to non-obese males. Percentage body fat (r = -0.416), triceps skin fold thickness (r = -0.427) and calf skin fold thickness (r = -0.381) strongly correlate to VO2max/kg body weight. Therefore the exercise programs can be best designed to increase caloric expenditure and thus to decrease body fat rather than to improve aerobic fitness.     

心率变异和心肺功能试验对先天性心脏病术后危险性的预测

目的通过对先天性心脏病开胸术患者和健康对照组的研究,确立一些新的对术后近期并发症危险性有预测价值的指标。方法45例开胸术患者和45名健康人分别作为病例组和对照组,病例组组内比较时,根据术后近期并发症严重程度进行分级,收集入选者的临床资料、动态心电图和心肺功能试验数据等资料。结果①开胸术患者的最大通气量(MV)、呼吸商(RQ)、最大摄氧量(VO2max)、最大二氧化碳排出量(VCO2max)、最大氧脉搏(VO2max/HR)、最大公斤摄氧量(VO2max/kg)、最大氧代谢(MET)、无氧域(ATVO2max)、最大功率负荷(Wmax)、运动时间、高频(HF)、低频(LF)等指标明显低于正常对照组;②心率变异性和心肺功能试验指标与开胸术后近期并发症严重程度存在相关性。③可信度最高的是Wmax达到0.898,其次是VO2max/kg和HF(静息状态)分别达到0.875和0.813。相比较而言,ATVO2max和VO2max信度比较低分别是0.789和0.766。结论心率变异和运动心肺功能试验可能成为新的预测开胸术后近期并发症的方法,Wmax、VO2max/kg和HF为较好的预测指标。     

Effects of neuroleptic drugs,clonidine and lithium on the expression of conditioned behavioral excitation in rats

Rats with a history of daily (21 days) amphetamine (2.5 mg/kg) treatment showed enhanced activity when under placebo in their amphetamine-associated environment. We found that this conditioned effect was reduced by haloperidol (0.06; 0.125; 0.25 mg/kg), pimozide (0.25; 0.5 mg/kg) and sulpiride (8; 16; 32 mg/kg) but only at doses similar to or, in the case of pimozide, higher than those required to antagonize the unconditioned stimulant effects of amphetamine (2.5 mg/kg). Conversely, we observed that clonidine (7; 15; 30; 60 g/kg) or lithium regimen (between days 15 and 21) leading to lithium plasma levels of 1.3±0.1 mEq/1, abolished amphetamine-conditioned hyperactivity but did not affect the unconditioned stimulation of amphetamine or locomotor activity in control rats. Moreover, we found that hyperactivity induced by the daily anticipation of food delivery shared identical pharmacological sensitivity with the behavioural excitation produced by a conditioning history with amphetamine. In light of the antimanic properties of lithium and clonidine and the ability of this latter drug to reduce noradrenergic transmission, our findings raise the posibility that incentive activity may model noradrenergic-dependent aspects of mania.     

Evaluation of fast disintegrating lansoprazole tablet in human subjects

Fast disintegrating lansoprazole tablet (LFDT) has been developed as a multiple unit formulation and evaluated using human subjects as compared to the conventional lansoprazole (LPZ) capsule containing enteric coated granules. Twelve healthy male volunteers, who were confirmed as extensive metabolizers (EMs) based on the plasma levels of LPZ sulphone metabolite, were enrolled into the study and genotype of CYP2C19 was confirmed. They kept 30 mg LFDT in their mouths for 2 min and the saliva was recovered without swallow. Eight subjects did not show LPZ in their serum after intake. Although LPZ was detected in 4 subjects' serum, their concentrations were less than 5 ng/mL. LPZ was thought to be not absorbed from the oral cavity. LFDT was orally administered to 12 healthy male EMs at two doses, 15 mg and 30 mg, and serum LPZ concentrations were measured. The mean C(max) and AUC(0-24) were 474.1+/-254.0 ng/mL and 1105.3+/-1101.4 ng.h/mL (15 mg) and 992.8+/-384.3 ng/mL and 2216.5+/-1270.1 ng.h/mL (30 mg). By comparing to that obtained after oral administration of the same doses of LPZ capsule, serum LPZ concentration vs. time curve was almost the same level, i.e., C(max) and AUC(0-24) did not have significant differences. From these results, LFDT has been shown to be equivalent to LPZ capsule and will show the same acid suppressing effects in the clinical situation.     

Effects of chronic caffeine pre-exposure on conditioned and unconditioned psychomotor activity induced by nicotine and amphetamine in rats

Three experiments examined the effects of chronic pre-exposure to caffeine on the subsequent conditioned and unconditioned locomotor activating effects of nicotine or amphetamine in rats. Rats were given daily intraperitoneal injections of caffeine anhydrous (0, 10 or 30 mg/kg base) for 30 days. Conditioning (environment-drug pairings) began after the last day of caffeine pre-exposure. Pre-exposure to 30 mg/kg of caffeine enhanced the acute and chronic locomotor effects of amphetamine (0.5 mg/kg). A similar enhancement of activity was not seen with the high (0.421 mg/kg base) or low dose (0.175 mg/kg) of nicotine. In a drug-free test, the distinct environment paired with amphetamine and the high dose of nicotine evoked increases in activity relative to controls. Caffeine pre-exposure did not affect expression of this conditioned hyperactivity. These effects of caffeine pre-exposure on amphetamine-induced activity could not be attributed to non-specific effects of caffeine.     

CONTROLLED COMPARISON OF EFFECTS OF EXERCISE AND ALCOHOL ON BLOOD PRESSURE AND SERUM HIGH DENSITY LIPOPROTEIN CHOLESTEROL IN SEDENTARY MALES

1. Seventy-two sedentary male drinkers, aged 20-45 years, and with mean blood pressure (BP) at entry of 132 +/- 1.2/73 +/- 0.9 mmHg, completed a 4 week study during which they were assigned randomly to either drink a low alcohol beer (effectively reducing their weekly alcohol intake from 481 +/- 47 mL to 52 +/- 5 mL) or to continue their normal drinking habits. 2. Within these two groups subjects were further assigned to either a moderate exercise programme of three 30 min sessions per week of stationary cycling at 60-70% maximum workload or to a control light exercise programme where they pedalled against zero or minimal resistance. 3. Both alcohol restriction and moderate exercise were associated with mean falls in bodyweight of 0.5 kg. After adjustment for bodyweight a significant main effect of alcohol restriction on systolic BP (-4.1 +/- 1.7 mmHg, P less than 0.05) and diastolic BP (-1.6 +/- 0.8 mmHg, P = 0.05) was demonstrated. There was no significant main effect of moderate exercise on systolic or diastolic blood pressure despite a significant improvement in physical fitness (maximal oxygen uptake increasing from 33.2 +/- 0.8 mL/kg per min to 35.5 +/- 0.1 mL/kg per min). 4. Significant falls in high density lipoprotein cholesterol (HDLC) and triglyceride levels seen with alcohol restriction were unaffected by the increase in fitness, the magnitude of the fall being similar in both the moderate and light exercise groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of exercise on the serum level and urinary excretion of tetracycline,doxycycline and sulphamethizole

Summary The serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7–8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p<0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.     

Pharmacokinetics of glucarpidase in subjects with normal and impaired renal function

Glucarpidase (formerly known as carboxypeptidase G2 or CPG2) is being evaluated for the adjunctive treatment of patients experiencing, or at risk of, methotrexate toxicity attributable to its delayed elimination. Delayed elimination of methotrexate can occur in patients with methotrexate-induced renal toxicity. In this study, glucarpidase pharmacokinetics were assessed in volunteer subjects with normal (n = 8) and severely impaired (n = 4) renal function. Each subject received a single intravenous dose of glucarpidase 50 U/kg (equivalent to 114.5 microg/kg) infused over 5 minutes. The mean maximum serum concentration (C(max)) for glucarpidase in renally impaired subjects was 2.9 microg/mL, the mean half-life (t(1/2)) was 10.0 hours, and the mean area under the serum concentration-time curve from time zero to infinity (AUC(0-infinity)) was 24.5 microg x h/mL. Similar values were found in subjects with normal renal function (mean C(max) 3.1 microg/mL, mean t(1/2) 9.0 hours, and mean AUC(0-infinity) 23.4 microg x h/mL). The results indicated little effect of renal impairment on the serum pharmacokinetics of glucarpidase.     

Sensory and associative effects of morphine and naloxone in classical conditioning of the rabbit nictitating membrane response

In Experiment I, classical conditioning of the rabbit's nictitating membrane response was accomplished by the pairing of tone and light conditioned stimuli with a shock unconditioned stimulus applied to the paraorbital region of the head. Morphine (5 mg/kg) significantly retarded the acquisition of conditioned responses to both conditioned stimuli. Moreover, morphine had no effect on nonassociative responding (baseline responding or responding to tone and light stimuli) or on the latency and amplitude of the unconditioned response elicited by shock during the explicitly unpaired presentations of tone, light and shock stimuli. The retardant effect of morphine on acquisition of conditioned responses was blocked by naloxone (1 mg/kg). In Experiment II, morphine (0.2–10 mg/kg) had no effect on the intensity threshold of the shock unconditioned stimulus for elicitation of unconditioned responses or on the latencies of the elicited responses. However, morphine (5 and 10 mg/kg) did produce a small but significant decrease in the amplitude of unconditioned responses elicited by the two highest shock intensities employed (3 and 4 mA). This latter effect of morphine was completely blocked by naloxone (1 mg/kg). In Experiment III, morphine (5 mg/kg) blocked the sensory processing of a tone conditioned stimulus, in previously trained animals, as measured by a significant (24 dB) elevation in the intensity threshold of the conditioned stimulus for elicitation of conditioned responses and an increase in the latency of the elicited response. Naloxone (1 mg/kg) completely blocked the effects of morphine on the sensory processing of the tone-conditioned stimulus. The retardant effect of morphine on the acquisition of conditioned responses appears to be primarily due to an action on opioid receptors that produces a decrease in the sensory processing of the conditioned stimulus.     

Effects of morphine and LSD on the classically conditioned nictitating membrane response

Two experiments were carried out to determine the effects of LSD and morphine on the unconditioned nictitating membrane response of the rabbit elicited by 5 intensities of a 100 msec puff of air directed at the cornea, and on the acquisition of conditioned responses to a tone and light conditioned stimulus using the air-puff as an unconditioned stimulus. In Experiment 1, LSD tartrate (0.013 mg/kg) had no effect of the frequency, amplitude, magnitude or latency of the unconditioned response. However, LSD significantly enhanced the rate of acquisition of conditioned responses to both tone and light conditioned stimuli. In Experiment 2, morphine sulfate (5 mg/kg) had no effect on the frequency, amplitude, magnitude or latency of the unconditioned response, but significantly retarded the acquisition of conditioned responses to both tone and light conditioned stimuli. The results indicated that the enhancement of acquisition produced by LSD and the retardation of acquisition produced by morphine were not due to effects of the drugs on either the sensory processing of the air-puff unconditioned stimulus or on the motoric expression of the unconditioned response.     

Pharmacokinetics of Subcutaneous Recombinant Methionyl Human Leptin Administration in Healthy Subjects in the Fed and Fasting States

BACKGROUND: Recombinant methionyl human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, and it has been suggested that leptin replacement may reverse metabolic adaptations during weight loss interventions. The pharmacokinetics of subcutaneously administered r-metHuLeptin have been recently published, but whether pharmacokinetic parameters are altered by short-term fasting, adiposity and/or gender has not yet been evaluated. OBJECTIVE: The objective of this study was to characterize pharmacokinetic parameters following subcutaneous r-metHuLeptin administration at doses in the physiological to supra-physiological to pharmacological range in the fed state and during 3-day complete fasting in lean and obese subjects, including both men and women. METHODS: We analysed pharmacokinetic profiles in five lean men, five obese men and five lean women following subcutaneous administration of physiological (0.01 mg/kg), supra-physiological (0.1 mg/kg) and pharmacological (0.3 mg/kg) doses of r-metHuLeptin given once in the fed state and once daily during 3-day complete caloric deprivation (fasting). RESULTS: With r-metHuLeptin administration at 0.01 mg/kg, leptin concentrations ranged up to approximately 7 ng/mL in lean men, approximately 20 ng/mL in obese men and approximately 30 ng/mL in lean women in the fed state. There was a significant effect of 3-day fasting: it decreased baseline leptin concentrations, peak serum concentration (C(max)) and area under the serum concentration-time curve from time zero to infinity (AUC(infinity)) [all p < 0.0001] and increased clearance (p < 0.001), most prominently in lean men (p < 0.0001 across the groups). Administration of r-metHuLeptin at 0.1 mg/kg resulted in leptin concentrations up to approximately 70 ng/mL in lean men, approximately 100 ng/mL in obese men and approximately 150 ng/mL in lean women in the fed state. At this dose, there was a similar effect of fasting on the pharmacokinetic parameters as well as a decrease in the terminal-phase elimination half-life (p = 0.02), consistent with increased clearance, but the effect of fasting was less pronounced overall than with the 0.01 mg/kg dose. With r-metHuLeptin administration at 0.3 mg/kg, leptin concentrations ranged up to approximately 150 ng/mL in lean men, approximately 300 ng/mL in obese men and approximately 400 ng/mL in lean women in the fed state. At this dose, fasting increased clearance to a lesser degree (p = 0.046), mainly in lean men, suggesting that the fasting-induced increase in leptin clearance by the kidneys can plateau. Within each group, the subjects lost approximately 3-4 kg of bodyweight after 3 days of fasting (all p < 0.0001), but the amount and time course of weight loss did not differ according to the dose of r-metHuLeptin administered or the circulating leptin concentrations achieved. CONCLUSIONS: Short-term fasting in healthy individuals results in increased clearance of leptin; this contributes to hypoleptinaemia, which may serve as a signal to increase energy intake in the setting of caloric restriction. Obese individuals with greater energy stores at baseline have a blunted response to the fasting-induced increase in leptin clearance. Also, women have a differential response to fasting, with primarily decreased leptin production rather than increased clearance. These findings and the resulting formulas for calculating doses for r-metHuLeptin administration have important implications for future therapeutic use of r-metHuLeptin in conjunction with hypocaloric diets for the treatment of obesity.     

Comparison of the ability of (+)-amphetamine and caffeine to produce environment-specific conditioning

Animals with a history of receiving psychomotor stimulants in a specific environment show enhanced activity when injected with saline and placed there. In the present study, a Pavlovian paradigm was used to compare the unconditioned and conditioned activity effects of (+)-amphetamine (0.1, 0.5, 1.0, and 5.0 mg/kg), caffeine (0.1, 1.0, 10.0, and 30.0 mg/kg), and a saline group (n's=6–12). Rats experienced conditioning days with either drug or saline injected IP prior to a 60-min session in the activity monitor and the alternate saline or drug injected in the home cage following the session. On test days, all animals received saline in the activity monitors. Results revealed that amphetamine produced environment-specific conditioning in a dose-dependent manner; previous experience with 0.5, 1.0, and 5.0 but not 0.1 mg/kg in the activity monitor resulted in conditioned activity. A caffeine dose of 10.0 mg/kg produced stimulant effects on conditioning days and previous experience with the 1.0, 10.0, or 30.0 mg/kg dose in the activity monitor led to conditioned activity on test days. However, on test days the control groups as well as the 30.0 mg/kg experimental group showed significantly reduced activity as compared to the saline group. Thus, it appeared that caffeine produced hypoactivity 23 h after injection. Amphetamine produced conditioning in a dose-dependent manner, and the appearance of significant unconditioned activity during conditioning sessions was not necessary or sufficient to produce a conditioned effect. For caffeine there was some evidence of environment-specific conditioning, but it appears that between-group differences for caffeine may be accounted for by hypoactivity 23 h following injection.     

抽脂患者皮下注射利多卡因血清与唾液浓度的相关性及其药代动力学研究

本文利用高效液相色谱法对12名抽脂健康患者皮下注射利多卡因的血清、唾液及脂肪浓度进行了测定,探讨了血清与唾液中药物浓度的相关性,并比较了二者之间的药代动力学参数。患者的平均给药剂量为20mg/kg,单剂量给药。实验结果表明血清与唾液中药物浓度呈线性关系:r=0.8043(p<0.01),C_(血清)=0.3433C_(唾液)+0.2620(n=78).唾液与血清药物浓度比值为2.37±0.857(比值范围:1.02～4.09,n=78).测得血清及唾液药代动力学参数分别为:吸收速率常数(Ka)0.573±0.583h~(-1),0.478±0.270h~(-1);消除半衰期(t_(1/2)k)6.41±2.08h,5.68±1.76h;达峰时间(T_(max))6.63±1.46h,6.67±1.80h;峰浓度(C_(max))2.52±0.926μg/ml,6.31±2.30μg/ml.血清与唾液的动力学参数除峰浓度(C_(max))外,统计学上均无明显差异(P>0.05).患者被抽出脂肪的药物含量为给药总量的31.84%(20.69～47.90%).     

Changes in total body potassium, hemoglobin and bromine space after hypokinesia and physical exercise

It has been demonstrated that hypokinesia diminished muscular activity induces changes in several biochemical total body parameters, including those of potassium, hemoglobin and bromine spaces. Therefore the objective of this study was to evaluate the composition of the body in 5 essentially healthy men, aged 19-23 years, after a 60 days exposure to hypokinesia (HK). For the simulation of the hypokinetic effect the men were kept under a rigorous bed rest regime. Throughout the hypokinetic period the men routinely performed a set of physical exercises (PE). Total body potassium, hemoglobin, bromine space and cell mass were measured in the baseline period (BP) and during readaptation period (RP), that is, after the exposure to HK. There were demonstrable reductions in cell and hemoglobin masses. The impaired potassium and hemoglobin content did not affect concentration thereof in blood. It was concluded that the examined biochemical parameters of human organism underwent certain changes following the exposure to diminished muscular activity conditions, while at the same time it was revealed that PE cannot be used to counteract the development of adverse effects of hypokinesia.     

Influence of sex on the pharmacokinetic interaction of fleroxacin and ciprofloxacin with caffeine

BACKGROUND: Previous pharmacokinetic studies have shown that a number of the quinolones inhibit the metabolism of caffeine. OBJECTIVE: To evaluate the effect of sex on the interaction between two quinolones and caffeine.Design: Multiple-dose, double-blind, randomised, three-period crossover study. PARTICIPANTS: Twelve male and twelve female healthy volunteers. METHODS: Subjects received by mouth either fleroxacin 400 mg once daily and caffeine 100 mg three times daily, ciprofloxacin 500 mg twice daily and caffeine 100 mg three times daily, or caffeine alone, for 3 days. Subjects received each of the other regimens after 12-day washout periods. Plasma and urine concentrations were determined by validated high-performance liquid chromatography procedures and the data were analysed by noncompartmental linear pharmacokinetic methods. RESULTS: Analysis of the interaction by sex revealed that females showed a significant difference in caffeine pharmacokinetics in the presence of ciprofloxacin (area under the concentration-time curve [AUC], peak plasma concentration [C(max)], time to C(max) [t(max)] and apparent total body clearance [CL/F]) and fleroxacin (AUC and CL/F) when compared with males. Significant differences between sexes were also observed in the pharmacokinetics of ciprofloxacin (AUC, elimination rate constant [beta] and CL/F) and fleroxacin (C(max) and beta) in the presence of caffeine. However, these significant differences disappeared when AUC and C(max) were normalised to 70 kg bodyweight and CL/F was expressed as per kg bodyweight. CONCLUSION: The effect of quinolones on the pharmacokinetics of caffeine, and the reciprocal effect, are different between the sexes, due in part to different bodyweights.     

Conditioned hyperkinesia induced by cocaine in mice is dose-dependent but not correlated with the unconditioned response or the contextually-sensitized response

The aims of the study were to test whether drug dose is positively related to the magnitude of the conditioned response following sensitization to the behavioural effects of cocaine and to investigate the relationship between the conditioned response and cocaine-induced sensitization. Male mice (C57BL/6J) were first injected over seven successive days with either saline or cocaine at 2.5, 5, 10 or 20 mg/kg s.c., in the testing room. On the test day, 24 h after the last injection, mice from all conditions were challenged with saline in the testing room to test for conditioned cocaine effects. Mice were video-recorded and various behaviours were later scored using a time-sampling technique. Cocaine-elicited orofacial stereotypy was significantly sensitized at the two highest doses and dose-dependently conditioned at the three highest doses. Cocaine-increased locomotion was sensitized at the three highest doses and significantly conditioned at 10 and 20mg/kg. Cocaine-increased sniffing did not change over pretreatment at any dose, and was conditioned only at 10 mg/kg. Cocaine-decreased immobility also did not change over pretreatment at any dose, but was conditioned at 10 and 20mg/kg. Concomitantly, rearing was reduced by cocaine at 10 and 20mg/kg, without sensitization being induced, and it was reduced under saline challenge after 5 mg/kg cocaine, while cocaine-decreased grooming was sensitized at the three highest doses and conditioned at 10 and 20 mg/kg cocaine. There was a positive relation between the size of the conditioned response for orofacial stereotypy and the magnitude of the unconditioned stimulus (the doses), a result conforming to the Pavlovian account of the placebo effect. This could also be concluded from considering the behaviour patterns as components of a unique placebo effect (hyperkinetic syndrome), since orofacial stereotypy, very apparent at 20 mg/kg cocaine, interfered at that dose with the full-blown expression of locomotion and sniffing, both yielding (approximately) inverted U-shaped dose-effect curves. However, no correlation was found between the magnitude of the conditioned response and the amplitude of sensitization (the difference between the initial unconditioned non-sensitized response and the last unconditioned sensitized response), a finding which indicates that conditioned responding does not participate in the generation of the sensitized effects, contrary to the 'excitatory conditioning model of contextual sensitization'.     

Pharmacokinetics of telmisartan in healthy Chinese subjects after oral administration of two dosage levels

To study the pharmacolkinetics of telmisartan in healthy Chinese male subjects after oral administration of two dosage levels, 36 healthy subjects were divided into two groups and given a single oral dose of 40 or 80 mg telmisartan (CAS 144701-48-4, MicardisPlus). A sensitive liquid chromatography-tandem mass spectrometry method (LC-MS-MS) was used for the determination of telmisartan in plasma. Both, a non-compartmental and compartmental method were used for analysis of parameters of kinetics. The main pharmacokinetic parameters of the 40 mg and 80 mg regimen group were as follows: t(max) (1.76 +/- 1.75) h, (1.56 +/- 1.09) h, C(max) (163.2 +/- 128.4) ng/mL, (905.7 +/- 583.4) ng/mL, t1/2 (23.6 +/- 10.8) h, (23.0 +/- 6.4) h, AUC(o-t) (1456 +/- 1072) ng x h/mL, (6759 +/- 3754) ng x h/mL, AUC(o-infinity (1611 +/- 1180) ng x h/mL, (7588 +/- 4661) ng x h/mL, respectively. After dose normalization, there was significant difference for main pharmacokinetic parameters C(max) AUC(o-t) and AUC(o-infinity) between two dosage level groups. The plasma concentration-time profile of telmisartan was characterized by a high degree of inter-individual variability and the disposition of telmisartan in healthy Chinese subjects was dose-dependent. The pharmacokinetic parameters C(max) and AUC(o-inifinity) of the 80 mg regimen group increased to about 5-fold compared to that of the 40 mg regimen group, but there was no significant difference for t(max) and t1/2 between the two dose groups.     

Brief exposure to a mild stressor enhances morphine-conditioned place preference in male rats

Rationale Exposure to moderate tail shock [3, 0.75 s, 1 mA, 20 s interstimulus interval (ISI)] can enhance pain reactivity (hyperalgesia) in rats. This hyperalgesia reflects an unconditioned response that transfers across contexts and is associated with enhanced Pavlovian fear conditioning to aversive unconditioned stimuli (US). It is possible that moderate shock also enhances learning about appetitive stimuli such as a reinforcing drug.Objectives The present study examined the effect of moderate shock exposure on unconditioned psychomotor activation and appetitive conditioning using a morphine place-preference task.Methods During training, rats were given moderate shock or restraint and then received subcutaneous morphine at one of four doses (0.0, 0.2, 1.0, or 5.0 mg/kg) and were transferred to a conditioning apparatus. Five hours later, animals were given discrimination training in a different context. Animals received 2 days of training, each separated by a day of testing for preference. To test the impact of shock on psychomotor activation, subjects were given shock or restraint and one of two doses of morphine (0.0 mg/kg or 5.0 mg/kg) and placed in a box to monitor activity.Results Vehicle-treated shocked rats showed a conditioned place aversion. Subjects that received morphine showed a dose-dependent place preference that was facilitated by moderate shock exposure. Shock also enhanced the motor activation produced by morphine.Conclusions These results indicate that the affective state produced by moderate shock has a negative valence that is sufficient to support a conditioned place aversion. This state is associated with a general sensitization that enhances processing of appetitive US.     

Pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers

The objective of this study was to evaluate the pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers. The study consisted of 2 periods: period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem, and period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 400 mg carbamazepine. Between the 2 periods, the participants were treated for 15 days with a single daily dose of 400 mg carbamazepine. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using noncompartmental analysis. In the 2 periods of treatments, the mean peak plasma concentrations (C(max)) were 59 ng/mL (zolpidem alone) and 35 ng/mL (zolpidem after pretreatment with carbamazepine). The t(max), times taken to reach C(max), were 0.9 hours and 1.0 hour, respectively, and the total areas under the curve (AUC(0-∞)) were 234.9 ng·h/mL and 101.5 ng·h/mL, respectively. The half-life of zolpidem was 2.3 and 1.6 hours, respectively. Carbamazepine interacts with zolpidem in healthy volunteers and lowers its bioavailability by about 57%. The experimental data demonstrate the pharmacokinetic interaction between zolpidem and carbamazepine and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.