Circadian variation of tacrolimus disposition in liver allograft recipients

The aim of this study was to characterize the circadian variation of oral tacrolimus disposition in 8 stable liver allograft recipients. In the steady state, a total of 23 blood samples was taken before and after tacrolimus administration during a 24-hr period and the pharmacokinetic parameters were compared. The area under the curve (AUC) of tacrolimus after the morning dose was significantly larger than after the evening dose (211+/-43 ng x hr/ml [morning] vs. 179+/-45 ng x hr/ml [evening], P=0.02). The time to peak (Tmax) was significantly shorter after the morning dose than after the evening dose (1.6+/-0.7 hr [morning] vs. 2.9+/-0.6 hr [evening], P=0.002). The peak (Cmax) was significantly higher after the morning dose than after the evening dose (32.2+/-10.2 ng/ml [morning] vs. 19.1+/-4.3 ng/ml [evening], P=0.003). However, the trough (Cmin) was not significantly different between the morning dose and the evening dose (13.1+/-3.9 ng/ml [morning] vs. 13.3+/-4.4 ng/ml [evening], P=0.4). This study demonstrated that tacrolimus disposition in liver transplant patients was determined by administration time.     

Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation

OBJECTIVE: To study the response of cortisol and of prolactin (PRL) to specific stimuli in rheumatoid arthritis (RA). METHODS: We measured the response of cortisol to insulin induced hypoglycemia and of PRL to thyrotropin releasing hormone (TRH) in 10 patients with active RA and in 10 paired control subjects. All were women with regular menstrual cycles. They had never received corticosteroids before the study. The PRL concentration was assessed by chemiluminescence immune assay and the cortisol concentration by radioimmunoassay. RESULTS: The basal serum levels of cortisol (14.47+/-2.5 microg/dl) and PRL (10.1+/-1.3 ng/ml) in the RA group were not significantly different from those of the control group (12.3+/-1.1 microg/dl and 13.7+/-2.4 ng/ml, respectively). The peak value of cortisol after hypoglycemia was comparable in both groups (25.5+/-2.4 microg/dl in RA vs. 26.0+/-1.5 ng/ml in controls). The integrated cortisol response to hypoglycemia expressed as area under the response curve (AUC) did not differ significantly in either group (1927+/-196 in RA vs. 1828+/-84 in controls). The interval-specific "delta" cortisol response was significantly higher for the 30 to 45 min interval in controls compared to patients with RA (9.8+/-0.9 microg/dl vs. 6.1+/-1.1 microg/dl; p = 0.02). The peak of PRL after TRH did not differ significantly in both groups (56.4+/-6.4 ng/ml in RA vs. 66.3+/-7.7 ng/ml in controls) and the AUC of PRL secretion after TRH was comparable in both groups (3245+/-321 vs. 4128+/-541). CONCLUSION: Our findings suggest that active RA is associated with subtle dysfunction of the hypothalamic-pituitary-adrenal glucocorticoid function and normal PRL secretion.     

Are there special considerations in the prescription of serotonin reuptake inhibitors for women?

The aim of this study was to evaluate and compare the pharmacokinetics of naftidrofuryl (CAS 3200-06-4) after single oral administration of a 200 mg naftidrofuryl tablet (Praxilene) in Caucasian male and female elderly healthy volunteers versus young healthy volunteers. Thirty healthy volunteers were included in a randomised phase I trial in 3 parallel groups of 10 subjects aged 18-35 years (group 1), 60-70 years (group 2) and 70-80 years (group 3). Blood samples were taken over a period of 24 h after dosing for evaluation of the pharmacokinetics of naftidrofuryl. The Cmax, tmax, AUC0-t parameters were measured and t1/2 and AUC0-alpha were calculated by a model independent method. The mean (+/- SD) pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl for group 1 were as follows: tmax 3.5 h (median), Cmax 284 +/- 136 ng/ml, t1/2 3.69 +/- 1.30 h, AUC0-t 1865 +/- 905 h.ng/ml and AUC0-inf 2055 +/- 901 h.ng/ml; for group 2: tmax 2.75 h (median), Cmax 282 +/- 165 ng/ml, t1/2 3.03 +/- 1.08 h, AUC0-t 1783 +/- 1147 h.ng/ml and AUC0-inf 1856 +/- 1158 h.ng/ml; for group 3: tmax 2.5 h (median), Cmax 271 +/- 86 ng/ml, t1/2 3.50 +/- 1.29 h, AUC0-t 1742 +/- 544 h.ng/ml and AUC0-inf 1834 +/- 549 h.ng/ml. Statistical analysis was performed on the pharmacokinetic parameters with one-way ANOVA in order to compare each age group. The results of the pharmacokinetic and statistical analysis showed no significant difference between each age group. The mean pharmacokinetic parameters of naftidrofuryl after single oral administration of 200 mg of naftidrofuryl in the whole population were as follows: tmax 2.75 h (median), for Cmax 279 +/- 128 ng/ml, t1/2 3.41 +/- 1.22 h, AUC0-t 1797 +/- 870 h.ng/ml for AUC0-inf 1910 +/- 877 h.ng/ml. In conclusion, advanced age did not appear to influence the pharmacokinetic profile of oral naftidrofuryl, and therefore it is not necessary to adjust the dosage of naftidrofuryl in this population.     

Phase I trial of cremophor EL with bolus doxorubicin

Cremophor EL (cremophor), a component of the paclitaxel formulation, can potentially reverse P-glycoprotein-associated multidrug resistance. A Phase I trial of cremophor as a 6-h infusion every 3 weeks was performed with bolus doxorubicin (50 mg/m2). The cremophor dose was escalated from 1 to 60 ml/m2. A standard paclitaxel premedication was given before cremophor. Using a bioassay, potentially active cremophor levels (> or = 1 microl/ml) were measured in plasma from patients receiving cremophor doses of 30, 45, and 60 ml/m2. A cross-over design was used to assess the influence of cremophor 30 ml/m2 on the pharmacokinetics of doxorubicin and doxorubicinol. The plasma area under the concentration versus time curve (AUC) of doxorubicin increased from 1448 +/- 350 to 1786 +/- 264 ng/ml x h (P = 0.02) in the presence of cremophor, whereas the AUC of doxorubicinol increased from 252 +/- 104 to 486 +/- 107 ng/ml x h (P = 0.02). This pharmacokinetic interaction was associated with significantly increased neutropenia. With reduction of the doxorubicin dose to 35 mg/m2, the cremophor dose was increased to 60 ml/m2. Dose-limiting toxicities occurred in two of six patients after 45 ml/m2 and two of four patients after 60 ml/m2, which included febrile neutropenia and grade III cremophor-related toxicities of rash, pruritus, headache, and hypotension. All patients who received 45 ml/m2 cremophor reached plasma levels > or = 1.5 microl/ml, but at 60 ml/m2, only two of four reached this level, and the calculated plasma clearance of cremophor was significantly faster at this dose. One patient with hepatoma resistant to epirubicin achieved a near-complete response. Cremophor 45 ml/m2 over 6 h with 35 mg/m2 doxorubicin is recommended for further studies. The pharmacokinetic interaction between cremophor and doxorubicin is quantitatively similar to that described in trials of paclitaxel with doxorubicin and suggests that the cremophor in the paclitaxel formulation is responsible.     

Long-term cyclosporin A pharmacokinetic profiles in pediatric renal transplant recipients

To study the long-term effect of cyclosporin A (CyA), 94 6-h and 29 12-h pharmacokinetic profiles were evaluated in 32 children at least 1 year after renal transplantation. Children weighing less than 25 kg needed significantly higher doses of CyA than those weighing more than 25 kg (9.8 vs 5.3 mg/kg per day; P < 0.001) to achieve similar trough levels (TL). The average dose of CyA required to achieve the target TL declined gradually with time after transplantation. The average area under the curve over 6 h (AUC/6) correlated strongly with the AUC/12 (r = 0.967; P < 0.001). The AUC/6 of patients with biopsy-proven CyA toxicity was significantly higher than for those without toxicity (Mann-Whitney U-test P < 0.05) despite similar TL. We conclude that AUC monitoring for 6 h provides valuable information not only on TL but also on the absorption and elimination characteristics of CyA as well as on the potential for CyA toxicity.     

Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206 +/- 70 ml/hr/kg) was significantly slower with a smaller volume of distribution (0.95 +/- 0.32 L/kg) when compared with the white group (327 +/- 129 ml/hr/kg, P = 0.03; volume of distribution = 1.33 +/- 0.27 L/kg, P = 0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732 +/- 443 ng.hr/ml in blacks and 539 +/- 361 ng.hr/ml in whites (P = 0.17, black vs. white). The mean cortisol suppression half-life was 4.31 +/- 1.54 hr in black recipients and 4.11 +/- 1.49 hr in whites (P = 0.48). The mean return cortisol AUC for the black patients was 327 +/- 279 ng.hr/ml and 370 +/- 207 ng.hr/ml for white patients (P = 0.28). The serum cortisol nadir for black patients was 12.3 +/- 7.2 ng/ml, which was significantly higher than the cortisol nadir in white patients (6.4 +/- 4.4 ng/ml; P = 0.03). A majority (94%) of patients (9 black, 8 white) had moon facies and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 of 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had higher cortisol AUCs with lower methylprednisolone clearances than the white group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Intensive training and cardiac autonomic control in high level athletes

The bioavailability of propranolol depends on the degree of liver metabolism. Orally but not intravenously administered propranolol is heavily metabolized. In the present study we assessed the pharmacokinetics and pharmacodynamics of sublingual propranolol. Fourteen severely hypertensive patients (diastolic blood pressure (DBP) > or = 115 mmHg), aged 40 to 66 years, were randomly chosen to receive a single dose of 40 mg propranolol hydrochloride by sublingual or peroral administration. Systolic (SBP) and diastolic (DBP) blood pressures, heart rate (HR) for pharmacodynamics and blood samples for noncompartmental pharmacokinetics were obtained at baseline and at 10, 20, 30, 60 and 120 min after the single dose. Significant reductions in BP and HR were obtained, but differences in these parameters were not observed when sublingual and peroral administrations were compared as follows: SBP (17 vs 18%, P = NS), DBP (14 vs 8%, P = NS) and HR (22 vs 28%, P = NS), respectively. The pharmacokinetic parameters obtained after sublingual or peroral drug administration were: peak plasma concentration (CMAX): 147 +/- 72 vs 41 +/- 12 ng/ml, P < 0.05; time to reach CMAX (TMAX): 34 +/- 18 vs 52 +/- 11 min, P < 0.05; biological half-life (t1/2b): 0.91 +/- 0.54 vs 2.41 +/- 1.16 h, P < 0.05; area under the curve (AUCT): 245 +/- 134 vs 79 +/- 54 ng h-1 ml-1, P < 0.05; total body clearance (CLT/F): 44 +/- 23 vs 26 +/- 12 ml min-1 kg-1, P = NS. Systemic availability measured by the AUCT ratio indicates that extension of bioavailability was increased 3 times by the sublingual route. Mouth paresthesia was the main adverse effect observed after sublingual administration. Sublingual propranolol administration showed a better pharmacokinetic profile and this route of administration may be an alternative for intravenous or oral administration.     

Alterations in growth and body composition during puberty: III. Influence of maturation, gender, body composition, fat distribution, aerobic fitness, and energy expenditure on nocturnal growth hormone release

We examined the relationships among gender, sexual maturation, four-compartment model estimates of body composition, body fat distribution (magnetic resonance imaging for abdominal visceral fat and anthropometrics), aerobic fitness, basal and total energy expenditure, and overnight GH release in an ultrasensitive chemiluminescence assay in healthy prepubertal and pubertal boys (n = 18 and 11, respectively) and girls (n = 12 and 18, respectively). Blood samples were withdrawn every 10 min from 1800-0600 h to determine the area under the serum GH-time curve (AUC), sum of the GH peak heights (sigma GH peak heights), and the mean nadir GH concentration. GH release was greater in the pubertal than prepubertal subjects due to an increase in sigma GH peak heights (43.8 +/- 3.6 vs. 24.1 +/- 3.5 ng.mL-1, P = 0.0002) and mean nadir (1.7 +/- 0.2 vs. 0.7 +/- 0.2 ng.mL-1, P = 0.0002), but not peak number (4.3 +/- 0.2 vs. 4.5 +/- 0.2). The girls had a greater sigma GH peak heights (39.0 +/- 3.5 vs. 28.8 +/- 3.6 ng.mL-1, P = 0.05) and mean nadir concentration (1.4 +/- 0.2 vs. 0.9 +/- 0.2 ng.mL-1, P = 0.05) than the boys. Significant inverse relationships existed between sigma GH peak heights (r = -0.35, P = 0.06) or mean nadir (r = -0.39, P = 0.04) and four-compartment percent body fat for all boys but not for all girls or when combining all subjects. For all girls, significant inverse relationships existed between sigma GH peak heights (r = -0.39, P = 0.03) or mean nadir (r = -0.37, P = 0.04) and waist/hip ratio. Similar inverse relationships in all boys or all subjects were not significant. Forward stepwise regression analysis determined that bone age (i.e. maturation, primary factor) and gender were the significant predictors of AUC, sigma GH peak heights, and mean nadir. The influence of maturation reflects rising sex steroid concentrations, and the gender differences appear to be because of differences in estradiol concentrations rather than to body composition or body fat distribution.     

Cholecystokinin-8 regulation of NGF concentrations in adult mouse brain through a mechanism involving CCK(A) and CCK(B) receptors

STUDY OBJECTIVE: To assess the potential for a drug-drug interaction between valspodar, a P-glycoprotein (mdrl) 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 Cmax,b (2.3+/-0.4 vs 2.4+/-0.5 microg/ml) and AUCb (19.8+/-4.8 vs 19.6+/-4.9 microg x 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 (Cmax 88+/-23 vs 91+/-20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400+/-87 vs 494+/-90 ng x hr/ml). Regression analysis of valspodar Cmax,b and AUCb 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.     

Important microsatellite markers in the investigation of replication errors (RER) in colorectal carcinomas

PURPOSE: Our purpose was to assess the value of monitoring serum P and inhibin A to determine how values might improve the clinical monitoring of natural cycle in vitro fertilization (IVF)-embryo transfer (ET) patients. METHODS: All patients (n = 26) who underwent natural-cycle IVF-ET (n = 35) were analyzed. Groups were evaluated according to patients who had a spontaneous luteinizing hormone (LH) surge (group I) and women receiving human chorionic gonadotropin (hCG) who underwent subsequent oocyte aspiration (group II). Group II was further evaluated according to women who did (n = 10) and did not (n = 7) have an ET. All cycles were evaluated with serial transvaginal ultrasonography and serum estradiol, progesterone, and inhibin A. When follicle maturity was achieved, hCG, 10,000 IU, was administered intramuscularly if a LH surge was not detected. Transvaginal ultrasound-guided aspiration was performed 34-36 hr after hCG administration followed by a 48-hr transcervical ET. RESULTS: No differences were seen in cycles the day prior to (d-1) and the day of a spontaneous LH surge, (n = 18) or hCG (d-0)(n = 17) in group I or group II with respect to lead follicular diameter (d-1, 15.3 +/- 0.6 vs. 14.2 +/- 0.9 mm; d-0, 17.4 +/- 0.8 vs. 17.8 +/- 0.6 mm) and serum estradiol (d-1, 148 +/- 15 vs. 150 +/- 15 pg/ml; d-0, 218 +/- 15 vs. 199 +/- 16 pg/ml), respectively. However, serum progesterone was significantly elevated in group I compared with group II on d-1 (0.82 +/- 0.6 vs. 0.48 +/- 0.04 ng/ml; P < 0.05) and d-0 (1.1 +/- 0.12 vs. 0.63 +/- 0.08 ng/ml; P < 0.05). Inhibin A was significantly greater on d-1 in group I (24 +/- 2.5 vs. 15 +/- 2.2 pg/ml; P < 0.05). In group II, cycles that resulted in an ET (n = 10) compared with group II cycles that did not (n = 7) revealed a significant difference in serum progesterone (0.51 +/- 0.05 vs. 0.7 +/- 0.07 ng/ml; P < 0.05) and inhibin A (15 +/- 2.5 vs. 37.3 +/- 5 pg/ml; P < 0.05) the day of hCG. CONCLUSIONS: The possible application of serum progesterone and inhibin A in managing natural-cycle IVF-ET is suggested. These assays may predict women who should be set up for egg retrieval, while cancelling others in spite of the absence of an LH surge.     

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.     

Effect of supplemental oxygen on supramaximal exercise performance and recovery in cystic fibrosis

The effects of supplemental O2 on recovery from supramaximal exercise and subsequent performance remain unknown. If recovery from exercise could be enhanced in individuals with chronic lung disease, subsequent supramaximal exercise performance could also be improved. Recovery from supramaximal exercise and subsequent supramaximal exercise performance were assessed after 10 min of breathing 100% O2 or room air (RA) in 17 cystic fibrosis (CF) patients [25 +/- 10 (SD) yr old, 53% men, forced expired volume in 1 s = 62 +/- 21% predicted] and 17 normal subjects (25 +/- 8 yr old, 59% men, forced expired volume in 1 s = 112 +/- 15% predicted). Supramaximal performance was assessed as the work of sustained bicycling at a load of 130% of the maximum load achieved during a graded maximal exercise. Peak minute ventilation (VE) and heart rate (HR) were lower in CF patients at the end of each supramaximal bout than in controls. In CF patients, single-exponential time decay constants indicated faster recovery of HR (tau HR = 86 +/- 8 and 73 +/- 6 s in RA and O2, respectively, P < 0.01). Similarly, fast and slow time constants of two-exponential equations providing the best fit for ventilatory recovery were improved in CF patients during O2 breathing (tau 1VE = 132.1 +/- 10.5 vs. 82.5 +/- 10.4 s; tau 2VE = 880.3 +/- 300.1 vs. 368.6 +/- 107.1 s, P < 0.01). However, no such improvements occurred in controls. Supramaximal performance after O2 improved in CF patients (109 +/- 6% of the 1st bout after O2 vs. 94 +/- 6% in RA, P < 0.01). O2 supplementation had no effect on subsequent performance in controls (97 +/- 3% in O2 vs. 93 +/- 3% in RA). We conclude that supplemental O2 after a short bout of supramaximal exercise accelerates recovery and preserves subsequent supramaximal performance in patients with CF.     

Dysregulation of the hypothalamo-pituitary axis in rheumatoid arthritis

OBJECTIVE: To study the dynamic response of the hypothalamo-pituitary- adrenal axis and of prolactin (PRL) pituitary secretion in rheumatoid arthritis (RA). METHODS: We performed a cortisol releasing hormone (CRH) provocation test followed by determination of adrenocorticotropin hormone (ACTH), beta-endorphin, and cortisol concentration, and then a thyrotropin releasing hormone (TRH) provocation test followed by assessment of PRL pituitary secretion in 10 patients with RA and 5 control subjects. All were women under 40 years of age. Hormone concentrations were assessed by radioimmunoassay. RESULTS: Basal PRL cortisol, and ACTH concentrations were similar in patients with RA and controls. We observed a dissociation between the pituitary secretion of beta-endorphin and of ACTH in response to CRH in RA. The ACTH peak and total ACTH production (area under the curve, AUC) were similar in the 2 groups. In contrast, basal beta-endorphin was increased in RA (12.6 +/- 1.41 vs 8.29 +/- 0.144 pg/ml), and the response upregulated (AUC: 83,080 +/- 12,000 vs 54,200 +/- 2400) after CRH compared to controls (p < 0.05). Cortisol adrenal response curve was blunted, but did not reach statistical significance. In contrast, the PRL response to TRH was increased at 120 and 150 min (3461 +/- 303 vs 1897 +/- 520 muIU/ml)(p < 0.01) in patients with RA, independent of disease activity. CONCLUSION: We observed upregulated pituitary PRL secretion in RA, and a dissociation of ACTH stress. The implication concerning the neuroendocrine system in the chronic immune response in RA is discussed.     

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.     

Serial prognostic capabilities of electrocardiographic indices of infarcted and hibernating myocardium in predicting short- and long-term outcome following coronary artery bypass surgery

Concentrations and ex vivo production of interleukin 1 beta (IL-1), tumour necrosis alpha (TNF), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA) and TNF soluble receptors (sTNF-receptors, P55 and P75) were measured in bronchoalveolar lavage (BAL) fluid and blood in 23 HIV-seropositive (HIV+) patients with Pneumocystis carinii pneumonia (PCP) and compared with values found in healthy HIV-seronegative (HIV-) controls and asymptomatic HIV+ subjects. Concentrations of the proinflammatory cytokine IL-1 beta were increased in BAL fluid of HIV+ patients with PCP (184 +/- 47 pg mL-1) compared with undetectable levels in healthy control subjects (P = 0.0001). In plasma of these patients higher concentrations of the anti-inflammatory cytokine IL-1RA were found during acute PCP than after recovery (2.1 +/- 0.7 vs. 0.5 +/- 0.2 ng mL-1, P = 0.01). No correlations could be found between cytokine concentrations and clinical severity of the infection. Corticosteroid treatment did not influence cytokine concentrations in BAL or blood, nor did it suppress the production in alveolar cells. In whole-blood cultures, however, lipopolysaccharide (LPS)-stimulated production was significantly suppressed for IL-1 (1.3 vs. 5.5 ng mL-1, P = 0.009) and for IL-6 (0.6 vs. 2.5 ng mL-1, P = 0.01). The overall data show that in HIV+ patients with PCP (similar to what we had found previously in HIV-patients with PCP) proinflammatory cytokines are more prominently present in BAL, whereas anti-inflammatory reaction is predominant in the circulation.     

Detection of the change point in oxygen uptake during an incremental exercise test using recursive residuals: relationship to the plasma lactate accumulation and blood acid base balance

BACKGROUND: Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents. METHODS: This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers, with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin, (2) administration of a single dose of 20 mg pravastatin, (3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks. RESULTS: Diltiazem significantly (P < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 +/- 1525 ng/ml/min (mean +/- SD) to 12886 +/- 6558 ng/ml/min and maximum serum concentration (Cmax) from 6 +/- 2 to 26 +/- 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, Cmax, or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 +/- 58 ng/ml) and pravastatin (110 +/- 30 ng/ml) study arms. CONCLUSION: Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.     

Comparative study of the effects of ouabain and digoxin on blood pressure of rats

OBJECTIVE: To compare the effect of ouabain on the blood pressure of rats with that of digoxin to find the evidences of the relationship between endogenous ouabain (EO) and development of hypertension. METHODS: Sprague-Dawley rats, which were divided into 3 groups, were infused with ouabain (23 x 75 micrograms.kg-1/day, i.p.), digoxin (36 x 84 micrograms.kg-1/day, i.p.) and normal saline (NS) once a day respectively. Systolic blood pressure and body weight were recorded weekly. Five weeks later, rats of ouabain group were randomly assigned to three infusion subgroups: Oc group, continued with ouabain infusion; Od group, added digoxin (73 x 68 micrograms.kg-1/day, i.p.) and Os group, stopped administration of ouabain. Another week later, direct blood pressure was recorded in aorta. Systolic and diastolic cardiac function, plasma renin activity and aldosterone levels of all the rats were measured. RESULTS: After a latent period of one week, blood pressure of Ouabain group increased significantly [95.4 +/- 11.8 mmHg (1 mmHg = 0.133 kPa) at the beginning of the experiment vs 122.5 +/- 16.9 mmHg at the end of week 6, P < 0.05] with normal plasma renin activity and higher aldosterone (1.28 +/- 0.45 ng/ml vs 0.69 +/- 0.27 ng/ml, P < 0.05). The blood pressure decreased after either withdrawal of ouabain or addition of digoxin (116.3 +/- 14.4 mmHg vs 100 +/- 10.7 mmHg, P < 0.05; 123.9 +/- 13.9 vs 103.3 +/- 10.5 mmHg, P < 0.05, respectively). No difference of blood pressure was found between the digoxin and NS group. CONCLUSIONS: Our results suggested that EO might be one of the causes of the development of hypertension. Aldosterone might play some role in the mechanism of ouabain-induced hypertension. Digoxin can not induce hypertension. There is a great difference between the effect of ouabain and digoxin on the blood pressure. Moreover, digoxin can reverse the hypertension induced by ouabain.     

Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: results of a double-blind placebo-controlled study with open follow-up

It is known that GH stimulates bone turnover and that GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4 IU daily) in 20 patients for 6 months and an extended open study of 6 to 12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 +/- 0.02 vs 2.32 +/- 0.02 mmol/l, P = 0.037) and phosphate (0.97 +/- 0.06 vs 0.75 +/- 0.05 mmol/l, P = 0.011) increased and the index of phosphate excretion (0.03 +/- 0.03 vs 0.19 +/- 0.02, P < 0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 +/- 11.8 vs 17.4 +/- 1.8 ng/ml, P < 0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 +/- 26.4 vs 124.0 +/- 15.5 ng/ml, P = 0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 +/- 1.2 vs 3.3 +/- 0.5 ng/ml, P < 0.001; urinary hydroxyproline, 0.035 +/- 0.006 vs 0.018 +/- 0.002 mg/100 ml glomerular filtration rate, P = 0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306 +/- 45.3 vs 88.7 +/- 22.5 ng/ml, P < 0.001). An analysis of the data compiled from 18 patients treated with rhGH for 12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 +/- 0.058 vs 1.133 +/- 0.046 g/cm2, P = 0.015), femoral neck (1.009 +/- 0.051 vs 0.936 +/- 0.034 g/cm2, P = 0.004), Ward's triangle (0.881 +/- 0.055 vs 0.816 +/- 0.04 g/cm2, P = 0.019) and the trochanteric region (0.869 +/- 0.046 vs 0.801 +/- 0.033 g/cm2, P = 0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P = 0.030, and femoral neck 9.7 vs 4.2%, P = 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months. BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.     

Oral ganciclovir dosing in transplant recipients and dialysis patients based on renal function

BACKGROUND: An oral formulation of ganciclovir (GCV) was recently approved for the prevention of cytomegalovirus disease in solid organ transplant recipients. This study was designed to determine the bioavailability of GCV and to test a dosing algorithm in transplant and dialysis patients with different levels of renal function. METHODS: Pharmacokinetic studies were carried out in 23 patients who were either a recipient of an organ transplant or on hemodialysis. Drug dosing was established by the following algorithm based on calculated creatinine clearance (CrCl): CrCl = [(140-age) x body weight]/(72 x Cr) x 0.85 for women that is, CrCl >50 ml/min, 1000 mg every 8 hr; CrCl of 25-50 ml/min, 1000 mg every 24 hr; CrCl of 10-24 ml/ min, 500 mg every day; CrCl < 10 ml/min (or on dialysis), 500 mg every other day after dialysis. GCV was taken within 30 min after a meal. The patients received oral GCV for between 12 days and 14 weeks. Serum specimens (or plasma from patients on hemodialysis) obtained at steady state were analyzed for GCV concentrations by high-performance liquid chromatography. In nine of the transplant recipients, absolute bioavailability was determined by comparing GCV levels after single oral and intravenous doses of GCV. RESULTS: The following GCV concentrations (mean +/-SD) were determined: with CrCl of > or =70 ml/min, the minimum steady-state concentration (Cmin) and maximum concentration (Cmax) were 0.78+/-0.46 microg/ml and 1.42+/-0.37 microg/ml, respectively, with a 24-hr area under the concentration time curve (AUC0-24) of 24.7+/-7.8 microg x hr/ml; with CrCl of 50-69 ml/min, the Cmin and Cmax were 1.93+/-0.48 and 2.57+/-0.39 microg/ml, respectively, with an AUC0-24 of 52.1+/-10.1 microg x hr/ml; with CrCl of 25-50 ml/min, the Cmin and Cmax were 0.41+/-0.27 and 1.17+/-0.32 microg/ml, respectively, with an AUC0-24 of 14.6+/-7.4 microg x hr/ml. For one patient with a CrCl of 23.8 ml/min, the Cmin and Cmax were 0.32 and 0.7 microg/ml, respectively, with an AUC0-24 of 10.7 microg x hr/ml. With CrCl of <10 ml/min, the mean Cmin and Cmax were 0.75+/-0.42 and 1.59+/-0.55 microg/ml, respectively, with a mean AUC0-24 of 64.6+/-18.8 microg x hr/ml. Absolute bioavailability, for the nine patients so analyzed, was 7.2+/-2.4%. For those patients with end-stage renal failure, GCV concentrations fell during dialysis from a mean of 1.47+/-0.48 microg/ml before dialysis to 0.69+/-0.38 microg/ml after dialysis. CONCLUSIONS: The bioavailability of oral GCV in transplant patients was similar to that observed in human immunodeficiency virus-infected patients. However, levels between 0.5 and 1 microg/ml (within the IC50 of most cytomegalovirus isolates) could be achieved with tolerable oral doses. The proposed dosing algorithm resulted in adequate levels for patients with CrCl greater than 50 ml/min and for patients on dialysis. For patients with CrCl between 10 and 50 ml/min, the levels achieved were low and these patients would likely benefit from increased doses.     

Cyclosporine therapy after cardiac transplantation causes hypertension and renal vasoconstriction without sympathetic activation

BACKGROUND: Hypertension frequently complicates the use of cyclosporine A (CyA) therapy, and it has been suggested that sympathoexcitation may be the underlying mechanism in this form of hypertension. METHODS AND RESULTS: To further investigate the possibility of a neurogenic mechanism for this hypertensive effect, we studied the effects of CyA on renal blood flow (n = 11), forearm blood flow (n = 8), and sympathetic nervous system activity, assessed by renal and whole-body radiolabeled norepinephrine plasma kinetics and muscle sympathetic nerve firing (using microneurography) in cardiac transplant recipients receiving CyA and a reference group of healthy age-matched control subjects (n = 17). In 11 cardiac transplant patients (2 hours after cyclosporine dose), renal blood flow was significantly lower than that in 8 control subjects (680 +/- 88 vs 1285 +/- 58 mL/min, P < .001). In 5 of these transplant patients, renal blood flow was measured before and for 2 hours after oral cyclosporine and fell progressively over this period, by 37% (P < .01). Total body and renal norepinephrine spillover rates in transplant patients were similar to those in control subjects (3070 +/- 538 vs 2618 +/- 313 pmol/min and 579 +/- 124 vs 573 +/- 95 pmol/min, respectively), and there was no progressive effect in the 2 hours after cyclosporine dosing. Forearm blood flow was increased 2 hours after CyA administration (1.74 +/- 0.31 to 3.12 +/- 0.50 mL x 100 mL-1 x min-1, P < .001), whereas mean arterial blood pressure and noninvasively determined cardiac output (indirect Fick method) were unchanged. Muscle sympathetic nerve discharge rates recorded in 6 of these transplant patients were not different from those in 9 healthy control subjects (37.9 +/- 10.1 vs 41.3 +/- 2.3 bursts per 100 beats per minute). During 90 to 120 minutes of recording after cyclosporine dosing, nerve firing rates remained unchanged. CONCLUSIONS: CyA therapy causes acute renal vasoconstriction without accompanying systemic hemodynamic effects. These renal effects are nonneural, not being attributable to sympathoexcitation.