ABSTRACT
Ezetimibe is a novel selective inhibitor of intestinal cholesterol absorption, which has been shown to significantly decrease low-density lipoprotein cholesterol (LDL-C). In this article, the relationship between plasma ezetimibe concentrations and lowering of LDL-C is determined using Emax and regression models. Data from two phase II double-blind placebo-controlled studies (n = 232 and 177) were used in which daily doses of ezetimibe ranging from 0.25 to 10 mg were administered for 12 weeks. Ezetimibe concentrations correlated significantly with percentage change in LDL-C from baseline (%LDL-C). Reductions in %LDL-C of 10%, 15%, and 20% were achieved with concentrations in the ranges 0 to 2, 2 to 15, and > 15 ng/ml, respectively, as compared with placebo. To achieve > 15% reduction in LDL-C, patients need to maintain trough concentrations > 15 ng/ml, taking plasma concentrations as a surrogate for concentrations at the enterocyte. Based on the doses administered, the 10 mg dose had the highest likelihood of sustaining such concentrations, confirming that a daily 10 mg dose of ezetimibe is an optimal therapeutic dose in the treatment of hypercholesterolemia.
Subject(s)
Anticholesteremic Agents/blood , Anticholesteremic Agents/therapeutic use , Azetidines/blood , Azetidines/therapeutic use , Cholesterol, LDL/blood , Hypercholesterolemia/drug therapy , Adolescent , Adult , Aged , Algorithms , Anticholesteremic Agents/adverse effects , Azetidines/adverse effects , Chromatography, Liquid , Dose-Response Relationship, Drug , Ezetimibe , Female , Humans , Hypercholesterolemia/blood , Linear Models , Male , Mass Spectrometry , Middle AgedABSTRACT
BACKGROUND: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, is in clinical development for the treatment of hypercholesterolemia. It is rapidly absorbed and glucuronidated in the intestine. The parent compound and its conjugated metabolite undergo enterohepatic recirculation, resulting in multiple peaks in the plasma concentration-time profile. OBJECTIVE: The purpose of this study was to develop a population pharmacokinetic (PPK) model for ezetimibe that incorporates enterohepatic recirculation. METHODS: A population compartment model incorporating input from the gallbladder, consistent with food intake, was developed to account for enterohepatic recirculation. The amount recycled was allowed to vary within a subject and between subjects, accommodating variability in bile secretion. The data used consisted of 90 profiles from healthy subjects who received single or multiple doses of ezetimibe 10 or 20 mg. Modeling was carried out using a nonlinear mixed-effect function in the S-PLUS statistical program. RESULTS: The amount of ezetimibe recycled into the central compartment was estimated to be approximately 17% to 20% of the total amount absorbed, independent of the volume of distribution. The intersubject coefficient of variation was 46% to 80% in the absorption rate constant, 27% in the distribution phase, and approximately 50% in the volume of distribution. CONCLUSIONS: PPK models adapted for enterohepatic recirculation allowed a formal assessment of the magnitude and frequency of the enterohepatic recirculation process, and the associated intersubject and intrasubject variability in healthy subjects. The PPK approach also helped to assess the correlation between the observed maximum or minimum (24 hours postdose) concentration with the model-based area under the curve, confirming the appropriateness of the former measures as a surrogate of drug exposure for a possible correlation with pharmacodynamics.
Subject(s)
Anticholesteremic Agents/pharmacokinetics , Azetidines/pharmacokinetics , Enterohepatic Circulation , Adult , Algorithms , Anticholesteremic Agents/blood , Area Under Curve , Azetidines/blood , Ezetimibe , Female , Half-Life , Humans , Male , Models, BiologicalABSTRACT
BACKGROUND: This study quantified pharmacokinetic changes in pegylated and nonpegylated interferon alfa-2b during 48 weeks of treatment and the influences of covariates on the basis of sparsely sampled serum concentrations and activity values. Possible relationships between pharmacokinetic and pharmacodynamic variables were investigated. METHODS: Patients with chronic hepatitis C were enrolled in a clinical trial that compared the efficacy of pegylated interferon alfa-2b with interferon alfa-2b. Single blood samples were obtained from each patient at weeks 4, 12, 24, 36, and 48. Three pharmacostatistical models were developed for 2 immunoassays and 1 bioassay. RESULTS: Apparent clearance values of pegylated interferon alfa-2b and interferon alfa-2b at the end of treatment declined 33.7% and 80.0%, respectively, from their week 4 values. Bioactivity increased 41% to 58% at week 48 for different treatment groups. Changes were greatest in the first weeks of administration and diminished during the subsequent months. Body weight had a modest positive effect on clearance values and activity. Within each dose level, no significant associations were observed between pharmacokinetic variables and any pharmacodynamic variables (hepatitis C virus--RNA responses or changes in neutrophils and platelets). CONCLUSIONS: This analysis confirms earlier observations of progressive pharmacokinetic changes in the patients with hepatitis C during 48 weeks of treatment. The absence of a relationship between toxicity or efficacy variables and interferon concentration or activity (within a dose level) suggests that clinical management of patients (eg, for efficacy or to manage toxicity) should be based on clinically derived dosing guidelines rather than on serum concentration or activity criteria.
Subject(s)
Antiviral Agents/pharmacokinetics , Hepatitis C/metabolism , Interferon-alpha , Interferon-alpha/pharmacokinetics , Polyethylene Glycols , Adolescent , Adult , Aged , Algorithms , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Blood Platelets/metabolism , Chronic Disease , Female , Hepatitis C/drug therapy , Humans , Interferon alpha-2 , Interferon-alpha/adverse effects , Interferon-alpha/therapeutic use , Logistic Models , Male , Middle Aged , Models, Biological , Neutrophils/metabolism , Population , Recombinant ProteinsABSTRACT
UNLABELLED: Co-artemether is an oral tablet of artemether (20 mg) and lumefantrine (120 mg) for the treatment of falciparum malaria. Administration in the presence of mefloquine is likely, as co-artemether may be used following failure of antimalarial prophylaxis or treatment with mefloquine. OBJECTIVE: The effects on the QTc interval were compared among treatment with three doses of mefloquine (500, 250, 250 mg over 12 h) followed by six doses of co-artemether (6 x 4 tablets over 60 h) and either treatment alone. The study was performed in a randomised, double-blind, parallel group design in 14 healthy male subjects per dose group. METHODS: Electrocardiograms (ECGs) were recorded before dosing and repeatedly thereafter. The Bazett formula was used to calculate the QTc interval. The maximum and average QTc intervals for the first, third and sixth dosing intervals of co-artemether treatment were compared among treatments. Drug plasma concentrations were determined at identical times with the ECG recordings for exploratory pharmacokinetic/pharmacodynamic evaluation. RESULTS: No clinically relevant differences in the QTc interval were observed after sequential administration of mefloquine and co-artemether relative to either treatment given alone, and there were no clinically relevant study drug-related effects on the QTc interval after either treatment. Plasma drug measurements revealed adequate systemic exposure to artemether, dihydroartemisinin, lumefantrine and mefloquine, well in line with the clinical setting. No correlation between the length of the QTc interval and plasma drug concentrations was found for any of the compounds. CONCLUSIONS: Untoward effects on the QTc interval are unlikely to occur when co-artemether is administered following prophylaxis or treatment with mefloquine.
Subject(s)
Antimalarials/pharmacology , Artemisinins , Fluorenes/pharmacology , Heart/drug effects , Mefloquine/pharmacology , Sesquiterpenes/pharmacology , Adult , Antimalarials/adverse effects , Antimalarials/pharmacokinetics , Artemether , Artemether, Lumefantrine Drug Combination , Chromatography, High Pressure Liquid , Double-Blind Method , Drug Administration Schedule , Drug Combinations , Drug Interactions , Electrocardiography , Ethanolamines , Fluorenes/adverse effects , Fluorenes/pharmacokinetics , Humans , Male , Mefloquine/pharmacokinetics , Middle Aged , Sesquiterpenes/adverse effects , Sesquiterpenes/pharmacokineticsABSTRACT
Forty-two healthy subjects were randomized in a parallel three-group design trial to investigate potential electrocardiographic and pharmacokinetic interactions between the new antimalarial co-artemether, a combination of artemether and lumefantrine (both of which are predominantly metabolized through CYP3A4), and mefloquine, another antimalarial described as a substrate (and possible inhibitor) of CYP3A4. Subjects were assigned to one of the three possible treatment groups (i.e., co-artemether alone or mefloquine alone or the combination of both). The dosage was 1000 mg mefloquine (divided into three doses over 12 h) followed 12 h later by six applications of co-artemether (40 mg artemether+480 mg lumefantrine each) over 60 h. The study medications were generally well tolerated after all treatments. Concomitant administration with mefloquine caused statistically significant lower (around 30-40%) plasma concentrations of lumefantrine than when co-artemether was administered alone. Even if important, this decrease in lumefantrine exposure was considered unlikely to impact clinical efficacy given the wide therapeutic index of co-artemether and the usual high variability in lumefantrine plasma levels, mostly and more importantly influenced by food intake. However, patients should be encouraged to eat at dosing times to compensate for this decreased bioavailability. The pharmacokinetics of artemether, DHA or mefloquine were not affected. Artemether concentrations significantly decreased over doses, independently of mefloquine co-administration, while DHA concentrations slightly (not significantly) increased. Therefore, no clinically relevant risks due to pharmacokinetic drug-drug interaction are expected at the enzymatic level following co-administration of co-artemether with CYP3A4 substrates with similar affinity to that of mefloquine.
Subject(s)
Antimalarials/pharmacology , Antimalarials/pharmacokinetics , Artemisinins , Mefloquine/pharmacology , Mefloquine/pharmacokinetics , Sesquiterpenes/pharmacology , Sesquiterpenes/pharmacokinetics , Adult , Antimalarials/adverse effects , Area Under Curve , Artemether , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/biosynthesis , Double-Blind Method , Drug Interactions , Electrocardiography/drug effects , Enzyme Induction/drug effects , Heart/drug effects , Humans , Hydrocortisone/analogs & derivatives , Hydrocortisone/urine , Male , Mefloquine/adverse effects , Middle Aged , Mixed Function Oxygenases/biosynthesis , Sesquiterpenes/adverse effectsABSTRACT
The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria. Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 h. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) microgram/ml after regimen A, 9. 0 (1.1 and 19.8) microgram/ml after regimen B, and 8 (1.4 and 17.4) microgram/ml after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 microgram/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.
Subject(s)
Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Artemisinins , Ethanolamines/pharmacokinetics , Ethanolamines/therapeutic use , Fluorenes/pharmacokinetics , Fluorenes/therapeutic use , Malaria, Falciparum/drug therapy , Adult , Animals , Area Under Curve , Artemether , Biological Availability , Child , Double-Blind Method , Drug Therapy, Combination , Electrocardiography , Food-Drug Interactions , Humans , Lumefantrine , Plasmodium falciparum/isolation & purification , Prospective Studies , Sesquiterpenes/therapeutic use , Treatment OutcomeABSTRACT
The combination of artemether and lumefantrine (benflumetol) is a new and very well tolerated oral antimalarial drug effective even against multidrug-resistant falciparum malaria. The artemether component is absorbed rapidly and biotransformed to dihydroartemisinin, and both are eliminated with terminal half-lives of around 1 hour. These are very active antimalarials which give a rapid reduction in parasite biomass and consequent rapid resolution of symptoms. The lumefantrine component is absorbed variably in malaria, and is eliminated more slowly (half-life of 3 to 6 days). Absorption is very dependent on coadministration with fat, and so improves markedly with recovery from malaria. Thus artemether clears most of the infection, and the lumefantrine concentrations that remain at the end of the 3- to 5-day treatment course are responsible for eliminating the residual 100 to 10 000 parasites. The area under the curve of plasma lumefantrine concentrations versus time, or its correlate the plasma concentration on day 7. has proved an important determinant of therapeutic response. Characterisation of these pharmacokinetic-pharmacodynamic relationships provided the basis for dosage optimisation, an approach that could be applied to other antimalarial drugs.
Subject(s)
Antimalarials/pharmacology , Artemisinins , Ethanolamines/pharmacology , Ethanolamines/pharmacokinetics , Fluorenes/pharmacology , Fluorenes/pharmacokinetics , Malaria/metabolism , Plasmodium falciparum/physiology , Sesquiterpenes/pharmacokinetics , Animals , Antimalarials/administration & dosage , Antimalarials/adverse effects , Antimalarials/pharmacokinetics , Artemether , Clinical Trials as Topic , Drug Combinations , Drug Resistance, Microbial , Drug Resistance, Multiple , Ethanolamines/administration & dosage , Ethanolamines/adverse effects , Fluorenes/administration & dosage , Fluorenes/adverse effects , Food-Drug Interactions , Humans , LumefantrineABSTRACT
We review the role of cross-over trials in pharmacokinetic and pharmacodynamic studies, in particular as applied in phase I. Design and analysis considerations are covered. We also consider the use of pharmacokinetic and pharmacodynamic theories in planning cross-over trials. Finally some practical considerations are covered.
Subject(s)
Clinical Trials, Phase I as Topic/statistics & numerical data , Pharmacokinetics , Pharmacology , Biological Availability , Biometry , Cross-Over Studies , Dose-Response Relationship, Drug , Drug Interactions , Humans , Linear Models , Models, Biological , Models, Statistical , Nonlinear Dynamics , Safety , Therapeutic EquivalencyABSTRACT
Artemether-lumefantrine is a new fixed antimalarial combination effective against multidrug-resistant falciparum malaria. A prospective electrocardiographic study was conducted in 150 patients receiving artemetherlumefantrine and 50 treated with artesunate-mefloquine. There was no evidence for clinically significant changes in the electrocardiographic intervals and in particular no relationship between plasma concentrations of lumefantrine and QTc prolongation. Artemether-lumefantrine does not have significant cardiac effects at therapeutic doses.
Subject(s)
Antimalarials/pharmacology , Artemisinins , Ethanolamines/pharmacology , Fluorenes/pharmacology , Heart/drug effects , Malaria, Falciparum/drug therapy , Sesquiterpenes/pharmacology , Adolescent , Adult , Antimalarials/adverse effects , Antimalarials/blood , Artemether , Child , Child, Preschool , Drug Therapy, Combination , Electrocardiography/drug effects , Ethanolamines/adverse effects , Ethanolamines/blood , Female , Fluorenes/adverse effects , Fluorenes/blood , Humans , Lumefantrine , Male , Middle Aged , Sesquiterpenes/adverse effectsABSTRACT
AIMS: To investigate the pharmacokinetic and pharmacodynamic properties of artemether and benflumetol in a fixed combination tablet (CGP 56697) and to offer an explanation for the lower than expected cure rate in a Thai clinical trial. METHODS: Two hundred and sixty patients were enrolled into a randomized, double-blind, parallel group, dose-finding trial. CGP 56697 was given orally, either as: A, 4 x 4 tablets over 48 h; B, 4 x 2 tablets over 48 h or C, 3 x 4 tablets over 24 h. Each tablet contained artemether 20 mg amd benflumetol 120 mg. The pharmacokinetics were determined using a population-based approach combining full profiles (42 patients) and sparse data (218 patients). Parasite clearance time and 28 day cure rate were correlated with the derived pharmacokinetic parameters. RESULTS: The median absorption half-life of benflumetol was 5.3 h, with a tmax of 10 h and terminal elimination half-life of 4.5 days. For artemether (and its metabolite, dihydroartemisinin), the corresponding values were 1.9 (1.9) h, 1.8 (1.2) h, and 0.84 (0.43) h. The variability in bioavailability of artemether and dihydroartemisinin was large both between doses and between patients, but was less pronounced for benflumetol. Compared with the first dose, benflumetol bioavailability was estimated to increase three-fold by the third and fourth doses. Higher artemether or dihydroartemisinin AUC was found to decrease parasite clearance time. Higher benflumetol AUC was found to significantly increase the chance of cure. CONCLUSIONS: Using a population-based approach it was confirmed that the pharmacokinetic and pharmacodynamic properties of benflumetol and artemether differ markedly. Benflumetol AUC is associated with cure and the effect of benflumetol when coadministered with artemether is to prevent recrudescence. The mode of action of benflumetol is consistent with its longer elimination half-life. A short course of low-dose artemether, which is rapidly absorbed and has a short elimination half-life, produced effective parasite clearance. The complementary pharmacokinetic and pharmacodynamic properties of benflumetol and artemether was the main rationale for developing a fixed-dose combination. While the 4 x 4 dose regimen is very effective in most endemic areas, the poorer absorption (2.5 fold lower than in China) and the more resistant parasites in Thailand require higher doses of this drug.
Subject(s)
Antimalarials/pharmacokinetics , Artemisinins , Fluorenes/pharmacokinetics , Malaria/metabolism , Sesquiterpenes/pharmacokinetics , Adolescent , Adult , Antimalarials/pharmacology , Antimalarials/therapeutic use , Artemether , Artemether, Lumefantrine Drug Combination , Double-Blind Method , Drug Combinations , Ethanolamines/pharmacokinetics , Female , Fluorenes/pharmacology , Fluorenes/therapeutic use , Humans , Lumefantrine , Malaria/drug therapy , Male , Middle Aged , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic use , Treatment OutcomeSubject(s)
Antimalarials/blood , Ethanolamines/blood , Fluorenes/blood , Malaria, Falciparum/blood , Adolescent , Adult , Aged , Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Capillaries , Ethanolamines/pharmacokinetics , Ethanolamines/therapeutic use , Fluorenes/pharmacokinetics , Fluorenes/therapeutic use , Humans , Lumefantrine , Malaria, Falciparum/drug therapy , Middle Aged , VeinsABSTRACT
Twelve young (mean age 23 years, range 18-28) and 12 elderly (mean age 76 years, range 65-89) volunteers were given a single oral dose of 80 mg valsartan after an overnight fast. Each group consisted of six male and six female subjects. Mean systemic exposure to valsartan was higher in the elderly when compared with the young (AUC(0-24 h), 52% increase and AUC(0-infinity), 70% increase). Variability, as shown by the coefficient of variation (CV), was larger for the elderly subjects and ANOVA of the log transformed AUC showed a significant difference between the two groups. This difference was largely brought about by five elderly subjects (one male, four females), whose AUC was about 2-fold higher than the rest of the group. For the remaining elderly subjects, plasma valsartan AUC was similar to that observed for the young volunteers. This higher systemic exposure in five of the elderly subjects is not thought to be of clinical relevance when data from the patient population are considered. Other covariates--such as body weight, comedication, creatinine clearance, valsartan kinetics (absorption rate, distribution, and elimination)--did not explain the higher AUC in this subset of the elderly group. Data from the present study were compared with population kinetic data obtained from larger clinical trials including hypertensive patients in all age groups. Using this population approach, there was no difference in the pharmacokinetics of valsartan between male and female patients. Also, a relationship between plasma clearance of valsartan and age was established. The median age of patients in the hypertensive pool was 55 years. For an average 70-year-old patient, plasma clearance of valsartan is predicted to fall by 22% compared with an average 55-year-old. For the population this difference is not sufficient to warrant initial dose adjustment based on age per se. The covariate age, does not completely explain the variability in the pharmacokinetics of valsartan within the general population. The treatment was well tolerated.
Subject(s)
Aging/metabolism , Antihypertensive Agents/pharmacokinetics , Tetrazoles/pharmacokinetics , Valine/analogs & derivatives , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Aging/blood , Analysis of Variance , Antihypertensive Agents/adverse effects , Antihypertensive Agents/blood , Area Under Curve , Female , Humans , Male , Middle Aged , Tetrazoles/adverse effects , Tetrazoles/blood , Valine/adverse effects , Valine/blood , Valine/pharmacokinetics , ValsartanABSTRACT
Letrozole is a new non-steroidal inhibitor of the aromatase enzyme system. It is currently under development for the treatment of postmenopausal women with advanced breast cancer. To investigate the influence of food on the bioavailability of letrozole, 12 healthy male volunteers were treated under fed and fasted conditions with single oral doses of 2.5 mg letrozole in film-coated tablets. Plasma concentration profiles were determined. No significant difference in the extent of absorption (AUC or AUC0-8 h) was observed between the two treatments but the rate of letrozole absorption decreased slightly under fed conditions. However, in view of the half-life of about 2 d this small change in the absorption rate is not considered to be of clinical relevance for treatment with repeated administrations.
Subject(s)
Aromatase Inhibitors , Enzyme Inhibitors/pharmacokinetics , Food-Drug Interactions , Nitriles/pharmacokinetics , Triazoles/pharmacokinetics , Absorption , Administration, Oral , Adult , Analysis of Variance , Area Under Curve , Biological Availability , Cross-Over Studies , Eating , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/blood , Fasting/blood , Humans , Letrozole , Male , Nitriles/administration & dosage , Nitriles/blood , Reproducibility of Results , Tablets, Enteric-Coated , Triazoles/administration & dosage , Triazoles/bloodABSTRACT
OBJECTIVE: Bioavailability of estradiol delivered from a newly developed matrix-type transdermal therapeutic system (MTTS) was compared with that of the conventional reservoir-type system (RTTS). Both formulations have a nominal delivery rate of 50 micrograms per day of 17 beta-estradiol (E2). Plasma concentrations of E2 and estrone (E1) were determined at steady state during a 96-h application of each formulation to 34 postmenopausal volunteers, using a two-stage randomized two-period crossover design. RESULTS: The MTTS proved to be equivalent to the RTTS with respect to the extent of E2 absorption. Due to differences in patch design and composition, the rate of absorption was different between the two systems, with less fluctuating E2 plasma levels during application of the matrix system. Local tolerability and adhesion of MTTS appeared to be better than those of the reservoir system.
Subject(s)
Estradiol/pharmacokinetics , Administration, Cutaneous , Biological Availability , Cross-Over Studies , Estradiol/administration & dosage , Estradiol/adverse effects , Estrogen Replacement Therapy , Estrone/blood , Humans , Middle AgedABSTRACT
The aim of this double blind placebo-controlled cross-over study was to evaluate the effects of fadrozole, a new oral nonsteroidal aromatase inhibitor, on basal and stimulated cortisol and aldosterone secretion at a daily dosage of 4 mg given for 14 days to eight healthy men. After 2 weeks of treatment, fadrozole, compared with placebo, effectively suppressed plasma estrogen levels (P less than 0.05 at 0800 h), but did not affect glucocorticoid secretion either under basal conditions or after stimulation with ACTH. Basal plasma aldosterone levels were not significantly different with fadrozole treatment compared to those after placebo treatment. However, compared with pretreatment values, basal aldosterone secretion appeared impaired (P less than 0.05). A statistically significant blunting of the responses of plasma aldosterone to ACTH (P less than 0.01) and upright posture (P less than 0.01) after fadrozole compared with placebo treatment further indicated that fadrozole impaired basal aldosterone secretion. This attenuation of aldosterone secretion was accompanied by a rise of PRA in the basal condition (P = 0.05) and after stimulation by 40 mg furosemide (P less than 0.01) and upright posture (P less than 0.01). An increase in deoxycorticosterone was observed after fadrozole treatment compared with pretreatment values (P less than 0.01) and after stimulation with ACTH compared with placebo (P less than 0.05). This study confirms that fadrozole given in daily doses of 4 mg is an effective aromatase inhibitor which does not affect glucocorticoid secretion. However, this dose may induce an impairment of aldosterone secretion which is modest and revealed mainly under specific stimulatory conditions, and does not lead to clinical symptoms of hemodynamic dysregulation or a relevant disturbance of serum electrolytes.
Subject(s)
Aldosterone/metabolism , Estrogen Antagonists/pharmacology , Imidazoles/pharmacology , Nitriles/pharmacology , Adult , Aldosterone/blood , Cosyntropin/pharmacology , Desoxycorticosterone/blood , Double-Blind Method , Estradiol/blood , Estrone/blood , Fadrozole , Furosemide/pharmacology , Humans , Hydrocortisone/blood , Hydrocortisone/metabolism , Posture , Reference Values , Renin/bloodABSTRACT
Crossover studies have been successfully conducted in the case of continuous responses. Existing procedures of analysis for ordinal responses, on the other hand, are rarely satisfactory unless strict, usually unrealistic, assumptions are made. In this paper we investigate a random effects model and show that the model is simple and general. Interpretation of parameters is easy, though with a complicated fitting procedure.
Subject(s)
Clinical Trials as Topic/methods , Models, Statistical , Data Interpretation, Statistical , Mathematical Computing , Probability , Random AllocationABSTRACT
Ninety-seven patients with asymptomatic carotid bruits were followed up 5 to 13 years or until the occurrence of transient ischemic attacks, stroke or death. In 11% of the patients transient ischemic attacks developed and in 19%, strokes. Symptoms that developed in more than half of the patients did so within 2 years and 90% within 6 years of detection of the bruit. Seventeen of 18 strokes occurred without antecedent transient ischemic attacks. Fifty-three of the patients underwent 94 major noncarotid operations with no postoperative strokes. Death occurred in 37% of the patients during the follow-up period, and 90% of the deaths were due to cardiac problems or stroke.
Subject(s)
Carotid Artery Diseases/diagnosis , Adult , Aged , Auscultation , Cerebrovascular Disorders/epidemiology , Female , Follow-Up Studies , Humans , Ischemic Attack, Transient/epidemiology , Male , Middle Aged , Time FactorsSubject(s)
Aneurysm/etiology , Brachial Artery , Brachial Plexus , Nerve Compression Syndromes/complications , Subclavian Artery , Thromboembolism/etiology , Adult , Aged , Aneurysm/surgery , Arm/blood supply , Female , Humans , Male , Methods , Nerve Compression Syndromes/surgery , Thromboembolism/surgeryABSTRACT
Preoperative recognitiion of horseshoe or pelvic kidney with abdominal aortic aneurysm greatly facilitates proper operative care of such patients. Operative management of three reported patients varied significantly, depending on complicated and anomalous blood supply to the kidney.