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Biomedical subjects

M B Regazzi

Publications and source records attributed to M B Regazzi.

At least 55 records · Page 3Linked to original sources
PubMed1995

Efficacy and pharmacokinetics of simvastatin in heart transplant recipients.

OBJECTIVE: To evaluate the efficacy and safety of simvastatin administered to a group of heart transplant patients receiving triple-drug immunosuppressive therapy. We also assessed the potential pharmacokinetic interaction between simvastatin and cyclosporine by comparing mean plasma concentrations of simvastatin beta-hydroxy acid, the major metabolite of the drug, in a group of heart transplant patients treated with cyclosporine and in a control group of patients who had not received heart transplants. Both groups received long-term (> 6 wk) simvastatin therapy. DESIGN: We monitored hyperlipidemia in 20 hypercholesterolemic heart transplant patients receiving simvastatin 10 mg/d and triple-drug immunosuppressive therapy. Changes in laboratory results before and after 4 months of simvastatin therapy were considered. The same laboratory data were monitored in a control group of 20 nonhypercholesterolemic heart transplant patients who were not treated with simvastatin but were receiving triple-drug immunosuppressive therapy. Plasma concentrations of simvastatin beta-hydroxy acid were measured in 14 hypercholesterolemic patients, 7 of whom had received heart transplants and 7 who had not. SETTING: The Division of Cardiology and the First Medical Clinic for the clinical study, as well as the Department of Pharmacology for the pharmacokinetic analysis. PARTICIPANTS: Forty heart transplant patients and 7 hypercholesterolemic nontransplant patients. MAIN OUTCOME MEASURES: Effectiveness of simvastatin was determined by comparing cholesterol and lipoprotein plasma concentrations in 20 patients who underwent heart transplant and were treated with simvastatin for 4 months. The safety of the drug was determined by analyzing changes in laboratory results in the treated group and in the control group, both those who had received heart transplants and those who had received immunosuppressive therapy. RESULTS: After 4 months of simvastatin therapy, total cholesterol decreased by 12.5% and low-density lipoprotein cholesterol decreased by 21.3%. The only statistically significant laboratory change was an increase of 28.7% in the alanine aminotransferase concentrations. Plasma concentrations of simvastatin beta-hydroxy acid were higher in heart transplant patients than in those who had not received heart transplants, the control group. CONCLUSIONS: Low-dosage simvastatin treatment seems to be safe and sufficiently effective to decrease cholesterol concentrations. Concomitant treatment with immunosuppressive therapy (primarily cyclosporine) in heart transplant patients appeared to cause a reduced metabolic clearance of simvastatin from the plasma. More extensive studies on the interaction between simvastatin and cyclosporine are needed to understand the marked variability found in the response to simvastatin.

Adult↗
PubMed1994

Once daily felodipine in preventing ergonovine-induced myocardial ischaemia in Prinzmetal's variant angina.

The efficacy of extended-release felodipine in preventing ergonovine-induced myocardial ischaemia was assessed in 14 patients (12 male, two female, aged 56 +/- 7 years) with Prinzmetal's variant angina. Four of the patients had normal coronary arteries, eight had one-vessel and two had two-vessel disease. The ergonovine test was performed once in basal conditions and twice 5 days after beginning the oral administration of felodipine 20 mg o.d., 4 and 24 h after the last administration. During a continuous 6-lead ECG recording, ergonovine was injected at doses of 25, 50, 100, 200, and 400 micrograms at 5 min intervals. Blood samples for felodipine plasma concentrations were drawn at the time of the tests. The basal ergonovine test was positive in all 14 patients (seven with anterior and seven with inferior ST segment elevation > 0.1 mV) at a mean ergonovine dose of 162 +/- 138 micrograms. The test was repeated 4 h after the last felodipine administration and was negative in 13 patients (93%), but 24 h after the last drug administration, eight patients (57%) had a positive test response (five with anterior, three with inferior ST segment elevation) at a higher ergonovine dose than at baseline (150 vs 97 micrograms, P = 0.042). The only differences between patients with a negative and a positive test were the mean values of the left ventricular end-diastolic pressure (9.3 vs 14.9 mmHg, P = 0.002) and the ergonovine doses used in the baseline tests (250 vs 97 micrograms, P = 0.034).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

High-performance liquid chromatography determination of pravastatin in plasma.

Pravastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that reduces plasma cholesterol levels. Some analytical methods have been described for determination of pravastatin levels in biological fluids, but these methods are rather cumbersome and involve expensive specialized equipment, usually not available in a clinical setting. A new technique, reversed-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection capability, has been developed for the analytical determination of pravastatin in plasma. Extraction and sample clean-up procedures are simple and rapid to execute, yet yield chromatograms virtually free of interference from endogenous plasma constituents and other antihypercholesterolemic agents or drugs usually taken concomitantly with pravastatin. Our detection limit for pravastatin was 2 ng/ml. Standard curves were linear between 5 and 200 ng/ml, with a coefficient of variation (CV) of < 10% at the limits of quantitation. This method was used to study pravastatin plasma levels in two hypercholesterolemic heart-transplant recipients and two hypercholesterolemic nontransplanted patients. We conclude that the method reported here would be ideal for therapeutic pravastatin monitoring in patients.

Chromatography, High Pressure Liquid↗
PubMed1994

Evaluation of two buflomedil tablet formulations in patients with atherosclerotic disease.

The bioequivalence of a 600-mg methocel tablet containing buflomedil hydrochloride in sustained-release form was determined relative to a 300-mg CAP/carbovax-coated tablet of buflomedil hydrochloride in immediate-release form. The tablets were given to 20 patients in a double-blind placebo-controlled clinical study with cross-over between the administration plans. The 300-mg tablets were given b.i.d., at 8 a.m. and 8 p.m. while the 600-mg tablets were taken once a day at 8 a.m. (+placebo at 8 p.m.). Plasma samples were collected at appropriate times up to 24 h after administration and were analyzed for buflomedil with a validated high-performance liquid chromatographic procedure. Results showed an overall significant mean difference in absorption rate between the two formulations. The mean tmax (5.5 +/- 3.5 h) for the 600-mg tablet was longer (P < 0.001) than the tmax value (1.8 +/- 0.8 h) seen after administration of the first 300-mg tablet. Analysis of AUC(O-infinity) values indicated that the sustained-release preparation (32.1 +/- 20.7 micrograms/ml h) was not significantly different from the 300-mg tablet b.i.d. (28.7 +/- 16.0 micrograms/ml h). Furthermore, it was seen that single administration of a 600-mg sustained-release tablet of buflomedil hydrochloride delivered the same amount of total drug as a 300-mg tablet given twice a day.

Aged↗
PubMed1994

Busulfan.

OBJECTIVE: To review the current published studies evaluating the pharmacokinetics, clinical efficacy, safety, and toxicity of busulfan in pediatric and adult patients. DATA SOURCES: English-language literature published between 1953 and 1993 was analyzed; pertinent literature was reviewed. STUDY SELECTION: Emphasis was placed on pharmacologic studies and clinical trials involving busulfan therapy both in myeloproliferative disorders and in conditioning regimens for autologous or allogeneic bone marrow transplantation. DATA EXTRACTION: Data from both pediatric and adult studies were evaluated; emphasis was placed on the relationship between plasma concentrations of busulfan and its efficacy and toxicity. DATA SYNTHESIS: Busulfan has been used widely at conventional dosages (1-12 mg/d) for the treatment of patients with chronic myelogenous leukemia (CML). Busulfan at high doses (usually 16 mg/kg) given with other cytotoxic drugs (especially cyclophosphamide) is a common preparative regimen in patients undergoing allogeneic or autologous bone marrow transplantation (BMT) for acute or chronic leukemia and other nonmalignant disorders (e.g., hemoglobinopathies, inborn error of immune system, congenital metabolic disorders). Pharmacokinetics of high-dose busulfan are age-dependent. Busulfan systemic exposure and, thus, tissue and tumor exposure are lower in children than with adults. Relationships between toxicity (principally neutropenia, hepatic veno-occlusive disease, incidence of seizures) and drug exposure were found for busulfan. CONCLUSIONS: Busulfan is a useful, sufficiently safe drug in the treatment of patients with CML. At higher dosages, busulfan is a fundamental part of myeloablative therapies for patients undergoing BMT. As the pharmacokinetics and metabolism of busulfan is further understood, there is great potential for improving treatment outcome. An assessment of maximal tolerated exposure determined by therapeutic drug monitoring may decrease the incidence and lethality of regimen-related toxicities.

Age Factors↗
PubMed1993

Disposition of high-dose busulfan in pediatric patients undergoing bone marrow transplantation.

We studied the pharmacokinetics of busulfan (16 mg/kg) in 16 pediatric patients affected by malignant and nonmalignant disorders between 6 months and 19 years of age (mean +/- SD, 5.7 +/- 6.5 years) who were undergoing allogenic (15 patients) and autologous (one patient) bone marrow transplantation. In all children, the conditioning regimen consisted of busulfan given orally at a dose of 1 mg/kg every 6 hours for 16 doses (total dose, 16 mg/kg), associated with other drugs. The pharmacokinetics of busulfan was studied during the 6-hour dosing interval on the third day of therapy by use of a high-performance liquid chromatographic assay. The value for the time to reach maximum concentration, expressed as mean +/- SD, was 1.1 +/- 0.5 hour; maximum concentration was 609.6 +/- 225.3 ng/ml; steady-state concentration was 358.9 +/- 135.5 ng/ml; area under the plasma concentration-time curve was 2153.6 +/- 813.1 ng.hr/ml; oral clearance was 0.535 +/- 0.226 L/hr/kg; and half-life was 2.4 +/- 0.8 hours. Age-related differences in busulfan disposition were observed. The mean busulfan oral clearance in a group of 10 patients with an age range from 6 months to 3 years was 0.619 L/hr/kg, whereas six patients whose ages ranged from 7 to 19 years had a oral clearance of 0.396 L/hr/kg. The half-lives for busulfan during infancy decrease continuously until early childhood but were prolonged in older children. No significant relationship between systemic exposure to busulfan and drug effect was observed.

Administration, Oral↗
PubMed1993

Plasma levels after oral methotrexate in children with juvenile rheumatoid arthritis.

Plasma levels of methotrexate (MTX) after oral administration of 6.4 to 11.2 mg/m2/week (mean 8.5 mg/m2/week) were studied in 33 children with severe juvenile rheumatoid arthritis (JRA). MTX concentrations were measured by a fluorescence polarization immunoassay (TDx) at 1, 2, 3, and 24 h after administration. The maximum level was observed in most patients after 1 h. No significant correlation was found between MTX dosage and the 1, 2, and 3-h plasma levels. No patient showed values in the range of probable toxicity 24 h after administration. A stepwise multiple regression analysis on 1, 2, and 3-h MTX levels, selected clinical features, dosage and duration of MTX therapy, and concomitant drug treatment showed that MTX concentrations at the different time points tend to be closely related; among the other variables, only concurrent treatment with salicylates was found to affect significantly the 3-h level. Serial determinations performed in 20 patients at the same oral dosage showed a wide interindividual and intraindividual variability of the plasma levels from the first dose to the next. Variable and unpredictable levels were observed also in most of the 8 patients studied after one or more increases of MTX dosage. No difference in MTX concentrations was observed between patients who responded to treatment and those who failed to respond, and between patients who had serum transaminase elevation and those who did not. Our results suggest that, until the pharmacokinetics of low dose MTX is clarified, routine therapeutic monitoring of MTX has a limited value in the clinical management of children with JRA.

Administration, Oral↗
PubMed1992

Optimization of sampling time for cyclosporine monitoring in transplant patients.

Cyclosporine (CsA) dosing is based on CsA plasma or blood concentrations measured 12 to 24 hours after drug administration (trough levels). This study evaluated the relationship between the timing of CsA concentrations and subsequent pharmacokinetic parameters to predict an optimal sampling period. Plasma samples were obtained from 22 patients before their morning dose of CsA and at 2, 4, 6, 8, 10, and 12 hours after the dose on the 7th and on the 21st day after heart transplantation. The plasma samples were assayed by both HPLC and FPIA. The Cmax for CsA was achieved over a period ranging from 2 to 6 hours (mean/median = 4.7/4.0) during the day 7 and the day 21 studies. The mean (+/- SD) half-life was 3.2 (1.0) hours on day 7 and 2.9 (1.1) hours on day 21, (P > 0.05); the mean apparent oral clearance was 276 (117) L/hr on the day 7 and 269 (209) L/hr on day 21, (P > 0.05). When CsA plasma concentration by either FPIA and HPLC was monitored, the drug concentration best correlated with AUC was found to correspond to the plasma samples taken 4 to 8 hours after drug administration. The authors conclude that through blood sampling for therapeutic drug monitoring of CsA is not optimal, and that further studies are necessary to correlate concentration monitoring during the dosing interval with pharmacologic and toxicologic parameters.

Adolescent↗
PubMed1992

Pharmacokinetics of nicorandil in patients with normal and impaired renal function.

The pharmacokinetics of oral nicorandil 20 mg 12 hourly for 9 doses was evaluated in 21 hospitalized patients with angina pectoris due to coronary heart disease and with normal and impaired renal function. Patients were divided into 3 groups based on creatinine clearance (CLCr): GROUP I (n = 6) greater than 80 ml/min, GROUP II (n = 8) 20-80 ml/min, and GROUP III (n = 7) less than 20 ml/min. After the first dose, the total clearance of nicorandil (CL) value did not change with increasing renal failure and so was not dependent on creatine clearance. After the last dose CL was 51 l.h-1 in Group I, 44 l.h-1 in Group II and 56 l.h-1 in Group III, and it was not related to creatinine clearance. The percentage of the dose excreted in the urine was 0.4%. No significant difference was noted in any of the other pharmacokinetic parameters examined in the three groups, not even on comparing values obtained on the first and last days of treatment. The findings suggest that there is no need to change the dose of nicorandil in subjects with different degrees of renal failure.

Administration, Oral↗
PubMed1992

Pharmacokinetics of ofloxacin in elderly patients and in healthy young subjects.

The pharmacokinetics of ofloxacin, a fluoroquinolone widely used in the treatment of bacterial infections, may be different according to age, owing to the biological differences that exist between an elderly organism and a young subject, especially as regards the renal and the hepatic function. In our study the pharmacokinetics of ofloxacin in 12 elderly patients was found to be different from those of 12 healthy young volunteers. The elimination half-life (t1/2) was slightly shorter in the young subjects than in the elderly: 6.2 (0.9)h against 8.5(1.2)h respectively. The oral total clearance was lower in the geriatric patients compared to the young healthy volunteers: 83.3(16.6) ml/min in the first group, and 23.3(33.3) ml/min in the second group. AUC and peak plasma concentration in elderly exceeded those noted in young healthy volunteers. The results of this study suggest that, compared with younger subjects, older patients experience delayed elimination of ofloxacin. It would be reasonable, from a pharmacokinetic point of view, to limit the dose of ofloxacin in patients more than 75 years old, at least to one half of that given to younger patients.

Administration, Oral↗
PubMed1992

[The bioavailability of nicorandil after oral administration of a single dose of 10 or 20 mg preparations].

To evaluate the bioavailability of 4 different formulations of nicorandil, 10 mg and 20 mg (Bracco) versus 10 mg ang 20 mg (Merck), we have carried out a study involving 24 young healthy volunteers. The drug was administered in single oral dose and the plasma concentration levels were evaluated by HPLC method. From the results obtained, we have seen that both the 2 products of 10 mg (A and B) and the 2 products of 20 mg (C and D) are equivalent and have high relative bioavailability: it reaches the values of 96.5% (A versus B) and 120% (C versus D). As regards the 2 formulation of 20 mg, the results of bioavailability are confirmed by data obtained from dissolution study in vitro, where the dissolution is almost complete in 30 minutes.

Adult↗
PubMed1991

The effect of aging on the pharmacokinetics of nizatidine.

A single oral dose of 300 mg of nizatidine was administered to two groups of volunteers: a first group of 12 young healthy subjects and a second group of 12 elderly patients, in order to compare the pharmacokinetic parameters and to verify a possible influence of the age on nizatidine's kinetics. Blood samples were collected periodically and plasma concentrations of the drug were determined by a specific HPLC method. The results evidenced differences among the pharmacokinetic parameters of the two groups: the mean of Cmax was higher in the elderly than in the young (3.28 mg/ml against 2.23 mg/ml), the peak time was prolonged in the elderly (2.1 h against 1.00 h) and the AUC values were higher too (12.17 in the elderly and 7.99 in the young). Only the elimination half-life t1/2 was slightly higher in the elderly (1.8 h against 1.7 h in the young).

Adult↗
PubMed1991

Pharmacokinetics of omeprazole in cirrhotic patients.

Omeprazole (CAS 73590-58-6), an H+, K+ ATPase inhibitor, is a potent suppressor of gastric acid secretion and a very active substance in the treatment of duodenal and gastric ulcers. The kinetic profile of omeprazole is well defined for healthy volunteers and for some high-risk population, but not so far for patients with liver disease. As the substance is mainly metabolized in the liver, changes in liver circulation and/or function might lead to changes in the pharmacokinetics of omeprazole. Aim of the study was to evaluate the kinetic profile in patients with liver disease and compare the results obtained in healthy volunteers, 16 subjects were included in the study: 8 patients with liver cirrhosis and 8 healthy volunteers. A single oral dose of omeprazole 20 mg was administered: plasma samples were collected for 24 h since omeprazole administration. The principal pharmacokinetic parameters were estimated for the two studied populations.

Adult↗
PubMed1990

Measurement of cyclosporine in plasma of cardiac allograft recipients by fluorescence polarization immunoassay.

The Abbott TDx fluorescence polarization immunoassay (FPIA) procedure for measuring cyclosporine A (CsA) was evaluated and compared with the Sandoz polyclonal radioimmunoassay (CsA RIA kit) method. This drug assay was evaluated for precision, calibration, stability, and accuracy. Within-run precision studies utilizing 25 replicate analyses of the three control preparations (containing CsA in the 60-800 ng/ml range) resulted in coefficients of variation (CV) ranging from 1.0 to 9.1%. The CVs of between-run precision determined by assaying the same control drug levels for five consecutive working days ranged from 3.9 to 4.6%. Calibration curve stability was assessed by examining the drift in control values over a 2-week period. Maximum plasma ranged from 82.6 to 108.2%. Four hundred plasma samples were obtained from 30 heart-transplant patients during the first 6 months of CsA therapy and each sample was analyzed simultaneously by TDx and RIA. Linear regression analysis of the results obtained for each patient (x = RIA, y = FPIA) revealed the following mean values: r = 0.87, (CV = 13.7%), slope = 1.47 (CV = 39.2%). Moreover, the concentration of CsA was determined in 35 patient samples both by TDx and high-performance liquid chromatography (HPLC). FPIA results up to 12 times higher than HPLC results have been noted.

Chromatography, High Pressure Liquid↗
PubMed1989

Bioequivalency of three tableted gallopamil products.

A three cross-study was conducted in 12 healthy male volunteers to evaluate the relative bioavailability of three different gallopamil tablets: Product A-Galcan 25 mg, Product B-Galcan 50 mg and Product C-Procorum 50 mg. Each dose was administered as a single tablet after an overnight fast, and blood samples were obtained for 12 hours. There was no statistically significant differences among the three products for the mean area under the plasma concentration-time curves (when corrected for the different doses). The relative bioavailability of Product A and B to Product C was respectively 96.3% (ESM = 12.4%) and 103.1% (ESM = 10.2%). Statistically significant (p less than 0.05) differences were found in Tmax between Product C (1.0 hr) and both Product A (2.1 hr) and Product B (2.4 hr). A longer-lasting absorption should always diminish peak to trough fluctuations during multiple dosing and to this extent Product B has some advantage over Product C.

Adult↗