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Biomedical subjects

N Zampaglione

Publications and source records attributed to N Zampaglione.

At least 19 recordsLinked to original sources
PubMed1995

Pharmacokinetics of isepamicin.

Isepamicin is a new aminoglycoside that has activity against many bacteria resistant to other aminoglycosides. The pharmacokinetics of isepamicin have been characterized in neonatal, pediatric, adult, elderly and renally impaired human populations as well as in clinical trials using the techniques of population pharmacokinetics. The pharmacokinetics of isepamicin are uncomplicated and generally similar to those of other aminoglycosides, although there is some evidence that it may have less tissue accumulation. The drug is completely absorbed following intramuscular administration. The drug is not metabolized and unchanged isepamicin accounts for all of the drug substance in plasma and urine. It is completely eliminated via the renal route; consequently dosing in patients with renal insufficiency has to be adjusted according to the degree of renal impairment. The pharmacokinetics of isepamicin are generally linear. Thus peak plasma concentrations and area under the plasma concentration curve (AUC) values are proportional to the administered dose while clearance (1.1-1.3 mL/min/kg), volume of distribution at steady state (0.23-0.29 L/kg) and half-life (2-2.5 h) are independent of dose. There is no significant accumulation of drug in the plasma with once- or twice-daily dosing. The isepamicin plasma concentration curve following a 1 g intravenous dose to healthy volunteers can be best characterized by a tri-exponential curve corresponding to a t1/2 alpha of 0.17 h, a t1/2 beta of 2.1 h, and a gamma-phase of 34 h. The t1/2 beta represents the elimination phase and changes with age and renal functions, while the gamma-phase represents the return of drug to plasma from a deep compartment including binding in renal tissue. The gamma-phase represents less than 3% of the total AUC and does not change with age. Isepamicin readily distributes to extracellular fluid and pulmonary tissue. In conclusion, isepamicin demonstrates predictable linear kinetics and is similar pharmacokinetically to other aminoglycosides. Preliminary indications of decreased tissue accumulation implied from pharmacokinetic and pharmacodynamic characteristics of isepamicin favour once-daily dosing.

Adolescent↗
PubMed1995

Pharmacokinetics of isepamicin in paediatric patients.

The pharmacokinetics of isepamicin were evaluated in 50 paediatric patients ranging from newborn to 13 years old. Children with subdivided according to age: Group I (6-13 years); Group II (4 months to 6 years); Group III (16 days to 4 months); and Group IV (newborn to 16 days). All patients received isepamicin 7.5 mg/kg every 12 hours except those in Group IV who received 7.5 mg/kg once daily. Isepamicin was administered initially as an intravenous 30-minute infusion and then either intravenously or intramuscularly for between 4 and 12 days. Plasma samples were obtained after the first or second dose on day 1 at 0, 0.5, 1, 4, 6, 8 and 12 hours after the initiation of dosing and at 0.5 and 12 hours on other dosing days. Additional samples were collected in the Group IV patients at 18, 20 and 24 hours. Isepamicin showed a similar plasma concentration-time profile in Groups I, II and III (children from 16 days to 13 years), and in these groups the profile was generally similar to that observed in adults. Neonates up to the age of 16 days (Group IV) showed a distinctly different pharmacokinetic profile: a significantly larger AUC, longer half-life, lower Cmax and lower total body clearance. Isepamicin 7.5 mg/kg administered once daily to children less than 16 days old and twice daily to children aged 16 days to 13 years appears to be pharmacokinetically appropriate. The drug was very well tolerated by children of all age groups.

Adolescent↗
PubMed1990

Pharmacokinetics of loratadine in patients with renal insufficiency.

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearance less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2 beta were observed between the three groups (8.7 +/- 5.9, 7.6 +/- 6.9, 8.6 +/- 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC infinity 0 however was significantly greater in group II subjects: (212.4 +/- 37.8, 469.5 +/- 95.4, 325.2 +/- 114.6 ng.hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half-life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.

Adult↗
PubMed1989

Single and multiple dose pharmacokinetic evaluation of flutamide in normal geriatric volunteers.

Single dose and steady-state pharmacokinetics of flutamide (F) and its active plasma metabolite, hydroxyflutamide (HF) were studied in twelve healthy geriatric volunteers administered 250 mg flutamide capsules on day 1 and 250 mg flutamide capsules three times a day on days 2 through 9. After oral administration, F was rapidly absorbed and metabolized. It was present in the plasma in small and variable concentrations, which precluded quantitative assessment of pharmacokinetic parameters for individual subjects. Steady-state plasma concentrations were reached on or before Day 6. The mean steady state Cmax (Day 9), 112.7 ng/ml, occurred at 1.3 hr. Pharmacokinetic analysis of mean data at steady-state gave a distribution and elimination half-life of 0.8 hr and 7.8 hours, respectively. The plasma levels for HF were much higher and less variable than F. The mean Cmax for HF averaged 894 ng/ml at 2.7 hours after a single dose and 1719 ng/ml (Day 9) at 1.9 hr after multiple doses. The distribution and elimination half-lives of HF at steady-state were 1.9 and 9.6 hours, respectively. The steady-state HF plasma concentrations were also achieved on or before Day 6 and were approximately twice those obtained after a single dose. From this study, it has been demonstrated that the pharmacokinetics of F and HF do not change appreciably upon multiple dosing of 250 mg F capsule given three times a day.

Administration, Oral↗
PubMed1988

Excretion of loratadine in human breast milk.

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40-mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration-time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration-time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and 4.2 micrograms of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8-hour collection interval. Through 48 hours, the mean milk-plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 micrograms of descarboethoxyloratadine (7.5 micrograms loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 micrograms loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4-kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Loratadine: multiple-dose pharmacokinetics.

The steady-state pharmacokinetics of loratadine (L), a new long-acting antihistamine devoid of CNS activity, was investigated in 12 healthy male volunteers. Each volunteer received 40-mg L capsules q24h for ten days. Blood samples were collected at various times on day 1, 5, 7, and 10 and assayed for L by radioimmunoassay (RIA) and for descarboethoxyloratadine (DCL), a known active metabolite, by high-performance liquid chromatography (HPLC). The plasma L and DCL concentration-time data in the disposition phases were fitted to a biexponential equation for pharmacokinetic analysis. Steady-state plasma L Cmax concentrations were reached at 1.5 hour (Tmax) after each dose. DCL steady-state Cmax values ranged 26 to 29 ng/mL at a Tmax ranging from 1.8 to 3 hours. The AUC at steady state, AUC tau, was 80 to 96 and 349 to 421 h X ng/mL for L and DCL, respectively. The accumulation indexes (Ra) based on AUC tau ratios, did not change for either compound after day 5. Ra values for L and DCL after the fifth dose were 1.4 and 1.9, respectively, indicating that there is little accumulation of either L or DCL after a multiple (once-a-day) dosage regimen. The t1/2 beta at steady state were 14.4 and 18.7 hours for L and DCL, respectively, which were similar to those reported following a single-dose L administration. Observed plasma drug concentrations were in good agreement with predicted values derived for pharmacokinetic parameters.

Adult↗
PubMed1987

Pharmacokinetics and dose proportionality of loratadine.

The dose proportionality and pharmacokinetics of loratadine, a new nonsedating antihistamine, were studied in 12 normal volunteers. In a three-way cross-over, each volunteer received a single 10-, 20-, or 40-mg loratadine capsule. Blood was collected up to 96 hours after dosing. Plasma loratadine concentrations were determined by radioimmunoassay (RIA), and those of a minor, but active metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Concentrations in the disposition phase were fitted to a biexponential equation for pharmacokinetic analysis. For dose proportionality, AUC- and Cmax-dose relationships were evaluated by linear regression. Also, pharmacokinetic parameters and dose-adjusted AUCs were compared by analysis of variance. Loratadine was rapidly absorbed, reaching Cmax values (4.7, 10.8, and 26.1 ng/mL) at 1.5, 1.0 and 1.2 hours for the 10-, 20-, and 40-mg doses, respectively. The loratadine t1/2 beta ranged from 7.8 to 11.0 hours. Descarboethoxyloratadine reached Cmax values (4.0, 9.9, and 16.0 ng/mL) at 3.7, 1.5, and 2.0 hours for the 10-, 20-, and 40-mg doses, respectively. Its t1/2 beta ranged from 17 to 24 hours. For both compounds, AUC- and Cmax-dose relationships were linear and there were no differences in the t1/2 beta, CL/F, or dose-adjusted AUC values among the treatments. Loratadine and descarboethoxyloratadine plasma concentrations and pharmacokinetics were not dose dependent.

Administration, Oral↗
PubMed1986

Relationships of brain and plasma levels of quazepam, flurazepam, and their metabolites with pharmacological activity in mice.

The relationships between the pharmacological activities of quazepam and flurazepam and the concentrations of each drug and its major active metabolites in brain and plasma following single oral doses of either drug to mice were investigated. At various time points after either quazepam or flurazepam administration, pharmacological activity was measured by the inhibition of electroconvulsive shock (ECS)-induced seizures. After quazepam, the plasma and brain samples obtained at the same time points were assayed for concentrations of quazepam, 2-oxoquazepam and N-desalkyl-2-oxoquazepam by specific GLC methods. After flurazepam, the plasma and brain samples were assayed for flurazepam, hydroxyethyl-flurazepam, and N-desalkyl-2-oxoquazepam, also by specific GLC methods. The results showed that both quazepam and flurazepam were rapidly metabolized and that parent drugs and metabolites were rapidly distributed to the brain. The brain levels of all the benzodiazepines analyzed in this study paralleled plasma levels. After quazepam, pharmacological activity most closely paralleled the combined brain concentrations of quazepam and 2-oxoquazepam rather than N-desalkyl-2-oxoquazepam levels. In contrast, following the flurazepam dose, activity most closely paralleled N-desalkyl-flurazepam concentrations. From these data, it can be concluded quazepam is distinctly different from flurazepam, and that, in the presence of quazepam and 2-oxoquazepam, N-desalkyl-2-oxoquazepam does not contribute extensively to the observed pharmacological activity.

Animals↗
PubMed1984

Excretion of quazepam into human breast milk.

Previous metabolic studies have established that two major metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, are present in plasma after dosing with quazepam, a new benzodiazepine hypnotic. The excretion of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam into human breast milk was studied in four lactating nonpregnant volunteers. Each volunteer received one 15-mg quazepam tablet following an overnight fast. Nursing of offspring was discontinued after drug administration. Milk and blood samples were collected prior to and at specified times (up to 48 hours) after dosing. Plasma and milk levels of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were determined by specific GLC methods. The concentrations of the three compounds found in milk appeared to depend on their relative lipophilicities, which were determined by log P values. The mean milk/plasma AUC ratios of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 4.19, 2.02, and 0.091, respectively. Levels of quazepam and 2-oxoquazepam declined at about the same rate in plasma and in milk. The total amount of the administered quazepam dose found in the milk as quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam through 48 hours was only 0.11 per cent.

Adult↗
PubMed1984

Gas chromatographic determination of quazepam and two major metabolites in human plasma.

Two rapid, sensitive, and specific gas chromatographic (GC) methods for the quantitative determination of quazepam (I), 7-chloro-5-(2-fluorophenyl-1,3-dihydro-1-(2,2,2-trifluoroethyl) -2H-1,4-benzodiazepine-2-thione, and its major active plasma metabolites, the 2-oxo compound (II) and the dealkylated oxo compound (III), have been developed; the first measures I and II and the second measures III. The compounds are extracted from plasma with toluene and quantitated by electron-capture detection using the internal standard method. The methods are capable of quantitating plasma levels of I and II as low as 0.75 ng/mL and plasma levels of III as low as 1.5 ng/mL. Correlation coefficients of standard curves were greater than 0.9995 for all compounds. Precision of the methods was measured at two different concentrations for each compound; the CV values were 3-6% for all three compounds. The recovery of all compounds was greater than 80%, and the ratio of recovery of each compound to that of its internal standard did not vary at different concentrations, indicating appropriate internal standards have been selected for the methods. Quazepam metabolites, other benzodiazepines, and drugs which are potential comedication do not interfere with either method. The methods were shown to be suitable for investigating the bioavailability and pharmacokinetics of quazepam at therapeutic doses.

Anti-Anxiety Agents↗
PubMed1984

Multiple-dose halazepam kinetics.

Halazepam is a benzodiazepine used in the management of anxiety disorders or short-term relief of anxiety. Our study was undertaken to evaluate its steady-state kinetics and those of its major active plasma metabolite N- desalkylhalazepam . Eleven healthy men aged 19 to 35 yr were given oral, 40-mg halazepam tablets every 8 hr for 14 days. Plasma samples were analyzed by gas chromatography to determine levels of halazepam and N- desalkylhalazepam . Halazepam kinetics can best be described by a two-compartment open model with first-order absorption kinetics. The elimination phase t1/2s of halazepam and N- desalkylhalazepam were 34.7 and 57.9 hr. Steady-state levels were predictable from kinetic data and were reached by the third day for halazepam and by the eleventh day for N- desalkylhalazepam .

Adult↗
PubMed1984

Effect of sleep on quazepam kinetics.

The effect of sleep on quazepam kinetics was studied in 12 normal adult men. In a randomized two-way crossover design, each subject received one 15-mg quazepam tablet either at night just before sleep or in the morning after a night's sleep. Blood samples were drawn before and at specified times (to 120 hr) after dosing. To assure that blood collection did not interfere with sleep, blood was drawn by an indwelling catheter from a large arm vein. Plasma concentrations of quazepam and its two major plasma metabolites (which are also active) 2-oxoquazepam and N-desalkyl-2-oxoquazepam (N-desalkylflurazepam) were determined by specific GLC methods. Kinetic analysis was by a two-compartment open model with first-order absorption/formation kinetics. Quazepam was rapidly absorbed with both administration times; absorption t 1/2 was 0.7 to 0.9 hr. Absorption lag time was slightly longer after the nighttime dose (1.0 and 0.6 hr). Maximum concentration and AUC of quazepam and 2-oxoquazepam and AUC of N-desalkyl-2-oxoquazepam were somewhat higher after nighttime dosing, most likely a result of decreased apparent volume of distribution of the central compartment after the nighttime dose (5.0 l/kg for nighttime dosing and 8.6 l/kg for morning dosing). The elimination t 1/2s of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam after the morning dose were 25, 28, and 79 hr, which did not differ from those values after the nighttime dose. In general, time of dosing had no appreciable effect on quazepam kinetics or those of its major active plasma metabolites. The small differences between the two dose times are not expected to have clinical significance.

Absorption↗
PubMed1984

Quazepam kinetics in the elderly.

The kinetics of quazepam, a benzodiazepine hypnotic, was studied in 10 geriatric subjects. Each received one 15-mg tablet of quazepam. Blood samples were collected before and at specified times (up to 672 hr) after dosing. Plasma concentrations of quazepam and its two major active plasma metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), were determined by specific GLC methods. Kinetics were best described by a two-compartment open model with first-order absorption/formation kinetics and standard equations. Quazepam was rapidly absorbed, with a t1/2 of 0.8 hr. The mean maximum plasma level (Cmax) was 29.3 ng/ml. The disposition t1/2s in the distribution (t1/2 alpha) and elimination (t1/2 beta) phases were 3.5 and 53.3 hr. 2-Oxoquazepam was rapidly formed with quazepam, with an apparent formation t1/2 of 0.8 hr. Mean Cmax was 14.5 ng/ml. The t1/2 alpha and t1/2 beta of 2-oxoquazepam were 4.2 and 43.1 hr, of the order of those of quazepam. The t1/2 beta of N-desalkyl-2-oxoquazepam, formed from 2-oxoquazepam, was 189.7 hr, much longer than that of its precursor. Comparison of these data with reported kinetic data in young subjects shows that t 1/2 betas of quazepam and 2-oxoquazepam increased only slightly or not at all with age, but that the t 1/2 beta of N-desalkyl-2-oxoquazepam in the elderly was more than twice that in young subjects.

Absorption↗
PubMed1984

Multiple-dose quazepam kinetics.

Quazepam, a benzodiazepine hypnotic, was studied in normal subjects to evaluate steady-state kinetics of quazepam and of its major active plasma metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, after 15 mg once daily by mouth for 14 days. The kinetics of quazepam and 2-oxoquazepam can be best described by a two-compartment open model with first-order absorption/formation kinetics. Quazepam was rapidly absorbed and its two major plasma metabolites appeared very quickly in systemic circulation. The elimination t 1/2s of quazepam, 2-oxoquazepam, and N-desalkyl-2-oxoquazepam were 41, 43, and 75 hr. Steady-state levels were predictable from the kinetic data and were reached by the seventh dose for quazepam and 2-oxoquazepam and by the thirteenth dose for N-desalkyl-2-oxoquazepam. These kinetic profiles may explain the clinical hypnotic effect of quazepam--rapid induction of sleep and long duration of clinical action without appreciable rebound insomnia.

Absorption↗
PubMed1983

Study of single and multiple dose pharmacokinetic/pharmacodynamic modeling of the antihypertensive effects of labetalol.

This was an open-label, two-phase crossover study of labetalol in 11 patients with mild to moderate hypertension. A two- to four-week outpatient placebo phase was followed by a three-day inpatient placebo period. Patients were then randomly assigned to receive either labetalol, 200 mg, as a single dose and three times a day for three days and, on the final day, another single dose or a similar sequence with 300 mg as the single dose and multiple twice a day treatment. A two-week placebo outpatient period was followed by the second phase of the study in which the treatment regimen was reversed for the two groups. Blood samples for the determination of free and conjugated labetalol plasma levels were collected, and blood pressures and heart rate were recorded sequentially for 24 hours after the first and last dose of labetalol, and during the multiple dose treatment period before and two hours after each dose as well as four times daily with the patient supine and upright. Of the 11 patients analyzed, five were men and six were women, ranging in age from 33 to 62 years. Labetalol (200 mg and 300 mg) was rapidly absorbed with peak concentrations achieved in approximately one hour. The pharmacokinetic data best fit a two-compartment pharmacokinetic model with first order absorption. At steady state, the absorption, distribution, and elimination kinetics were similar for both dosage regimens with elimination half life of 7.65 and 7.92 hours for the 200 mg three times a day and 300 mg twice a day regimens, respectively. During the multiple dosing period average steady-state plasma drug concentrations were 0.149 mg/ml and 0.145 mg/ml for the 300 mg twice a day and 200 mg three times a day regimens, respectively. Approximately 12 percent of total plasma labetalol was free drug. The balance was conjugated. The first dose of 200 mg or 300 mg of labetalol significantly (p less than 0.01) lowered standing and supine mean blood pressure over a period of eight to 12 hours, respectively, with peak effects occurring at two (standing) and four (supine) hours. A significant reduction (p less than 0.01) in supine mean blood pressure was present 24 hours after the initial dose of 300 mg. At steady state the antihypertensive effects of the 200 mg three times a day and the 300 mg twice a day dosage regimens were similar.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗