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Biomedical subjects

M C Meyer

Publications and source records attributed to M C Meyer.

At least 37 records · Page 2Linked to original sources
PubMed1998

The relative bioavailability and in vivo-in vitro correlations for four marketed carbamazepine tablets.

PURPOSE: To determine if three marketed generic carbamazepine tablets were bioequivalent to the innovator formulation, as well as to each other. In addition, to examine in vivo-in vitro relationships among the four formulations. METHODS: Each formulation was given as a single dose to 18 healthy male and female subjects using a crossover design. Blood samples were collected for 169 hr. Carbamazepine was assayed by HPLC with UV detection. RESULTS: In vivo fraction absorbed plots indicated that the three generic formulations were absorbed more rapidly than the innovator product, and the mean time of maximum plasma concentration was 6-7 hr sooner for the generic formulations. The mean maximum plasma concentration ranged from 17-19 percent higher for the generic products compared to the innovator, and the 90% confidence limits for Cmax data ranged from 11 1% to 126%. The mean AUC(0-infinity) for the generic products ranged from 101-104% compared to the innovator, and the confidence limits for AUC ranged from 97-108%. CONCLUSIONS: The generic products were all more rapidly absorbed than the innovator, but simulations of steady-state concentrations indicated that it would be unlikely that these differences would have any significant clinical effect. An excellent association was seen between the Cmax and the percent of drug dissolved in vitro. The correlation was used to accurately predict the Cmax of four other 200 mg tablets evaluated in an earlier study.

Adult↗
PubMed1998

Lack of in vivo/in vitro correlations for 50 mg and 250 mg primidone tablets.

PURPOSE: To determine if large differences in the in vitro dissolution profiles for primidone tablets would result in significant bioavailability differences. METHODS: Two separate bioavailability studies were conducted. The first study used 18 healthy subjects and compared the bioavailability of an old 50 mg tablet formulation, a new 50 mg tablet formulation, and a suspension containing 50 mg/ml of primidone. The second study enrolled 24 subjects who were to receive a new 250 mg tablet formulation, two lots of an old 250 mg tablet formulation and a 250 mg tablet from a second manufacturer. In vitro dissolution was conducted over 90 minutes, using USP 23 Apparatus 2 at 50 rpm, with 900 ml of water. RESULTS: Dissolution at 90 minutes for the old and new 50 mg tablets was approximately 20% and 100%, respectively. The dissolution of the four 250 mg tablets ranged from approximately 30% to 100%. The 50 mg tablet that dissolved slower had a longer Tmax and a 14% lower Cmax than the more rapidly dissolving tablet, but the AUC(0-infinity) values differed by only 3%. Only nine subjects completed the 250 mg study because of side effects. The differences in Cmax and AUC(0-infinity) among the four 250 mg tablets were less than 7%. CONCLUSIONS: Even though there were large differences in the in vitro dissolution of the 50 mg and the 250 mg primidone tablets, the two 50 mg tablets were shown to be bioequivalent, as were the four 250 mg tablets.

Adult↗
PubMed1998

Generic drug product equivalence: current status.

UNLABELLED: This activity is designed for healthcare professionals involved in the selection of multisource drug products. GOAL: To understand the basis for approval of generic drug products by the Food and Drug Administration. OBJECTIVES: 1. Identify the criteria employed by the Food and Drug Administration to approve generic drug products. 2. Discuss controversial issues that have been raised relative to generic drug products. 3. Identify narrow therapeutic index drugs. 4. Describe the different types of bioequivalence studies that are required by the Food and Drug Administration. 5. Discuss the responsibilities underlying the selection of multisource drug products by healthcare professionals.

Delayed-Action Preparations↗
PubMed1997

Estrogen replacement attenuates resistance artery adrenergic sensitivity via endothelial vasodilators.

The objective of this study was to determine whether chronic estrogen replacement alters adrenergic constriction and endothelium-dependent dilation in resistance arteries from the rat. Resistance-sized (< 200 microns) mesenteric arteries from castrated female Sprague-Dawley rats with (E2; 21 day, 0.5-mg pellet) and without (OvX) estrogen replacement were removed for in vitro study on a pressurized arteriograph system. Sensitivity to alpha-adrenergic constriction and the role of the endothelium in its modulation and of agonist-provoked endothelium-dependent relaxation were determined. Estrogen-treated rats had decreased heart rate as well as systolic and diastolic blood pressure. Arteries from estrogen-replaced rats were fivefold less sensitive to alpha 1-adrenergic stimulation with phenylephrine (50% effective concentration: E2, 3.2 +/- 1.1 microM; OvX, 0.6 +/- 0.2 microM; P < 0.05). This difference was abolished by endothelial denudation, blockade of cyclooxygenase (1 microM ibuprofen), or nitric oxide synthase blockade (0.24 mM N omega-nitro-L-arginine). There was no difference in muscarinic agonist-provoked relaxation or vascular smooth muscle sensitivity to prostacyclin or sodium nitroprusside. These results indicate that estrogen replacement decreases resistance artery adrenergic sensitivity by increasing the basal release of relaxing factors from the endothelium. This effect on small artery function may produce dual cardioprotective effects by decreasing peripheral resistance, blood pressure, and the likelihood of thrombosis.

Animals↗
PubMed1997

Relating formulation variables to in vitro dissolution using an artificial neural network.

The purpose of this paper was to investigate the effect of several experimental variables on the ability of a neural network to predict in vitro dissolution rate as a function of product formulation changes. Neural network software was trained with sets of hypothetical and experimental data consisting of 4-15 formulations with known in vitro drug dissolution profiles and the ability of the trained model to recognize patterns was validated against similar formations not used to train the neural network. The effect of selected variables, e.g., number of hidden-layer nodes and iterations, as well as the use of replicate or mean data on the accuracy of the predictions was investigated. The importance of optimizing the number of hidden-layer nodes and iterations was demonstrated. The prediction error increased for validation data sets that were outside the range of the training data set. Accurate predictions were obtained with as few as four formulations in the training set, provided the formulations were carefully chosen, and the number of formulation variables were small. Also, limiting the validation set to one formulation was not sufficient to validate the neural network model. Increasing the size of the training set, or replication of the input and output data, also provided more accurate predictions. The neural network accurately predicted in vitro drug release provided the neural network variables were optimized, and the training and validation data sets were appropriately selected.

Acetaminophen↗
PubMed1996

Clinically significant interactions of psychotropic agents with antipsychotic drugs.

Various psychotropic drugs are commonly combined with antipsychotic agents. Such combinations can induce pharmacodynamically based, presumably additive, beneficial (e.g. sedative or mood-altering) effects or adverse autonomic, cardiac depressant and CNS intoxicating effects. Clinically significant interactions also arise through competition with or induction of hepatic microsomal cytochrome P450 (CYP) enzymes, particularly the CYP1A2 and CYP2D6 isozymes by which most antipsychotics are oxidised. Such pharmacokinetic interactions can elevate circulating concentrations of antipsychotics (both typical agents and the atypical antipsychotic clozapine) to potentially toxic ranges, which may lead to increased risks of adverse effects. Such interactions occur particularly with serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor antidepressants. Metabolic interactions that lead to lesser increases in antipsychotic concentrations may arise in combining these drugs with other antidepressants, benzodiazepines or propranolol. In contrast, most anticonvulsants, except valproic acid (sodium valproate), induce the oxidative metabolism of antipsychotics and can lower their plasma concentrations to potentially subtherapeutic levels, with unpredictable increases after their discontinuation. Since simultaneous use of multiple psychotropic agents is increasingly common, special caution is required to avoid untoward consequences of interactive adverse effects due to drug interactions, which can sometimes be severe or life-threatening.

Antipsychotic Agents↗
PubMed1995

Electrocardiographic changes during desipramine and clomipramine treatment in children and adolescents.

OBJECTIVE: With the increased use of tricyclic antidepressants in children, and several reports of several sudden deaths associated with desipramine (DMI) treatment, systematic study of their cardiac effects is indicated. In the present study, DMI's and clomipramine's (CMI) short-term effects on the electrocardiogram (ECG) were compared, as well as the long-term effects of CMI. METHOD: The ECGs of 47 children and adolescents in treatment trials were examined at baseline, after 5 weeks of CMI and of DMI treatment, and during CMI maintenance (mean duration 24.6 months). RESULTS: At 5 weeks of CMI and of DMI treatment, the heart rate, PR, QRS, and QT-corrected (QTc) intervals on ECG were significantly increased from baseline (p < .05); DMI increased PR and QRS intervals more than CMI (p < .05), and CMI increased QTc more (p < .05). Tachycardia was the most common change (36%). More patients experienced an incomplete intraventricular conduction delay during DMI treatment (23%, 9/39) than during CMI (2%, 1/47) (p < .05). Four patients (9%) acutely developed a prolonged QTc during either DMI or CMI. Long-term maintenance ECGs during CMI treatment (n = 25) were not significantly different from that at week 5, although some individuals developed or resolved specific ECG changes. CONCLUSION: CMI and DMI both produced ECG changes typically reported for tricyclic antidepressants, and they differed on specific ECG changes. Changes in ECG measures for individuals from short to long term suggest that continued monitoring is required.

Adolescent↗
PubMed1995

Practical considerations in anticonvulsant therapy--Part 2.

Epilepsy is, for many patients, a lifelong condition that requires treatment with powerful drugs whose doses must be carefully titrated to avoid both breakthrough seizures and toxicity. The medication regimens used to treat epilepsy are further complicated by the fact that most seizure medications are metabolized in the liver and have the potential for serious pharmacokinetic drug-drug interactions with many other medications. Successful management of epilepsy requires a high degree of cooperation among the patient, the pharmacist, and the treating physician. Such cooperation can ensure that the appropriate treatment and drug preparation are selected, compliance is maintained, and dangerous drug-drug interactions are avoided.

Anticonvulsants↗
PubMed1993

Characteristics of vascular smooth muscle in the maternal resistance circulation during pregnancy in the rat.

OBJECTIVE: Our purpose was to determine if pregnancy results in a decrease in arterial sensitivity to receptor-independent stimuli and a change in vascular smooth muscle membrane potential. STUDY DESIGN: Mesenteric resistance arteries from late pregnant (n = 19) and age-matched virgin control (n = 20) Sprague-Dawley rats were studied in a pressurized arteriograph system or isometric myograph. RESULTS: Arteries from pregnant rats were less sensitive to membrane depolarization by K+ than were those from nonpregnant rats (mean effective concentration that produced a 50% response 49 vs 39 mmol/L, pregnant vs nonpregnant, p < 0.05). Arterial basal tone and the myogenic response to increasing pressure steps were also reduced in arteries from pregnant rats compared with nonpregnant controls. The vascular smooth muscle membrane of the arteries from the pregnant rats was hyperpolarized compared with that from the control rats (-64 mV from pregnant rats vs -57 mV from nonpregnant rats, p < 0.01). This was associated with a reduction in vasomotion in the arteries from the pregnant rats (10% for pregnant rats vs 45% from nonpregnant rats, p < 0.01). CONCLUSION: Pregnancy results in alterations of the vascular smooth muscle, including changes in the regulation of membrane potential and a reduced sensitivity to receptor-independent stimuli.

Animals↗
PubMed1993

The effect of gastric pH on the absorption of controlled-release theophylline dosage forms in humans.

The bioavailability of three marketed controlled-release dosage forms and a reference solution of theophylline was studied in eight subjects with normal gastric fluid acidity and seven subjects who were achlorhydric. Gastric pH was monitored with a Heidelberg capsule. One of the controlled-release dosage forms dissolved more rapidly in vitro when exposed to acid conditions, one dissolved more rapidly in pH 7.5 media, and the third dissolved at a rate independent of pH. Using a crossover design, each subject received each dosage form twice. Blood was sampled for up to 47 hr after each dose, and serum was assayed for theophylline by HPLC. The product which dissolved more rapidly under acid conditions in vitro exhibited a 3 hr longer Tmax in the achlorhydrics compared to the normal subjects. The product which dissolved more rapidly in the pH 7.5 media exhibited a relatively higher AUC(0-infinity) in the achlorhydric subjects than in normal subjects after the AUC data were normalized for clearance differences between the two subject groups. The in vivo bioavailability of these dosage forms could be related to the in vitro dissolution characteristics for some parameters. However, with the exception of the mean Tmax values, the mean bioavailability parameters differed by less than 20% between the two subjects groups.

Absorption↗
PubMed1993

Biopharmaceutical factors in seizure control and drug toxicity.

Problems related to bioequivalence and bioavailability for four antiepileptic drugs (AEDs) are reviewed. Bioequivalence and bioavailability of AEDs can be affected by many factors, including physicochemical characteristics of the agent, the dosage form, and physiological condition of the patient. In 1988, breakthrough seizures prompted an FDA investigation of one company's generic carbamazepine tablets. Results indicated that the manufacturer had changed its source of carbamazepine, which led to a wide range of dissolution characteristics for different lots of tablets. In two separate studies, clonazepam was shown to be more rapidly absorbed in patients with a normal gastric pH than in those with a higher-than-normal gastric pH. With phenytoin, which exhibits nonlinear pharmacokinetics, differences in the rate and extent of absorption can adversely affect the bioavailability of this agent. Finally, the bioequivalence of generic primidone was contested in an adolescent girl who appeared to experience more frequent seizures with a generic product than with a trade formulation. The effectiveness of a drug depends on complex interactions involving the drug, the drug product formulation, and the patient. Minimizing variability in the absorption process is particularly important with AEDs, because of their narrow therapeutic range.

Anticonvulsants↗
PubMed1992

The bioinequivalence of carbamazepine tablets with a history of clinical failures.

The bioavailability of three lots of a generic 200-mg carbamazepine tablet, which had been withdrawn from the market, was compared to the bioavailability of one lot of the innovator product in 24 healthy volunteers. Fifty-three lots of the generic product had been recalled by the manufacturer because of concerns over reports of clinical failures for several of the lots. The three generic lots tested in this study exhibited a wide range of bioavailability, as well as large differences in the in vitro dissolution rates. The mean maximum carbamazepine plasma concentrations for two of the generic lots were only 61-74% that of the innovator product, while the third lot was 142% of the innovator. The mean areas under the plasma concentration-time curve for the three generic lots ranged from 60 to 113% that of the innovator product. The results clearly indicate a significant difference in the rate and extent of absorption of the generic products compared to the innovator, as well as among the generic lots. A good relationship was found between the in vivo parameters and the in vitro dissolution results for the four dosage forms.

Adult↗
PubMed1992

Composition and mechanics of mesenteric resistance arteries from pregnant rats.

We tested the hypothesis that the systemic resistance vasculature of the rat is remodeled during pregnancy as evidenced by significant alterations in the passive mechanical properties and extracellular matrix proteins in mesenteric arteries. Mechanical characteristics were determined for arteries from 20-day pregnant rats (n = 6) and age-matched controls (n = 5). Lumen diameter and wall thickness were measured in pressurized arteries (250-microns diameter) using a dimension analyzing system. Distensibility (the relative change in diameter per unit change in pressure) was less in the arteries from the pregnant rats (P less than 0.01). The calculated stress-strain relationships and elastic moduli indicated that the arteries were less stiff by late gestation (P less than 0.05). Ultramicro amino acid analysis and radioimmunoassay were used to measure hydroxyproline, desmosine, and leucine as indicators of collagen, elastin, and total protein, respectively, in similar-sized arteries. Hydroxyproline/leucine (index of collagen) and desmosine/leucine (elastin concentration) decreased 19 and 15% by late gestation (P less than 0.05). The significant alterations in passive mechanics and in extracellular protein content support the concept that arterial wall remodeling in the peripheral vasculature may be one component of the cardiovascular adaptations during pregnancy.

Animals↗
PubMed1992

Hepatitis B surface antigen screening in a nonindigent population.

The recommendation for universal screening of all pregnant women for hepatitis B surface antigen (HBsAg) is based on data from publicly funded hospitals. We retrospectively reviewed screening results of 2,696 mothers who delivered between May 1989 and April 1990. Our population was 85% privately funded. Screening for HBsAg was positive in 0.07%, negative in 80.4% and not done in 19.6%. All positive screens would have been identified by screening only patients with recognized risk factors. We conclude that the sensitivity of identifiable risk factors to detect HBsAg carriers may be high in some populations. We speculate that universal screening in these populations is not cost efficient.

Carrier State↗
PubMed1991

Circadian rhythms in theophylline disposition: simulations and observations in the dog.

A constant-rate iv infusion of aminophylline approaching steady state in four dogs was used to investigate a circadian rhythm in theophylline disposition. A significant circadian rhythm (p less than 0.05, group cosinor analysis) was observed for serum theophylline concentrations and for the urinary excretion rates of theophylline and 3-methylxanthine. The phase relationship of the observed circadian rhythms in urinary pH to circadian changes in serum theophylline concentrations were supportive of a circadian rhythm in renal clearance of theophylline. Computer simulations indicated that circadian changes in serum theophylline concentration and urinary excretion of theophylline and its metabolites could be accounted for by a circadian rhythm in theophylline renal clearance and metabolism to 3-methylxanthine. A circadian rhythm in theophylline volume of distribution could not be totally dismissed as potentially having some effect on disposition. The timing of food intake is hypothesized to play a role in synchronizing the observed rhythm in serum theophylline concentrations.

Animals↗
PubMed1991

The effect of raising gastric pH with ranitidine on the absorption and elimination of theophylline from a sustained-release theophylline tablet.

Prior to evaluating the effect of ranitidine on theophylline absorption from a sustained-release theophylline tablet, the effect of ranitidine on the time course of gastric pH in 12 healthy subjects was evaluated with an encapsulated radio-telemetry device (Heidelberg capsule). Gastric pH was measured hourly from 7 AM to 1 PM prior to beginning ranitidine treatment at 2 PM (150 mg every 4 hr for eight doses). The next day, pH was again measured hourly from 7 AM to 7 PM. Subjects fasted overnight and remained fasted until lunch at 11 AM. Prior to ranitidine treatment, the mean morning gastric pH remained between 1.5 and 2.2. After lunch, the pH increased to 2.2-2.3. During ranitidine treatment the mean morning gastric pH measurements were 5.5 to 5.8, decreasing after lunch to 3.1 by 4 PM and increasing to 3.9 at 7 PM. One week later the subjects participated in a three-way crossover theophylline bioavailability study receiving at weekly intervals, single doses at 7 AM of (a) 5 x 100-mg immediate-release tablets, (b) 2 x 300-mg sustained-release theophylline tablets, and (c) 2 x 300-mg sustained-release theophylline tablets after ranitidine pretreatment of 150 mg every 4 hr beginning at 2 PM the previous day. The increase in gastric pH with ranitidine had no effect (P greater than 0.05) on the rate and extent of absorption or on the elimination rate of theophylline.

Adult↗