Biomedical subjects

B Levitt

Publications and source records attributed to B Levitt.

At least 19 recordsLinked to original sources

PubMed2005

Observation of centrifugally driven interchange instabilities in a plasma confined by a magnetic dipole.

Centrifugally driven interchange instabilities are observed in a laboratory plasma confined by a dipole magnetic field. The instabilities appear when an equatorial mesh is biased to drive a radial current that causes rapid axisymmetric plasma rotation. The observed instabilities are quasicoherent in the laboratory frame of reference; they have global radial mode structures and low azimuthal mode numbers, and they are modified by the presence of energetic, magnetically confined electrons. Results from a self-consistent nonlinear simulation reproduce the measured mode structures.

Journal Article↗

PubMed2003

Observation of nonlinear frequency-sweeping suppression with rf diffusion.

Nonlinear frequency sweeping of unstable waves in a laboratory plasma is suppressed upon application of rf fields. Frequency sweeping is driven by a population of energetic electrons trapped in a magnetic dipole field that excite drift-resonant potential fluctuations and create coherent structures in phase space. Self-consistent numerical simulation reproduces the suppression and suggests an explanation due to rf scattering of energetic electrons that destroys the phase-space structures.

Journal Article↗

PubMed2000

Who needs individual bioequivalence studies for narrow therapeutic index drugs? A case for warfarin.

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of "switching," an individual bioequivalence study involving a replicate-design study and three "switchings" in healthy subjects was undertaken using the U.S.-brand warfarin sodium tablet and a generic product. A randomized, single-center, open-label, single-dose, four-way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Liu's method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject-by-formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.

Adolescent↗

PubMed1999

A multiple-dose safety and bioequivalence study of a narrow therapeutic index drug: a case for carbamazepine.

BACKGROUND AND OBJECTIVES: Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use. METHODS: A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state. Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method. RESULTS: A total of 28 subjects completed the study. Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%. CONCLUSION: The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study.

Adult↗

PubMed1999

Expression of listeriolysin O and ActA by intracellular and extracellular Listeria monocytogenes.

Listeria monocytogenes requires listeriolysin O (LLO) and ActA, the products of hly and actA, respectively, to establish a productive intracellular infection. LLO is essential for vacuolar lysis and entry into the cytosol, while ActA is required for bacterial spread to adjacent cells. We have used a transcriptional reporter gene system to compare the expression of actA and hly during intracellular growth to that during growth in broth cultures. The hly and actA genes were transcriptionally fused to Escherichia coli lacZ and Bacillus pumilus cat-86 (cat), and the fusions were integrated in single copies into the L. monocytogenes chromosome. A chloramphenicol resistance assay indicated that the hly fusion but not the actA fusion was significantly activated in Luria-Bertani (LB) broth, and this finding correlated with LLO and ActA levels detectable in broth cultures. Quantitation of promoter activity on the basis of beta-galactosidase activity revealed up to 10-fold-higher level of expression of the hly fusion relative to the actA fusion in LB broth. In contrast, both fusions were active in the cytosol of J774 cells, and the activity of the actA fusion was approximately 3-fold higher than that of the hly fusion under these conditions. However, quantitative immunoprecipitation of ActA and LLO from infected J774 cells demonstrated approximately 70-fold more cytosolic ActA than cytosolic LLO. Finally, in comparison to induction in broth cultures, actA was highly induced (226-fold) and hly was moderately induced (20-fold) in J774 cells. Collectively, these results indicate that actA and hly are differentially regulated in response to the growth environment and that both genes are preferentially expressed during intracellular growth. Further, while the lower level of production of ActA than of LLO in broth can be accounted for by transcriptional regulation, the relative abundance of intracellular ActA compared to that of intracellular LLO is a function of additional, possibly host-mediated, factors.

Animals↗

PubMed1998

Existing and new criteria for bioequivalence evaluation of new controlled release (CR) products of carbamazepine.

While the three classical pharmacokinetic (PK) parameters, AUC, Cmax and tmax are adequate to assess bioequivalence of immediate release (IR) formulations, they are not designed to fully characterize the pharmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (CBZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (parameters). The following are the proposed new parameters: MRT (mean residence time), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mean of the concentrations within 25% of Cmax). The above proposed parameters, were utilized in a recent PK study of new CR products of CBZ (600 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ CR formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reached utilizing both the classical and the proposed new parameters. The new parameters showed that CBZ 600 granulate has similar rate of absorption as the two 600 mg CR tablets, but its extent of absorption was lower. The new parameters examined in this paper are more attractive than the single point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the plasma concentration versus time curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Adult↗

PubMed1998

SK&F107647: a synthetic hematoregulatory peptide in patients with solid tumor malignancies: a phase I trial.

SK&F107647 is a synthetic hematoregulatory peptide (HP) increases both the number and function of progenitor cells, enabling improved survival after lethal myelosuppression, lethal fungal infection, and lethal herpes simplex virus infection in murine models. This Phase I single-blind placebo-controlled dose-rising crossover trial examined the efficacy of SK&F107647 in patients who had incurable solid tumor malignancies. Sixteen patients were treated. Six adverse events in 3 patients were considered to be possibly related to SK& F107647; all were mild to moderate in nature (mild nervousness and agitation at 0.01 ng/kg, moderate fever and mild nausea at 0.1 ng/kg, elevated hepatic enzymes at 0.1 ng/kg, and mild vomiting at 1.0 ng/kg). Plasma half-life was 2.44 hours (+/-1.07 standard deviation). The observed area volume of distribution was 16.7 L (+/-7.7 standard deviation) and clearance was 5.04 L/hour (+/-1.83 standard deviation). When administered as a single 2-hour intravenous infusion at doses ranging from 0.01 to 100 ng/kg, SK&F107647 is safe and well tolerated.

Adjuvants, Immunologic↗

PubMed1998

Criteria to assess in vivo performance and bioequivalence of generic controlled-release formulations of carbamazepine.

PURPOSE: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled-release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time-concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), t(apical), and C(apical) (the arithmetic mean of the POT times and concentrations within 25% of Cmax, respectively). Additional parameters for multiple-dose studies include the percentage fluctuation and the flatness of the steady state-concentration curve. METHODS: These proposed parameters were used in two recent (single and multiple dose) two-way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. RESULTS: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time-concentration curves as assessed by visual inspection and the proposed parameters. CONCLUSIONS: The additional parameters examined may supplement the traditional single-point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption-rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Adolescent↗

PubMed1996

Interspecies pharmacokinetics of a novel hematoregulatory peptide (SK&F 107647) in rats, dogs, and oncologic patients.

PURPOSE: To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. METHODS: Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 mg/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). RESULTS: In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vd ss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a.W(b)), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vd(ss), and T(1/2) of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. CONCLUSIONS: Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.

Adjuvants, Immunologic↗

PubMed1989

Effects of phosphodiesterase inhibition on skeletal muscle vasculature.

The pathophysiology of the syndrome of congestive heart failure (CHF) includes 2 major components that closely interact. The first one is a reduction in ventricular performance, which is manifested initially during exercise and is later present at rest. The second one involves abnormalities of the peripheral circulation and organs, which become gradually more prominent and lead ultimately to symptoms. The exercise capacity of patients with chronic CHF is limited not only by an inadequate increase in cardiac output and an excessive increase in ventricular filling pressure, but also by a fixed vasodilatory response to exercise. Although the role of increased activity of the sympathetic and renin-angiotensin-aldosterone systems in the derangements of the peripheral circulation has been extensively investigated, the structural abnormalities of the arterial wall have received little emphasis in patients with CHF. Chronic reduction of the cardiac output may lead to endothelium-dependent reduction in arterial diameter and vasomotor response, which may in turn increase systemic vascular resistance and further reduce cardiac output. Therapeutic agents should be characterized by their acute and chronic effects not only on ventricular performance, but also on the peripheral circulation. More specifically, when one is concerned with the effect of a therapeutic intervention on exercise capacity, evaluation of its direct and indirect effects on the skeletal muscle vasculature is particularly important. Accordingly, the effects of phosphodiesterase inhibition on vascular smooth muscle tone and skeletal muscle vasculature are reviewed. In addition, the potential of phosphodiesterase inhibition to reverse structural abnormalities of the arterial wall is discussed.

Amrinone↗

PubMed1988

Evidence for heterogeneity between pre- and postjunctional alpha-2 adrenoceptors using 9-substituted 3-benzazepines.

A series of alpha adrenoceptor antagonists, including both reference compounds and the novel benzazepine antagonists, SK&F 86466 (6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine) and two of its 9-substituted derivatives, SK&F 101253 and SK&F 104078, were tested in vitro for affinity at central and peripheral alpha adrenoceptor subtypes. Peripheral alpha-1 adrenoceptor antagonist potency of these agents, as assessed by the receptor dissociation constant (KB) against norepinephrine-induced contraction in the rabbit aorta, correlated with the Ki value for inhibition of [3H]prazosin binding to central alpha-1 adrenoceptors in rat brain homogenates. Central alpha-2 adrenoceptor affinity, measured as the Ki for inhibition of [3H]rauwolscine binding to rat brain homogenates, correlated well with antagonist activity at peripheral postjunctional alpha-2 adrenoceptors as reflected by the KB against B-HT 920-induced contraction in canine saphenous vein. The 9-substituted benzazepines, SK&F 101253 and SK&F 104078, produce preferential blockade of postjunctional vs. prejunctional alpha-2 adrenoceptors in peripheral models. The high affinity of SK&F 104078 for postjunctional alpha-2 adrenoceptors in the canine saphenous vein was confirmed by its ability to inhibit [3H]rauwolscine binding to postjunctional alpha-2 adrenoceptors in this tissue. The observation that the Ki values for these antagonists against [3H] rauwolscine binding correlate with their KB values at the postjunctional alpha-2 adrenoceptors, rather than those at the prejunctional neuroinhibitory alpha-2 adrenoceptor, suggests a pharmacologic similarity between the postjunctional vascular alpha-2 adrenoceptors and the central [3H]rauwolscine binding site.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1986

Prejunctional alpha 2-adrenoceptors modulate stimulation-evoked norepinephrine release in rabbit lateral saphenous vein.

Segments of rabbit lateral saphenous vein prelabelled with [3H]noradrenaline were perfused and superfused with physiological salt solution. Tritium overflow evoked by transmural nerve stimulation (3 Hz for 2 min) was abolished by tetrodotoxin (1 microM). The selective alpha 2-adrenoceptor agonist UK 14,304 inhibited stimulation-evoked 3H-overflow in a concentration-dependent manner, with an IC50 of 71 nM. In contrast, the alpha 2-adrenoceptor agonist B-HT 933 had no effect on 3H-overflow in concentrations up to 10 microM. The selective alpha 2-adrenoceptor antagonists idazoxan and SKF 86466, as well as the non-selective alpha-antagonist phentolamine, facilitated the nerve stimulation evoked 3H-overflow, with an order of potency of idazoxan greater than or equal to phentolamine greater than SK&F 86466. Prazosin (100 nM) had little effect on 3H-overflow. These findings suggest that stimulation-evoked neurotransmitter release is modulated via prejunctional alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1986

Evidence against serotonin as a vasoconstrictor neurotransmitter in the rabbit basilar artery.

It has been suggested recently that serotonergic nerves distinct from the known adrenergic innervation are present in cerebral blood vessels. We have confirmed that serotonin is present in the wall of rabbit cerebral arteries using a high-performance liquid chromatography technique, with levels in the basilar artery of 0.27 +/- 0.04 microgram/g wet wt. Furthermore, adrenergic denervation in vitro with 6-hydroxydopamine, while substantially reducing norepinephrine content, did not alter serotonin levels in the basilar artery. However, it was not possible to demonstrate specific accumulation of [3H]serotonin into distinct serotonergic nerves. Both the basilar artery and ear artery (which has been shown not to be innervated with serotonergic nerves) accumulated [3H]serotonin when incubated with a low concentration (10(-8) M). However, [3H]serotonin accumulation was reduced markedly in 6-hydroxydopamine-treated vessels as well as in the presence of the norepinephrine uptake blocker, desmethylimipramine. Furthermore, pretreatment with the serotonin uptake blocker, fluoxetine, did not inhibit selectively [3H]serotonin accumulation in the basilar artery. Thus, the majority of [3H]serotonin accumulation can be attributed to adrenergic nerves. The possibility that serotonergic nerves contribute to the neurogenic constrictor response of the rabbit basilar artery was also tested. Adrenergic denervation with 6-hydroxydopamine in vitro abolished the constrictor response to transmural nerve stimulation completely, but levels of endogenous serotonin were not affected. Thus, although the presence of endogenous serotonin in cerebral arteries has been confirmed, this substance does not appear to contribute to the neurogenic vasoconstriction seen in this vessel.

Animals↗

PubMed1985

Pulmonary venous flow pattern--its relationship to cardiac dynamics. A pulsed Doppler echocardiographic study.

We studied the physiology of pulmonary venous flow in 13 normal subjects and five patients with atrial rhythm disorders and atrioventricular conduction disturbances with pulsed Doppler and two-dimensional echocardiography. The left atrium, mitral valve, and pulmonary venous ostia were visualized through the apical four-chamber view. Mitral and pulmonary venous flows were obtained by placing the Doppler sample volume at the appropriate orifice. Pulmonary venous flow was biphasic: a rapid filling wave was observed during systole when the mitral valve was closed; a second wave was observed in diastole during the rapid ventricular filling phase of mitral flow, but was significantly delayed. In patients without atrial contraction (atrial fibrillation and sinoatrial standstill), the initial rapid filling was greatly diminished and only the second diastolic wave appeared to contribute to left atrial filling. In patients with high-grade atrioventricular block, each atrial contraction was followed by a surge in flow from the pulmonary veins. These results are consistent with data obtained from invasive measurements in both dogs and man, and confirm the validity of the use of pulsed Doppler echocardiography in the study of pulmonary venous flow. We suggest that pulmonary venous flow is influenced by dynamic changes in left atrial pressure created by contraction and relaxation of the atrium and ventricle. The initial peak in pulmonary venous flow occurs with atrial relaxation simultaneously with the reduction of left atrial pressure, and the second peak occurs with left ventricular relaxation and rapid transmitral filling of the ventricle.

Adolescent↗

PubMed1985

Clinical use of digitalis materials.

Digitalis is a drug widely used in modern medicine for the control of ventricular response in atrial fibrillation and the treatment of congestive heart failure (CHF). Recently, the use of digitalis for the treatment of CHF in patients in sinus rhythm has become quite controversial. The findings of several clinical studies suggest a small but definite hemodynamic or clinical improvement in patients treated with digitalis. These effects are limited by the onset of toxicity, which is at least partially mediated via the central nervous system. If the inotropic effect of the drug could be separated from the central nervous system effect, much higher doses of digitalis could be tolerated and presumably a greater therapeutic effect could be obtained.

Animals↗

PubMed1985

Digitalis: its place in therapy.

Since the initial introduction of digitalis 200 years ago by Withering, its low therapeutic ratio has limited the use of this agent. The utility of digitalis in patients with congestive heart failure and a recent myocardial infarction has been questioned recently. Findings of rigorously controlled clinical studies suggest a small but definite hemodynamic and clinical improvement in patients administered digitalis. Congestive heart failure can be effectively treated without cardiac glycosides. However, when used judiciously, digitalis provides an additional agent in our therapeutic armamentarium. The inotropic, dormotropic, and vagomimetic properties are uniquely suited for the patient with supraventricular arrhythmias and compromised left ventricular function.

Digitalis Glycosides↗

PubMed1984

Specificity of capsaicin treatment in the cerebral vasculature.

Capsaicin has been shown to specifically deplete substance P from primary sensory afferents, including sensory nerves innervating blood vessels of the cerebral circulation as well as other vascular beds. In order to further document the specificity of this treatment, we examined the effect of capsaicin treatment on 3 other types of nerves in the guinea pig. Four tissues were examined: cerebral arteries, the mesenteric artery, the heart and iris. Norepinephrine content was not altered after capsaicin treatment, confirming that adrenergic nerves are unaffected. As indices of cholinergic nerves, activities of choline acetyltransferase and acetylcholinesterase were also unchanged after capsaicin treatment. In addition, no significant differences in levels of vasoactive intestinal peptide in cerebral arteries and the heart were found in animals treated with capsaicin. These findings underscore the specificity of capsaicin treatment for substance P containing nerves.

Acetylcholinesterase↗

PubMed1984

The assessment of antidysrhythmic drugs.

Assessments of efficacy of antidysrhythmic drugs at different clinical arrhythmia centers frequently produce discordant data, probably because of differences in patient population, technology to assess efficacy, study design, and concomitant drugs such as digitalis, diuretics, beta-adrenergic blocking agents, and calcium channel blockers. Furthermore, different doses employed may greatly influence the toxicity and efficacy of both conventional and experimental antiarrhythmic drugs. These variables make the design of studies in the field of antiarrhythmic therapy both difficult and of critical importance. The serious and complex nature of the disease entity against which these drugs are directed constitutes a considerable public health problem which requires that the problems be addressed in a definite and timely way.

Anti-Arrhythmia Agents↗