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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 127 records · Page 7Linked to original sources
PubMed1994

Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo.

Biotransformation of the tricyclic antidepressant desipramine (DMI) to its metabolite 2-hydroxy-desipramine (2-OH-DMI) was studied in vitro using microsomal preparations from human, monkey, mouse and rat liver. In all species 2-OH-DMI was the principal identified metabolite. Mean (+/- S.E.) reaction parameters in six human liver samples were: Vmax, 0.11 +/- .02 nmol/ml/min/mg protein; Km, 16.1 +/- 4.2 microM. Quinidine was a highly potent inhibitor of 2-OH-DMI formation (mean Ki = 0.053 microM), consistent with the presumed role of Cytochrome P450-2D6 in mediating this reaction. Ketoconazole was a much less potent inhibitor (mean Ki = 10.3 microM). Two serotonin-specific reuptake inhibitor (SSRI) antidepressants, and their respective metabolites, were evaluated as potential inhibitors of 2-OH-DMI formation. Fluoxetine (FLU) and norfluoxetine (NOR) were the most potent inhibitors (mean Ki values: 3.0 and 3.5 microM, respectively). Sertraline (SERT) and its metabolite desmethylsertraline (DES) also inhibited the reaction (mean Ki: 22.7 and 16.0 microM), but were significantly less potent than FLU or NOR. Values of Ki and Km measured in vitro were used to generate a theoretical prediction of the degree of clearance inhibition in vivo at any given concentration of substrate and inhibitor. The model was applied to a clinical study in which DMI clearance in humans was impaired by coadministration of FLU (yielding FLU and NOR in plasma) or by SERT (yielding SERT and DES in plasma). Use of plasma SSRI concentrations in the predictive model underestimated the actual impairment of DMI clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder.

A series of 237 patients with DSM-III-diagnosed panic disorder, or agoraphobia with panic attacks, received alprazolam as part of the placebo-controlled Cross-National Collaborative Panic Study. After a 1-week drug-free period, alprazolam dosage was titrated upward with the objective of reaching 6.0 mg/d in all patients. At week 3 of treatment, alprazolam plasma levels were significantly correlated with daily dosage (regression slope: 11.7 ng/mL per milligram per day) but with considerable individual variation. Among patients with spontaneous panic attacks, 70% of those with plasma alprazolam levels greater than 20 ng/mL achieved complete remission vs 31% of those with levels less than 20 ng/mL. Situational panic attack remission increased in frequency with increasing plasma levels, but the relationship was not significant. Patient- and physician-rated global improvement and Hamilton Anxiety and Depression Scale score reductions were maximal at 20 to 39 ng/mL, with no further benefit at higher levels. Central nervous system-depressant side effects increased in frequency with higher plasma levels. Between weeks 3 and 8 of treatment, physicians were permitted to adjust dosage (maximum: 10 mg/d) to optimize response. At week 8, the dose-concentration relationship was essentially identical (regression slope: 10.8 ng/mL per milligram per day), but plasma levels were no longer related to efficacy or side effects. Thus, monitoring of plasma alprazolam concentrations may have a clinically useful role during short-term treatment of panic disorder.

Adolescent↗
PubMed1993

Chronic benzodiazepine administration. XII. Anticonvulsant cross-tolerance but distinct neurochemical effects of alprazolam and lorazepam.

Tolerance to the sedative and anticonvulsant effects of benzodiazepines has been reported, but cross-tolerance among benzodiazepines is poorly characterized. To evaluate cross-tolerance between lorazepam and alprazolam in a reliable anticonvulsant pharmacodynamic model, we treated mice with either drug for 14 days, and with the two drugs sequentially for 7 days each. Pentylenetetrazole-induced seizure thresholds were similar in mice treated for 14 days with lorazepam or alprazolam, 2 mg/kg/day. For both compounds, a discontinuation effect characterized by reduced seizure threshold occurred at 4 days after discontinuation. Substitution of alprazolam for lorazepam after 1 week, and vice versa, did not interrupt tolerance. [3H]flumazenil binding in vivo was downregulated in cortex after 14 days of either drug. However, binding was also reduced in hippocampus for lorazepam but not for alprazolam. Substitution of alprazolam for lorazepam resulted in downregulation in cortex only, similar to lorazepam alone. Conversely, substitution of lorazepam for alprazolam led to binding changes similar to lorazepam alone. These data demonstrate cross-tolerance to the convulsant effects of pentylenetetrazole between lorazepam and alprazolam. However, effects of the two compounds on benzodiazepine receptor binding in hippocampus remain distinct.

Alprazolam↗
PubMed1993

Cognitive effects of beta-adrenergic antagonists after single doses: pharmacokinetics and pharmacodynamics of propranolol, atenolol, lorazepam, and placebo.

The behavioral effects of two beta-adrenergic receptor antagonists, selected to represent differing lipophilicity, were evaluated in a double-blind, single-dose, parallel-group study. A group of 55 healthy volunteers (mean age, 28 years) received single oral doses of placebo, atenolol (50 mg), propranolol (40 mg), or lorazepam (2 mg). Plasma drug concentrations, self-ratings of sedation and mood, observer ratings of sedation, and performance on the Digit Symbol Substitution Test (DSST) were assessed at multiple times during 24 hours after drug administration. Information acquisition and recall were tested at 3 and 24 hours after drug administration. Lorazepam significantly increased sedation and fatigue, impaired DSST performance, and impaired memory. The time course of these changes was highly consistent with plasma lorazepam concentrations. In contrast, atenolol and propranolol produced at most small changes in self-ratings and observer ratings and did not alter DSST performance or memory. Under experimental conditions that are sensitive to the depressant effects of a typical benzodiazepine, single doses of atenolol and propranolol produced no meaningful changes, compared with placebo.

Adrenergic beta-Antagonists↗
PubMed1993

Chronic benzodiazepine administration. XI. Concurrent administration of PK11195 attenuates lorazepam discontinuation effects.

Benzodiazepine discontinuation is associated with alterations in motor activity and gamma-aminobutyric acid-A receptor upregulation in a mouse model. Prior studies indicate that concurrent administration of the compound N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3- carboxamide (PK1195), a "peripheral" site benzodiazepine antagonist, can attenuate the effects of lorazepam on tolerance and receptor alterations. To evaluate the effects of PK11195 administration on benzodiazepine discontinuation, we administered lorazepam (2 mg/kg per day), PK 11195 (1 to 10 mg/kg per day) or the combination to mice for 7 days, and then evaluated pentylenetetrazole-induced seizure threshold and benzodiazepine binding at days 1, 4, and 7 after discontinuation. Seizure threshold was reduced at 4 days after lorazepam discontinuation; this effect was attenuated by coadministration of PK11195 at 5 mg/kg per day. Lorazepam discontinuation effects were not altered by PK11195 at 1 mg/kg per day, whereas the 10-mg/kg dose was not different from 5 mg/kg per day. The competitive ligand Ro5-4864 at 10 mg/kg per day, blocked the effects of PK11195 on lorazepam discontinuation. Benzodiazepine receptor binding in vivo was increased in the cortex and hippocampus at 4 days postlorazepam discontinuation. This effect was attenuated in the hippocampus but not in the cortex by concurrent administration of PK1195. These data indicate that concurrent administration of PK11195 may attenuate discontinuation effects of lorazepam.

Animals↗
PubMed1993

Alprazolam metabolism in vitro: studies of human, monkey, mouse, and rat liver microsomes.

Biotransformation of the triazolobenzodiazepine alprazolam (ALP) was studied in vitro using hepatic microsomal preparations from human, monkey, mouse, and rat liver tissue. Two principal hydroxylated metabolites were identified: 4-hydroxy- and alpha-hydroxy-alprazolam (4-OH-ALP and alpha-OH-ALP). In all species, rates of 4-OH-ALP formation exceeded those of alpha-OH-ALP. In human liver microsomes, ratios of 4-OH-ALP/alpha-OH-ALP reaction velocities calculated at clinically relevant plasma concentrations of ALP ranged from 7 to 17, qualitatively consistent with, but numerically larger than, the ratio of the plasma levels of the two metabolites during clinical use of ALP in humans. Km values for both 4-OH-ALP (170-305 microM) and alpha-OH-ALP (63-441 microM) considerably exceeded the usual maximum plasma concentration observed in humans (200 ng/ml, 0.65 microM), consistent with the linear (dose-independent) pharmacokinetic characteristics of ALP observed in humans. Thus formation of 4-OH-ALP via hydroxylation is the major route of ALP metabolism. This pathway is probably mediated by the cytochrome P-450-3A subfamily. Factors that impair the activity of this cytochrome subtype are likely to impair clearance of ALP in vivo.

Adult↗
PubMed1993

Possible interaction between fluoxetine and pimozide causing sinus bradycardia.

Fluoxetine has been reported to have interactions with antipsychotics and other antidepressants with symptoms of toxicity of these drugs. We report a case of a possible interaction with pimozide which led to a potentially life threatening bradycardia. Careful monitoring should be done when these two drugs are prescribed at the same time, especially in the elderly and in patients with cardiac disease.

Aged↗
PubMed1993

Clinical pharmacokinetics of antidepressants in the elderly. Therapeutic implications.

The prevalence of depression in the elderly suggests that a substantial number of older patients will be treated with an antidepressant medication such as one of the tricyclics, trazodone, fluoxetine or lithium. The physiological changes that accompany aging raise the possibilities of altered pharmacokinetics, patterns of efficacy and adverse effect profiles. The literature addressing the subject of antidepressant use in the elderly has not provided a clear, consistent picture of how these drugs behave in this population in comparison with younger patients. Particularly in the case of the tricyclic antidepressants (TCAs), a large degree of interindividual variation in drug clearance (CL) confounds attempts to find differences attributable to age per se. Study design, however, is also a problem in that very few investigators include a young control group, choosing instead to compare their data with previously reported outcomes. Designations of statistical significance and positive correlation also differ among investigators, and the clinical significance of any finding is not always addressed. The available data suggest that imipramine CL is reduced in the elderly and that amitriptyline CL may be reduced. Desipramine CL does not appear to be affected by age, although decreased renal function in the elderly may lead to accumulation of the hydroxylated metabolite, the clinical importance of which is not known. Nortriptyline is the most thoroughly studied TCA in the elderly. CL seems decisively lower only in elderly patients with concurrent medical illness. The hydroxylated metabolite probably accumulates with diminishing renal function. Not enough data are available on doxepin to make a conclusion. Trazodone CL is diminished somewhat in elderly men. Lithium CL appears to diminish with the declining renal function associated with aging. Fluoxetine data are sparse. Available data do not show any decrease in CL of the parent drug; more information is needed on the metabolite norfluoxetine. Although knowledge of CL changes with aging can help the clinician more accurately achieve the desired steady-state concentration of a drug during long term therapy, much work is still needed to evaluate the relationships among drug concentrations at steady-state, efficacy and adverse effects in the elderly.

Aged↗
PubMed1993

Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications.

The triazolobenzodiazepine alprazolam is biotransformed by hepatic microsomal oxidation, yielding two hydroxylated metabolites (4-hydroxy- and a-hydroxy-alprazolam) as the principal metabolic products. Both metabolites have lower benzodiazepine receptor affinity than the parent compound and at steady state appear in plasma at concentrations considerably lower than intact alprazolam. Thus, clinical activity during treatment with alprazolam is essentially entirely attributable to intact alprazolam. The cytochrome P450 IIIA subfamily appears to mediate alprazolam metabolism in humans. This cytochrome subfamily is not subject to variation due to genetic polymorphism. Ketoconazole, cimetidine, macrolide antibiotics, and serotonin-reuptake-inhibitor antidepressants impair alprazolam biotransformation in vitro. Reduced clearance of alprazolam in vivo has been demonstrated for drugs in this group that have been studied in humans; for those not yet studied, impaired alprazolam clearance should be anticipated during coadministration. Studies of plasma alprazolam concentration versus clinical response during short-term treatment of panic disorder indicate that therapeutic response at steady-state plasma levels of 20 to 40 ng/mL is significantly greater than at levels less than 20 ng/mL. Substantial additional benefit from plasma levels greater than 40 ng/mL is not consistently demonstrated. However, side effects attributable to benzodiazepine agonist activity (e.g., drowsiness, sedation) increase in frequency with increasing steady-state plasma levels. Concentration-response data indicate that monitoring of alprazolam plasma levels can be of considerable clinical value during treatment of panic disorder.

Alprazolam↗