Fluoxetine impairs clearance of alprazolam but not of clonazepam.

Volunteer male subjects received single 1.0 mg oral doses of alprazolam and of clonazepam on two occasions, during coadministration of 40 mg/day fluoxetine or of placebo. When the sequence of trials was placebo first and fluoxetine second, fluoxetine coadministration significantly prolonged alprazolam half-life (20 versus 17 hours) and reduced clearance (48 versus 61 ml/min). No effect of fluoxetine was seen when fluoxetine was given first and placebo second, because norfluoxetine persisted into the placebo phase even though fluoxetine had been discontinued 2 weeks earlier. Fluoxetine had no significant effects on clonazepam elimination half-life or clearance regardless of the sequence of fluoxetine and placebo administration. In the fluoxetine-placebo sequence, fluoxetine significantly increased the rate of clonazepam absorption. Thus fluoxetine appears to impair clearance of alprazolam by way of microsomal oxidation but does not alter clearance of clonazepam by way of nitroreduction. The very slow elimination of norfluoxetine should be considered in the design of clinical or pharmacokinetic studies that involve fluoxetine.

2-benzazepines. 5. Synthesis of pyrimido[5,4-d][2]benzazepines and their evaluation as anxiolytic agents.

A series of 5H-pyrimido[5,4-d][2]benzazepines has been synthesized, starting from the corresponding 2-benzazepin-5-ones, and evaluated as potential anxiolytic agents. Selected compounds from this series show a pharmacological profile of action different than that of diazepam. They are more potent than diazepam in the anti-pentylenetetrazole test and in the [3H]diazepam binding assay, yet show less activity in the inclined screen test. A pharmacological data profile is given for 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (7c). The structure-activity relationships of these potential anxiolytic agents are discussed.

N-isopropyl-[123I] p-iodoamphetamine: single-pass brain uptake and washout; binding to brain synaptosomes; and localization in dog and monkey brain.

The kinetics of N-isopropyl-p-[123I]iodoamphetamine in rat brains were determined by serial measurements of brain uptake index (BUI) after intracarotid injection; also studied were its effects on amine uptake and release in rat's brain cortical synaptosomes; and its in vivo distribution in the dog and monkey. Serial BUI correspond to a first-pass extraction efficiency of 100% and a washout half-time of approximately 318 sec. The S-(+)-isomer inhibited norepinephrine uptake in synaptosomes as strongly as D-amphetamine, but was more potent in inhibiting synaptosomal uptake of serotonin. Both isomers were comparable to D-amphetamine in causing release of serotonin from synaptosomes, but the S-(+)-isomer promoted release of dopamine, whereas D-amphetamine did not. No specific localization in brain nuclei of the dog was seen, but there was progressive accumulation in the eyes. Rapid initial brain uptake in the ketamine-sedated monkey was noted, and further slow brain uptake occurred during the next 20 min but without retinal localization. High levels of brain activity were maintained for several hours. The quantitative initial single-pass clearance of the agent in the brain suggests its use in evaluation of regional brain perfusion. Its interaction with brain amine-binding sites suggests its possible application in studies of cerebral amine metabolism.

Heart norepinephrine levels after exercise training in the rat.

Rats exercise trained by swimming one hour daily five days per week for three months developed cardiac hypertrophy. The NE concentration (0.469 mug/g) and total NE content (0.741/mug) of the hypertrophied hearts were not significantly different from levels in hearts of unexercised control rats.

[3H]CL 218,872, a novel triazolopyridazine which labels the benzodiazepine receptors in rat brain.

We examined the specific binding of [3H]CL 218,872, a novel triazolopyridazine to benzodiazepine receptors in the rat cerebral cortex. Two binding sites with KD values of about 10-30 nM and 200-600 nM were demonstrated. A number of benzodiazepine anxiolytics inhibited [3H]CL 218,872 binding in a manner which correlates with the potency of these drugs for inhibiting [3H]benzodiazepine binding. Our initial studies show that [3H]CL 218,872 can label the benzodiazepine receptors and may prove to be a useful probe for studying benzodiazepine heterogeneity and regulation.

A pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of pharmacological activity of the benzodiazepines.

Ex vivo receptor binding as a function of time was determined in Charles River rats. The pharmacokinetic and protein binding parameters in man as well as the ex vivo receptor binding parameters in rat brain for three benzodiazepine induction agents, diazepam, lorazepam and midazolam, were used to develop and test a pharmacokinetic/pharmacodynamic/receptor binding model. The model was subsequently used to predict changes in receptor binding and pharmacodynamics as a function of changes in pharmacokinetics. The model was found to be a good predictor of the relative onset and duration of the sedative and amnesic properties in normal subjects as well as in the presence of certain patho-physiological conditions and certain drug interactions.

A pharmacoeconomic model to evaluate antibiotic costs.

STUDY OBJECTIVES: To characterize patient sociodemographics and health, describe vancomycin treatment parameters and clinician-rated outcomes, and determine costs associated with treatment including preparation and administration, adverse events, and toxicity. DESIGN: A prospective study to develop a model for costs associated with antibiotic treatment (vancomycin). SETTING: A community hospital. PATIENTS: One hundred adults with active infections. INTERVENTIONS: Mean duration of therapy was 10 days, and most patients received 2000 mg/day. Serum concentrations were monitored in two of three patients. Detailed cost analyses were completed on a subset of 26 patients selected at random from the overall sample. MEASUREMENTS AND MAIN RESULTS: Sepsis and skin and skin structure infections were the most common indications for vancomycin therapy. Treatment was effective in 81 patients, failed in 9, and was not evaluable in 10. Thirty-eight percent of patients experienced adverse events attributable to the drug. Phlebitis was common, and red man syndrome, nephrotoxicity, and ototoxicity were infrequent. CONCLUSIONS: Total cost of vancomycin treatment for 100 patients was $30,251: $23,855 for preparation and administration, $1710 for monitoring serum concentrations, and $4686 for treating adverse reactions. Drug costs accounted for only 55% of the total cost. Vancomycin is safe and effective, but phlebitis is underreported and significantly affects cost.

Mechanisms of action and clinical characteristics of three atypical antidepressants: venlafaxine, nefazodone, bupropion.

Tricyclic antidepressants have multiple sites of pharmacological actions which are responsible for their tolerability and toxicological problems as well as their efficacy. That fact has prompted the search for antidepressants with fewer sites of action. That search resulted in the serotonin selective reuptake inhibitors (SSRIs), with presumably only one site of action. Although the SSRIs are safer and better tolerated than the TCAs, a significant percentage of patients do not benefit from SSRIs. A group of "atypical antidepressants" including bupropion, nefazodone, and venlafaxine are known to have multiple sites of antidepressant action but do not interact at sites associated with side effects or tolerance. Thus this group of antidepressants present an important alternative to the SSRIs in the pharmacological therapy of depression. The basic pharmacological properties of bupropion, nefazodone, and venlafaxine are presented along with clinical profiles and the role of these three antidepressants in the pharmacotherapy of depression is discussed.

An outcomes study of an occupational medicine intervention program for the reduction of musculoskeletal disorders and cumulative trauma disorders in the workplace.

Upper-extremity musculoskeletal pains or disorders (MSDs) account for a significant number of work-related illnesses in the US workforce. Although the concept of MSD prevention is appealing, little has been done to demonstrate the successful application and benefit of these programs. In 1995, an aircraft manufacturer established a unique risk-management program based on the individual risk assessment (CtdMAP) for new hires. The MSD intervention program was designed to prospectively evaluate each new employee for their individual risk of developing MSDs in the workplace. Before job placement, individuals at higher risk were assigned to a period of transitional work. Workers' compensation costs decreases per year were 16%, 3%, 24%, and 12%, while work hours increased by 56%. Employer-estimated savings in direct workers' compensation costs per year were $469,990, $678,337, $1,936,105, and $1,995,759.

Correlation of changes in the GABA-ergic system with the development of spasticity in paraplegic cats.

Following spinal cord transection there occurred decreases in Km and Vmax of glutamate decarboxylase (GAD) both above and below the lesion, and an initial decrease in the concentration of GABA. Concomitantly, there was a gradual decrease in presynaptic inhibition. Eight to 12 weeks after spinal cord transection, Km and Vmax for GAD returned to control values, but the GABA content of the spinal cord below the lesion increased significantly and presynaptic inhibition became maximally depressed. These results suggested that during the chronic phase of spinal cord injury there is a decrease in release of GABA, the interneuronal inhibitory neurotransmitter which mediates presynaptic inhibition. Diazepam, a GABA enhancer, increased presynaptic inhibition in acute and chronic spinal cats, this being accompanied by a reduction in somatic muscular spasticity. The degree of this enhancement by diazepam, however, is attenuated with gradual loss of presynaptic inhibition. In the acute cat, a conditioning volley applied to cutaneous afferents blocked the inhibition of the monosynaptic response to extensor motoneurones. In contrast, in chronic spinal cats (eight to 12 weeks), the duration of complete blockade was markedly reduced and was followed by a prolonged period which cutaneous nerve stimulation potentiated the monosynaptic discharge. Similar to GABA, there also occurred an increase of substance P below the level of the lesion. Other neurotransmitters (e.g., norepinephrine, serotonin) accumulated above and disappeared below the transection level. Although somatic msucular spasticity appears to be, to some extent, due to GABA dysfunction in the spinal cord, alterations in "normal" functioning of other neurotransmitters and the loss of supraspinal control also contribute to this state.