In vitro and in vivo evaluation of albumin-encapsulated primaquine diphosphate prepared by nebulization into heated oil.

Nebulization of an aqueous mixture of primaquine diphosphate and albumin into heated vegetable oil produces spherical particles with an average size of 6 microm. The microparticles are relatively stabile in buffers of pH 7.2 and 4.5 and completely degrade when exposed to proteolytic enzymes such as trypsin. Pharmacokinetic evaluation of the albumin-encapsulated primaquine diphosphate shows significantly higher levels in mouse liver tissue relative to free drug 2-48 h post-IP administration. Higher AUC (2.8x), lower steady-state volume of distribution (10x) and slower half-life (2.5x) relative to an equivalent dose of free primaquine diphosphate suggest liver targeting and sustained release of the drug from the microparticles.

Effects of fenfluramine on ejaculatory function, luteinizing hormone and testosterone levels in men with hypogonadotropic hypogonadism and premature ejaculation.

Serotonergic neurotransmission is associated with the regulation of aggressive behaviour, anxiety and affect. Serotonin (5-HT) reuptake inhibitors (SRIs) have been extensively utilized in the treatment of affective disorders; however, their use often results in ejaculatory inhibition. Serotonin appears to modulate male sexual function through its influence on luteinizing hormone (LH) secretion but only when the steady state is altered. Premature ejaculation (PME) is defined as persistent or recurrent ejaculation with minimal sexual stimulation (DMS-III-R). While the aetiology of PME remains unclear, an underlying anxiety disorder may be a major contributing factor. It has been recently suggested that patients with premature ejaculation (PME) have an associated hypogonadotropic hypogonadism. This study was undertaken to determine whether the administration of the SRI fenfluramine would result in changes in PME (inhibitory effect) and release of LH which could be indirectly measured through an increase in the production of testosterone (disinhibitory effect). Six patients with PME and hypogonadotropic hypogonadism were treated with fenfluramine (20 mg). Both inhibition of PME (based on graded couple's responses) and increased plasma LH and testosterone levels occurred following treatment. These observations strongly suggest a role for serotonergic modulation in the occurrence of PME.

n-pentyl N-acetylprolinate. A new skin penetration enhancer.

The activity of n-pentyl N-acetylprolinate (PNAP) as a transdermal penetration enhancer was investigated. PNAP was synthesized from L-proline by acetylation with acetic anhydride, followed by acid-catalyzed esterification with 1-pentanol. Structure confirmation was accomplished by IR and NMR spectroscopy and elemental analysis. Benzoic acid (BA) was used as a model drug, and the effect of PNAP on the flux of BA through human cadaver skin was evaluated. The central nervous system (CNS) toxicity of PNAP was evaluated by comparing the effects of intraperitoneal administration of PNAP to mice with those of laurocapram (Azone), a known penetration enhancer. Based on preliminary studies, PNAP appears to be an effective transdermal penetration enhancer, is nontoxic at low doses, and exhibits dose-related CNS toxicity at higher doses.

The oral antihypertensive activity of the methylated derivatives of phenyl-2-aminoethyl sulfide.

We have reported previously that phenyl-2-aminoethyl sulfide and its derivatives are excellent substrates for dopamine-beta-monooxygenase and produce an antihypertensive effect in spontaneously hypertensive rats after i.p. administration. In the studies reported herein, we demonstrate that alpha-methyl-phenyl-2-aminoethyl sulfide and 4-hydroxy-alpha-methyl-phenyl-2-aminoethyl sulfide, the methylated and hydroxymethylated derivatives of phenyl-2-aminoethyl sulfide, respectively, decrease mean arterial pressure in conscious, unrestrained spontaneously hypertensive rats after p.o. administration. This antihypertensive effect after p.o. administration occurs without the undesirable transient rise in blood pressure observed previously after i.p. administration. Results using the methodology of food-reinforced operant conditioned behavior are consistent with the interpretation that the ring hydroxylated derivatives, 4-hydroxy-phenyl-2-aminoethyl sulfide and 4-hydroxy-alpha-methyl-phenyl-2-aminoethyl sulfide, do not penetrate into the central nervous system. This finding supports our contention that the primary site of action for the antihypertensive activity of the sulfides may be the peripheral adrenergic nerve ending. In view of the current high degree of interest in chiral development, the enantiomeric specificity of the antihypertensive activity of alpha-methyl-phenyl-2-aminoethyl sulfide was also evaluated. Results from these studies demonstrate that the (S)-enantiomer of alpha-methyl-phenyl-2-aminoethyl sulfide is more effective in lowering blood pressure after p.o. administration than the (R)-enantiomer. The implications of our findings in terms of the mechanism of action of these compounds are discussed.

Clinical monitoring guidelines for neuroleptic and antidepressant drugs. Central State Hospital, Milledgeville, Georgia.

A description of clinical monitoring guidelines for neuroleptic and antidepressant drugs is presented. These guidelines were developed for use at a large, state-operated psychiatric facility to provide a framework for standardized monitoring and use practices for all residents being treated with these drugs. The guidelines include information related to routine monitoring for all residents as well as specific guidelines for monitoring residents in high risk groups.

Incidence of methaqualone in driving-under-the-influence (DUI) cases in the state of Georgia.

A retrospective study was undertaken to assess the range of blood methaqualone levels, which should be considered sufficient to produce deterioration of driving ability. Data from 974 driving-under-the influence (DUI) cases were subdivided into five major catagories based on whether drugs other than methaqualone were discovered during the analytical procedures. The range of blood methaqualone levels, which appear to cause significant motor skill impairment, are discussed for each category. Also included are data from 20 of these cases indicating the symptoms of methaqualone intoxication which were reported by arresting officers.

Actometric effects of intravenous cocaine in rats.

Intravenous infusions of cocaine, in dosages which have been reported to maintain self-administration behavior, were administered to cannulated rats. Ten identical infusions were administered at 6 min intervals within a session. The activity occuriring in the initial minute following infusions was compared to that produced by saline infusions. Dosages of 200, 400, 800 and 1200 microgram/kg significantly increased activity. However, this effect was not maintained throughout the session. The tenth infusion no longer increased activity as compared to the initial infusion. Therefore these data would not support the hypothesis that cocaine-induced activity was responsible for maintaining cocaine self-administration behavior in this species. Pretreatment with agents which disrupt the synthesis of dopamine and/or norepinephrine failed to antagonize this initial increase in activity. These data would suggest that the activity effect of cocaine is not dependent on newly synthesized pools of the catecholamines.

2-Azabicyclo (2.2.2)octane analogues of the prodine analgetics.

The synthesis and analgetic activity of analogues of prodine-type analgetics in which the conformation of the piperidine ring is restricted in the boat form using the 2-azabicyclo (2.2.2)octane nucleus are reported. One of these analogues, 2-methyl-6-trans-phenyl-6-cis-propionoxy-2-azabicyclo (2.2.2)octane (3), showed significant analgetic activity (ED50 equals 3.1 mg/kg).