High altitude may be synergistic with pulmonary hazards of appetite control medications fenfluramine and dexfenfluramine.

Clinical observations over the past 15 years incriminated first fenfluramine and recently dexfenfluramine in the provocation of primary pulmonary hypertension. Limited animal toxicology data tend to support this inference. The basis for respiratory pathology of high-altitude pulmonary malfunction, which reaches its maximal level in high-altitude pulmonary edema, evolves from and depends upon the occurrence of pulmonary hypertension. For this reason we hypothesize that high altitude and these two anorexic medications constitute a potentially synergistic combination, of which physicians treating patients for high-altitude illness, as well as those prescribing the drugs, should be aware.

Additive hypothermic effects of cocaine and nicardipine in guinea-pigs.

1. This study investigated the thermoregulatory effects of cocaine combined with two reported antidotal treatments for acute cocaine overdosage, calcium channel blocker therapy and cold ambient temperatures. 2. Cocaine and nicardipine alone lowered the core temperature of female guinea-pigs (ambient temperature, 5 degrees C) which resulted in a drop in core temperature of approximately 2 degrees C at their highest respective doses (40 mg/kg and 50 mg/kg). 3. Nicardipine administration 30 min prior to cocaine caused an almost 2-fold drop in temperature (3.75 degrees C) relative to either drug alone. 4. The data suggest that cocaine and nicardipine produce hypothermia by different, but additive, mechanisms.

Effect of methyl methacrylate on isolated atria and interaction with isoproterenol, atropine and calcium chloride.

1. Spontaneous rate and contractile force of isolated rat and rabbit atria suspended in a tissue bath were recorded before and after drugs. Methyl methacrylate monomer (MMA) alone both decreased force and increased rate dose-dependently. 2. Concentrations of calcium chloride or isoproterenol that alone increased both rate and force of rat atrial contraction were fully and only partially able, respectively, to restore force to normal after MMA. 3. Atropine prevented changes in rat atrial function from low-effective doses of MMA, but not higher ones; it also failed to prevent the reduction of contractile force by a calcium channel blocker, verapamil. 4. There are similarities but also differences between actions of MMA and verapamil on rat atria.

Acute cardiovascular effects of methyl methacrylate monomer: characterization and modification by cholinergic blockade, adrenergic stimulation and calcium chloride infusion.

1. Methyl methacrylate monomer (MMA) given by i.v. infusion to anesthetized dogs caused a sustained hypotension, bradycardia, reduction of cardiac output and stroke volume, and increased peripheral resistance. 2. Epinephrine i.v. could reverse the hypotension but not the bradycardia; isoproterenol i.v. could reverse the bradycardia but not the hypotension. 3. Bilateral cervical vagotomy prevented bradycardia but not other cardiovascular effects of MMA, and prevented all respiratory effects except hypoxemia. 4. Calcium chloride i.v. reversed all circulatory changes except bradycardia; a combination of atropine and calcium reversed all cardiovascular changes from MMA.

Factors in the lethality of i.v. phencyclidine in conscious dogs.

1. Pretreatment were pancuronium prevented convulsions and hyperthermia, but had no effect on acidemia or changes in cardiovascular parameters after intravenous (i.v.) infusion of phencyclidine (PCP). 2. While dogs survived higher amounts of PCP, they failed to regain spontaneous respiratory function. 3. Mechanical ventilation alone increased the mean lethal dose/time of PCP and reduced the effects of PCP on arterial systolic pressure, cardiac output, and PCO2. 4. EKG showed ventricular arrhythmias, which progressed to death. 5. Phenytoin pretreatment plus respiratory assistance increased the lethal dose and reduced PCP effects on cardiovascular parameters, body temperature, and cardiac rhythm. 6. Blocking of convulsions prevented hyperthermia and acidemia; respiratory support reduced circulatory effects, but respired dogs then died, at higher doses, from a primary myocardial toxicity of PCP.

Effect of sex steroids on cocaine lethality in male and female mice.

1. Endogenous sex steroid levels were altered in mice via gonadectomy, via physiological or supraphysiological doses of testosterone and/or estradiol, and via tamoxifen dosing to antagonize estrogens. 2. The role of sex hormones in susceptibility to cocaine lethality was examined via the response of mice after endocrine alterations to an intraperitoneal (i.p.) cocaine HCl (75 mg/kg). Incidence of deaths was significantly decreased only in sham-operated males receiving estradiol or tamoxifen and in ovariectomized or sham-operated females receiving doses of estradiol. 3. The levels of estradiol in both sexes appeared to be more influential than were levels of testosterone as a determinant of susceptibility to cocaine.

Respiratory and circulatory effects of centrally administered phencyclidine in anesthetized dogs.

1. Anesthetized dogs were given phencyclidine HCl (PCP) by intracerebroventricular (i.c.v.) injection. 2. Physiological parameters were monitored after consecutive doses of 0.5, 1.0 and 2.0 mg of PCP. 3. Dose-related changes seen, including bradycardia, hypotension and bradypnea, were opposite to those produced by i.v. doses. 4. Single doses of 1.0 or 2.0 mg of PCP confirmed the prior observations, and the latter provided the baseline for further observations on dogs receiving PCP before various i.c.v. pretreatments--atropine, haloperidol, phentolamine or propranolol--in efforts to characterize the central neurotransmitter system(s) involved in the PCP effects.

2-Amino- and 2-guanidino-1,2,3,4-tetrahydro-1,4-epoxynaphthalenes as conformationally defined analogues of alpha-adrenergic agents.

The exo- and endo-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-1,4-epoxynaphthalenes++ + (3b and 4b, respectively) were prepared and evaluated as conformationally defined analogues of the alpha 1-agonist methoxamine. Only compound 3b exhibited significant alpha 1-agonist activity in the field stimulated rat vas deferens assay. Since 3b closely approximates the antiperiplanar form of (1R,2S)-(-)-erythro-methoxamine, the results suggest that methoxamine interacts with the alpha 1-adrenoceptor in the trans extended form. The exo-guanidino derivative 5 was found to be a partial alpha 1-agonist. Among the exo- and endo-2-amino-1,2,3,4-tetrahydro-1,4-epoxynaphthalenes (3a and 4a, respectively) prepared as rigid analogues of norephedrine, compound 3a possessed agonist activity at both alpha 1- and alpha 2-adrenoceptors, whereas 4a was inactive at either receptor.

Toxicity of MDA (3,4-methylenedioxyamphetamine) considered for relevance to hazards of MDMA (Ecstasy) abuse.

Despite a paucity of data on its animal pharmacology and toxicology, MDMA [Ecstasy, XTC, ADAM; (+/-)-3,4-methylenedioxymethamphetamine] was introduced as an "underground" (FDA-unapproved) adjunct to psychotherapy in the late 1970's and early 1980's, in addition to its use as a recreational drug. Analysis of the limited experimental literature indicates that LD50's for MDMA in five species by several routes of administration tend to predict a significant human toxicity. MDMA was either equally toxic or slightly to moderately less toxic than its close congener, MDA, (+/-)-3,4-methylenedioxyamphetamine. It is suggested that extrapolation of the pharmacologic/toxicologic data available for MDA to MDMA should be assumed to be valid until disproven. Recently published canine data describe physiologic disturbances caused by acute overdosage of MDA, and also indicate the utility of chlorpromazine as an antidote preventing fatalities associated with severe hyperthermia, lactacidemia, hypertension and tachycardia. The toxicology of MDMA warrants further direct study in view of its continuing illegal distribution.

Effects of anesthesia and phenoxybenzamine on responses of dogs to IV subtoxic doses of 3,4-methylenedioxyamphetamine (MDA).

Racemic 3,4-methylenedioxyamphetamine HCl (MDA) was tested for acute intravenous (i.v.) lethality in mongrel dogs. The LD50 and 95% confidence limits were 8.1 (7.0-9.4) mg/kg, and the LD1 and LD99 were approximately 5 and 14 mg/kg. Subtoxic doses (0.1, 0.3, 1.0 and 3.0 mg/kg, i.v.) were tested for acute effects on cardiovascular and respiratory functions in conscious dogs prepared surgically under local anesthesia and also in dogs anesthetized with pentobarbital (30 mg/kg, i.v.). Four experimental groups were constituted, by pretreating or not, both conscious and anesthetized dogs with phenoxybenzamine HCl (15 mg/kg, i.v.). Arterial and left ventricular pressures tended to be elevated more by MDA in the anesthetized than in the conscious dogs. These and other cardiovascular parameters tended to be more fully antagonized by phenoxybenzamine in anesthetized than in conscious dogs. Respiratory rate was increased by higher doses, more so in the conscious group, but the increase was fully blocked by phenoxybenzamine. Possible clinical implications of the data are suggested.

Effects of an i.v. lethal dose of 3,4-methylenedioxyamphetamine (MDA) in the dog and antagonism by chlorpromazine.

A high intravenous (i.v.) dose of MDA (20 mg/kg) to mongrel dogs elevated body temperature, heart rate, mean arterial pressure and other cardiovascular parameters initially, but only the 1st two remained high. Other functions soon became quite depressed, and death shortly ensued. Arterial pO2 decreased, but pH and pCO2 showed a biphasic response after an initial decrease, Dogs that received chlorpromazine (10 mg/kg, i.v.) after MDA showed stabilization of physiological parameters, and survival through 48 hr.

A compact multichamber gas inhalation exposure system for mice.

A multi-unit, dynamic flow, inhalation exposure system which is capable of accommodating 12 mice per unit has been described. Components of the system include a mixing board, one or more glass distributing tubes, and detachable glass chamber tubes. The flow of a specified concentration of test gas exits from the mixing board, enters a distributing tube, and is then distributed equally to 12 chamber tubes housing one mouse each. Advantages includes quick equilibration time (10 min), relatively low flow rates (20 l/min per distributing tube), ease of disassembly for cleaning, compact size, modest expense and minimal temperature, pressure and physico-chemical effects.

2-(beta-Arylethylamino)- and 4-(beta-arylethylamino)quinazolines as phosphodiesterase inhibitors.

The existence of several forms of cAMP phosphodiesterase having differing kinetic characteristics suggests the feasibility of developing tissue-selective inhibitors of this enzyme. This observation is of particular importance in the development of therapeutic agents for the management of reversible obstructive airways disorders. The present report describes the design, synthesis and pharmacological characterization of a series of 6,7-dimethoxyquinazoline derivatives having beta-arylethylamine substituents at the 2- or 4-positions. The quinazoline nucleus is intended to confer a high degree of inhibitory activity for phosphodiesterase while the beta-aryethylamine moieties are designed to provide selectivity for adrenergically innervated tissue. The target compounds of this study, 6 and 7, were prepared via beta-arylethylamine displacement of chloride from an appropriate chloroquinazoline intermediate. The resulting products were evaluated for their ability to relax guinea pig tracheal smooth muscle and as inhibitors of phosphodiesterase.

Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse liver preparations.

Using a mouse liver microsomal preparation, it was found that the heterocyclic ring system of MPTP underwent an initial alpha-oxidation to give chemically reactive metabolites that may be associated with the induction of Parkinsonism by MPTP. Subsequent oxidative metabolic transformations of these intermediates were found to give a lactam metabolite and a pyridone metabolite that potentially may interact with the neurotransmitter system.

Conformationally restrained fentanyl analogues. 2. Synthesis and analgetic evaluation of perhydro-1,6-naphthyridin-2-ones.

Conformational flexibility of the N-acyl portion of fentanyl-type analgetics was restricted through the synthesis of novel perhydro-1,6-naphthyridin-2-one derivatives. Neither the cis-fused derivative (5a), the trans-fused derivative(5b), nor the enamide 8a possessed analgetic activity in the mouse tail-flick assay, reaffirming the sensitivity of this portion of 4-anilidopiperidine analgetics to conformational restraint.