Lethality of opioid and antihistaminic combinations in mice.

The lethality of morphine (37.5, 75, and 150 mg/kg) and tripelennamine (10,20,40 and 60 mg/kg), given alone and in combination, was evaluated in mice housed in groups of 16. When given alone, neither drug produced death at any dose. Combining the drugs produced supra-additive effects: some deaths occurred at all combination doses. The lethality of pentazocine (20, 40 and 80 mg/kg) and diphenhydramine (20, 40 and 80 mg/kg), given alone and in combination, also was evaluated. Neither drug alone produced death at any dose. Supra-additive effects were observed when the drugs were combined. These results are similar to earlier findings concerning the lethality of combinations of pentazocine and tripelennamine.

Lethality of pentazocine and tripelennamine combinations in mice housed individually and in groups.

Lethality of 80 mg/kg pentazocine alone; 40 mg/kg tripelennamine alone; 20 mg/kg tripelennamine in combination with 40, 60, and 80 mg/kg pentazocine; and 40 mg/kg tripelennamine in combination with 10, 20, and 40 mg/kg pentazocine was determined in mice housed individually and in groups. Results indicate that the lethality of pentazocine and tripelennamine combinations in mice is (1) dose-dependent, (2) potentiated relative to either drug alone, and (3) greater in group-housed than in individually-housed animals.

Prednisolone effects upon body and organ weights, water intake, and several behaviors.

Various behavioral sequelae have been noted in patients receiving prolonged, high-dose glucocorticoid therapy. The present study assayed several behavioral dimensions of rats receiving daily intramuscular injections of the synthetic glucocorticoid, prednisolone. Specifically, assessments of water intake, nociception, locomotion, and the grasping responses were conducted; measures of gonadal, adrenal, and total body weights were also taken. Twelve daily injections were given to four groups (N = 6/group) of immature male rats with each group receiving a different dose of drugs (0.0, 8.0, 16.0, 32.0 mg/kg). Prednisolone generally suppressed home-cage water intake, and latencies to hind paw-lick in the hot-plate assay. Measures of wheel running and the grasping response were generally enhanced. Absolute gonadal and adrenal weights as well as total body weights were decreased. Relative organ weights suggested that daily prednisolone treatments had produced suppression of the pituitary-adrenal axis. It was concluded that prednisolone is active in these assays and that such measures may be useful in studies of drug interaction with this agent.

p-Chlorophenylalanine effects on shock-induced attack and pressing responses in rats.

The literature concerning the effects of d,1-parachlorophenylalanine (PCPA) upon shock-induced aggression (SIA) was examined and found to be inconsistent. PCPA, a known serotonin depletor, has behavioral effects in a variety of other procedures which collectively suggest that PCPA should produce SIA enhancement. The present study analyzed PCPA (300 mg/kg, IP) effects upon SIA in rats restrained spatially close to an inanimate target and panel operandum. The results showed marked increases in both aggressive biting and panel-pressing for several days following each PCPA treatment, for each subject tested. These data were interpreted to indicate that serotonin depletion by PCPA does indeed enhance SIA but that this effect is not selective for aggression. Potential controlling variables are suggested to account for reports of no effect on SIA after PCPA treatment. It is concluded that procedural variables may be the critical determinants of variation in reported PCPA-aggression effects across studies, rather that hypothesized differences in neurochemical mediators.

Environmental determinants of parachloroamphetamine toxicity in rats.

The present investigation assessed PCA toxicity at 0.0, 5.0, and 10.0 mg/kg, in both social (4 rats per cage) and non-social (acrylic tube-restraint or tube restraint-plus-tail shock) circumstances with 16 rats per drug-environment condition. The results indicated that no dose of PCA alone yielded mortality under individual housing, and similarly no environmental circumstance by itself yielded mortality in the absence of PCA. However, various drug-environment interactions produced a dose-related enhancement of PCA toxicity. For both 5.0 mg/kg and 10 mg/kg parachloroamphetamine dose levels, restraint-plus-shock generated the highest percent mortality, followed by restraint-only, with conspecific aggregation producing a mortality incidence lower still. Further, the mortality displayed under each of these environmental conditions was greater for the 10.0 mg/kg PCA treatment than for the 5.0 mg/kg treatment. The results are discussed in terms of the relative aversiveness of the environmental setting and it is suggested that stress-related drug toxicity may be further analyzed in non-social settings. It is proposed that toxic environment-PCA interactions may result from altered cardiovascular and/or thermoregulatory processes, mediated by enhanced catecholaminergic activity.

Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole.

Antihistamines are being increasingly administered in combination with various other agents, with adverse drug reactions the frequent result. The present study consisted of two experiments. Experiment 1 examined the toxicological response of rats to nicotine tartrate (0.0, 2.0, 4.0, and 8.0 mg/kg) in combination with either of two H1-histamine receptor antagonists, the ethylene diamine tripelennamine HCl (0.0, 16.0, 32.0, and 64.0 mg/kg) or the aminoethyl ether diphenhydramine HCl (0.0, 32.0, 64.0, and 96.0 mg/kg). Adult female rats received intraperitoneal injections when housed 12 per cage and toxicological response (number dead per group) was assessed 24 hours post-treatment. The results showed that over the dose ranges employed, and when given alone, nicotine was completely non-lethal, tripelennamine was virtually non-lethal and diphenhydramine was toxic only at the highest dose (5 of 12, at 96.0 mg/kg). However, when nicotine and the antihistamines were delivered in combinations, the toxicological response was markedly altered. Tripelennamine in combination with nicotine yielded supra-additive interaction, with the degree of potentiation being a simple linear function of nicotine within each dose of tripelennamine. The interaction between nicotine and diphenhydramine was more complicated, with certain dose combinations yielding supra-additivity, yet with others yielding antagonism. It was suggested that seizure-precipitated cardiopulmonary collapse was the immediate cause of death, plausibly mediated by central mechanisms. As such, Experiment 2 examined the influence of adding the proconvulsant pentylenetetrazole (PTZ) (0.0, 10.0, and 20.0 mg/kg) to nicotine (0.0, 2.0, 4.0, and 8.0 mg/kg)-tripelennamine (0.0 and 32.0 mg/kg) combination treatments. Effects were assessed both at 1.0 and 24.0 hours post-injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Parachloroamphetamine toxicity in mice: influence of body weight, sex and dose.

Five doses of d,l-para-chloroamphetamine (0.0, 15,0, 30.0, 45.0 and 60.0 mg/kg) were used to challenge 10 groups of 16 male and 10 groups of 16 female CF-1 mice weighing either 16 to 25 g or 40 to 55 g. Twenty-four hours after intraperitoneal injection, rates of lethal toxicity were assessed. Effects for body weight and dose were found. In addition, a sex by dose interaction was demonstrated. It was hypothesized that the influence of weight might be related to thermoregulatory processes, since as weight rises, surface-to-volume ratios decline, and with them the efficiency of heat exchange. Caution is suggested in the interpretation of ontological studies of drug response.

Tripelennamine effects on body and organ weights, water intake, and several behaviors of rats.

The effects of 14 daily injections of tripelennamine on several dependent measures were determined in groups of rats that received 0.0 (vehicle only), 2.0, 4.0, 8,0, or 16.0 mg/kg of the drug.l Tripelennamine did not affect body weights, organ weights (heart, liver, adrenals, kidneys), or blood glucose levels. Daily water intake was, however, directly and significantly related to tripelennamine dose. The drug failed to influence performance in a grasping response assay, or locomotion as measured in running wheels when rats received footshocks immediately before assessment of locomotion. Tripelennamine did significantly reduce locomotion when rats were not shocked before testing. Nociception, as measured via a hot-plate assay, also was altered by the drug. Here, rats exposed to 16 mg/kg evinced paw-lick latencies far greater than those that received lower doses. These results indicate that tripelennamine produced observable behavioral effects at doses which are not obviously toxic.