Effects of FG 5893, a new compound with 5-HT1A receptor agonistic and 5-HT2 receptor antagonistic properties, on male rat sexual behavior.

In the present study male rat sexual behavior was used to explore the functional properties of FG 5893, a newly developed diphenylbutylpiperazinepyridyl derivative which is a 5-HT1A receptor agonist and a 5-HT2 receptor antagonist. Treatment with FG 5893 (0.1-6.0 mg kg-1) stimulated male rat sexual behavior, as evidenced by a decrease in the number of mounts and intromissions to elicit ejaculation, and a shortening of the ejaculation latency. The stimulatory effects varied in a dose-dependent manner, reaching a maximum at 3.0 mg kg-1. Pretreatment with (+/-)-pindolol (0.5 mg kg-1 -30 min), a selective 5-HT1A receptor antagonist, completely antagonized the stimulatory effects of FG 5893 (1 mg kg-1 -20 min) on male sexual behavior. In addition, the behavioral action of FG 5893 was investigated on various components of the 'serotonin behavior syndrome' including flat body posture, forepaw treading, and lower lip retraction. The effects obtained were compared with those induced by treatment with 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT), the prototype of a 5-HT1A receptor agonist. Compared to 8-OH-DPAT, a 100 times higher dose of FG 5893 (10 mg kg-1) was needed to elicit flat body posture while forepaw treading was never seen. Lower lip retraction was elicited by the lowest doses of FG 5893 (0.1 mg kg-1) and 8-OH-DPAT (0.03 mg kg-1). Treatment with (+/-)-pindolol reduced flat body posture elicited by 8-OH-DPAT and completely eradicated the flat body posture induced by FG 5893.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions of GABAA antagonists with deltamethrin, diazepam, pentobarbital, and SKF100330A in the rat dentate gyrus.

Activation of dentate gyrus granule cells leads to a period of depressed excitability mediated primarily by recurrent inhibition. This response can be increased in intensity and duration by drugs that enhance GABAA-mediated inhibition including GABA uptake blockers (SKF100330A), benzodiazepines (diazepam), and barbiturates (pentobarbital). It can be attenuated or abolished by administration of the GABAA antagonists picrotoxin and bicuculline. Type II pyrethroids, such as deltamethrin, produce effects in vitro which lead one to expect that they would decrease GABA-mediated inhibition. However, administration of deltamethrin to animals intensifies the inhibitory consequences of granule cell activation by many fold. To determine the role of GABAA-mediated mechanisms in the action of deltamethrin, we have looked at its antagonism by bicuculline and picrotoxin. Neither GABAA antagonist reduced the duration of the inhibition produced by deltamethrin. The only effect observed was a small but significant reduction in intensity of inhibition during the period of 10-40 msec after activation of the granule cells. For comparative purposes we have also examined the antagonism produced by bicuculline and picrotoxin on agents known to enhance GABAA-mediated inhibition. These antagonists were quite effective in antagonizing the enhancement of inhibition produced by diazepam and SKF 100330A. Bicuculline was also effective in antagonizing pentobarbital while picrotoxin was not. These results suggest that the prolongation of inhibition produced by deltamethrin in dentate granule cells does not result simply from an extension of GABAA-mediated inhibition, but rather derives from a different source.

Effects of aspirin upon the flushing reaction induced by niceritrol.

The usefulness of niceritrol as a lipid-lowering agent is limited by a prostaglandin-mediated flushing reaction after each dose occurring in the early stages of treatment. We have tested the effect of premedication with aspirin on the reaction to 250 mg niceritrol in 30 healthy male volunteers using both subjective and observed assessments of severity. Both 300 mg and 600 mg of aspirin significantly reduced the severity of flushing when compared with placebo. No significant difference was seen between the two dose levels. Prior dosing with aspirin may increase acceptability of niceritrol and hence improve compliance.

PUVA treatment inhibits nonimmunologic immediate contact reactions to benzoic acid and methyl nicotinate.

The effect of trioxsalen bath PUVA therapy on nonimmunologic immediate contact reactions (NIICRs) induced by benzoic acid (BA) and methyl nicotinate (MN) was studied in 12 dermatologic patients. One half of the back skin was covered with a cloth before each of ten irradiations on subsequent days. Four concentrations of each test substance were applied to the PUVA-exposed and nonexposed areas before any irradiation and after the 1st, 5th, and 10th PUVA treatment. Erythema and edema reactions were observed visually 40 minutes after BA and MN application, and changes in the skin blood flow were monitored using laser Doppler flowmetry (LDF). PUVA therapy suppressed the NIICRs in all concentrations of BA and MN on the PUVA-exposed area and occasionally on the nonexposed test sites. The suppressive effect was intesified during therapy.

Acetylsalicylic acid inhibits non-immunologic contact urticaria.

To investigate the mechanisms of non-immunologic contact urticaria (NICU), the effects of 1g + 1g of acetylsalicylic acid (ASA) on contact reactions to methyl nicotinate, diethyl fumarate, benzoic acid, cinnamic acid, cinnamic aldehyde and dimethyl sulfoxide were studied in 21 test subjects. Erythema and edema reactions were observed visually, and the changes in the skin blood flow were monitored using laser-Doppler flowmetry. ASA had a significant inhibitory effect on erythema from all 6 agents and also on edema from all substances except dimethyl sulfoxide. The mechanism of the effect may be a result of the inhibitory influence of ASA on prostaglandin bioformation. Thus, to avoid false negative test results, non-steroidal anti-inflammatory drugs should not be used during NICU tests.

The cellular inflammatory response in nicotinate skin reactions.

Sequential skin biopsies of nicotinate-treated skin from nine normal subjects, three aspirin-pretreated normal subjects and six atopic eczema patients were examined. An erythematous skin reaction was seen in the nine normal subjects and to a lesser degree in one atopic eczema patient, but not in the aspirin-pretreated subjects nor in five remaining atopics. Accumulation of a mononuclear cell perivascular infiltrate was seen from 15 min onwards in the normal subjects. Neutrophils became the predominant cell invading thickened vessel walls and in the perivascular space beginning at 2 h and persisting up to 48 h. Leucocytoclasis was observed at 24 h. Immunofluorescence studies showed only non-specific fibrinogen deposits in papillary capillaries in the three groups of subjects. The chloroacetate esterase reaction and immunohistochemical labelling with OKM I confirmed a marked neutrophilia at 2 h and 24 h. Neutrophils were seen in one atopic eczema patient, but were not observed in the remainder, nor in the skin of the aspirin-pretreated normal subjects. Topical application of nicotinate causes non-allergenic, leucocytoclastic vascular damage in normal skin which can be inhibited by aspirin and which is reduced or absent in atopic eczema.

An investigation of the angry back syndrome using Trafuril.

The angry back syndrome (ABS) was investigated using Trafuril cream and prostaglandin synthetase inhibitors. Trafuril produced an increase in the numbers and intensity of patch test reactions which was partly abrogated by aspirin and indomethacin. Irritant reactions were not affected. We suggest that Trafuril may increase the sensitivity of the patch testing system and that this may have useful clinical applications.

Aspirin blocks nicotinic acid-induced flushing.

Nicotinic acid flushing after placebo and 975-mg oral doses of aspirin was assessed in 29 normal subjects over a range of nicotinic acid doses. Intensity of flushing was assessed by the change in malar thermal circulation index (delta MTCI). Aspirin pretreatment resulted in smaller delta MTCIs at the higher doses of nicotinic acid. At the lower doses the change in the index after pretreatments with both aspirin and placebo remained low, suggesting that very little flushing was provoked by these doses. These results are compatible with the proposed mediation by prostaglandins of the nicotinic acid-induced flush. According to the delta MCTI method, flushing is quantitatively characterized as a nonquantal, dose-response reaction of variable intensity.

Is cutaneous flushing prostaglandin mediated?

Intravenous administration of nicotinic acid (25 mg), resulted in a readily reproducible facial flush. The development of this flush was inhibited by two prostaglandin synthetase inhibitors, indomethacin and benorylate, but was not affected by the administration of the opiate receptor antagonist naloxone. Indomethacin, the agent with the greater anti-prostaglandin activity, was markedly more effective than benorylate in inhibiting the nicotinic-acid-induced rise in facial temperature. These findings will be useful in the in vivo assessment of the activity of prostaglandin inhibitors.

Dissociation of the effects of nicotinic acid on vasodilatation and lipolysis by a prostaglandin synthesis inhibitor, indomethacin, in man.

The effects of nicotinic acid on plasma free fatty acid (FFA) concentration and forearm blood flow were studied in seven healthy fasting volunteers with and without pretreatment by indomethacin to see if some effects of nicotinic acid are mediated by release of endogenous prostaglandin. 1 g of nicotinic acid per os decreased plasma FFA concentration to a lowest value of 1/4 of initial level and increased forearm blood flow four times. When the same dose of nicotinic acid was given after pretreatment with indomethacin, the blood flow increase was only 1/3 of that without indomethacin. Indomethacin did not alter the rapid initial decrease in plasma FFA, although the period of low FFA concentration was shortened and the rebound to supranormal concentration was abolished. Thus the vasodilatory effect of nicotinic acid seems to be mediated by release of endogenous prostaglandin while the inhibition of lipolysis by the drug is mainly produced by other mechanisms.

Preliminary report of the effects of propranolol HCl on the discomfiture caused by niacin.

Subjective discomfort caused by nausea and hot, pruritic skin has been described in patients after ingestion of therapeutic dosages of niacin is shown by this study to be alleviated by propranolol HC1. A dosage of 2 mg, I.V., given incrementally, in a clinical trial of six patients is described. The peripheral vasodilator effects of niacin were attenuated in some subjects but not in others. However, all subjects reported relief of unpleasant symptoms. Serial vital signs were taken and no significant changes were found. It is postulated that propranolol HC1 exerts a calmative effect at the CNS level. In a series that utilized doses of 40 and 80 mg of propranolol HC1 taken orally 30 min prior to the ingestion of 500 or 1000 mg of niacin, a progressive increase in the onset of the niacin flush was observed. It is proposed that as the available plasma level of propranolol HC1 falls, the ratio of niacin to propranolol HC1 increases, exceeding the threshold at which the flush occurs. Both these studies suggest that further work is indicated to establish the possible therapeutic efficacy of propranolol HC1.

Modification of nicotinic acid and prostaglandin E1 antilipolytic action in vitro.

In epididymal adipose tissue from rats, human serum antagonizes inhibition of basal lipolysis by nicotinic acid in vitro. Under similar conditions caffeine-stimulated lipolysis was unaffected by the presence of human serum. Very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins were all found to antagonize the action of nicotinic acid on basal lipolysis. VLDL also antagonized prostaglandin E1 (PGE1)-inhibition of basal lipolysis in vitro. The fat cell membrane was suggested as the site at which human serum lipoproteins antagonize nicotinic acid or PGE1 antilipolytic action on basal lipolysis in vitro.

Pharmacological studies on surugatoxin, the toxic principle from Japanese ivory mollusc (Babylonia japonica).

1 Some pharmacological properties of surugatoxin (SGTX), a purified toxic substance from the Japanese ivory mollusc (Babylonia japonica), have been investigated. SGTX (50 nmol/kg i.v.) produced a prolonged fall of blood pressure in anaesthetized cats. This hypotensive effect was neither blocked by atropine and propranolol nor by spinal cord transection. 2 SGTX (37-50 nmol/kg i.v.) inhibited the hypertensive and hypotensive response to 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and to electrical stimulation of the splanchnic and vagal nerve, whereas it usually augmented the hypertensive response to adrenaline and to 4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) in anaesthetized cats. 3 Close intra-arterial injection of SGTX (6.2-12.3 nmol/kg) to the superior cervical ganglion blocked the contractile response of the nictitating membrane to preganglionic stimulation of cervical sympathetic nerve or injected DMPP, but not to postganglionic stimulation or to injected adrenaline and McN-A-343. 4 SGTX affected neither the indirectly nor the directly stimulated response of the rat isolated phrenic nerve-diaphragm at concentrations less than 12.3 mum. 5 The effect of SGTX on the contractile response to some agonists and on the twitch response to transmural stimulation in the guinea-pig isolated ileum was investigated. At less than 12.3 mumSGTX did not depress responses to acetylcholine or histamine. The curves for nicotine- and DMPP-induced contractions were shifted to the right and depressed gradually as the concentration of SGTX was increased (12.3 nm-1.23 mum). SGTX partially inhibited the contraction induced by 5-hyroxytryptamine and the transmurally-stimulated twitch response. 6 These results suggest that SGTX has a ganglion-blocking action. The mode of anti-nicotinic action of SGTX in the guinea-pig isolated ileum seems to differ from that of hexamethonium and tetraethylammonium and to resemble more closely that of mecamylamine.