Action of morphine on melatonin release in the rat.

Some data from the literature raised the possibility of an interaction between the opioidergic system and pineal secretion. The present study was undertaken in order to investigate the acute influence exerted by opioids upon plasma melatonin levels in the albino rat. Different doses of morphine hydrochloride were injected (1, 1.5, 2, 3 mg/kg) intraperitoneally into anaesthetized adult male rats bearing a cannula previously inserted into the carotid. Blood samples were collected subsequently at 30-min intervals, within a period of 90 min following drug administration. Plasma melatonin contents were determined by a radioimmunoassay (RIA) method. Acute administration resulted in a dose-dependent increase in plasma melatonin concentration when compared to the respective controls. This effect is blocked by pretreatment with Naloxone. The present result seem to support the hypothesis that the opioidergic system, in certain circumstances, might contribute to the activation of melatonin secretion.

Effect of an acute injection of melatonin on the basal secretion of hypophyseal hormones in prepubertal and pubertal healthy subjects.

It is well known that the pineal gland can modulate the secretion of pituitary hormones. Melatonin, the main hormone produced by the pineal gland, acts at the hypothalamic site, whereas hypophyseal sensitivity to melatonin seems to change with age. To investigate the influence of pubertal development on the role of the pineal gland in the regulation of the secretion of pituitary hormones, FSH, LH, Prl, TSH and GH responses to melatonin were evaluated in a group of 9 prepubertal and 10 pubertal healthy subjects of both sexes. Melatonin was given im at a dose of 0.2 mg/kg body weight at 3 p.m. Venous blood samples were drawn -20, 0, 20, 40, 60, 90, 120, 180 and 240 min, after melatonin injection. According to the same experimental protocol, venous blood samples were collected during a saline infusion on a separate occasion. FSH, LH, Prl, TSH and GH plasma levels were measured with RIA. In pubertal subjects, a significant rise in the mean Prl levels was seen 90 min after melatonin as compared with those during saline infusion. The Prl melatonin response area was significantly lower in prepubertal treated subjects and significantly higher in pubertal ones compared with the respective controls. The mean GH values showed a significant decrease 120 min after melatonin only in prepubertal subjects; no significant variations were seen in 8 of 10 pubertal subjects, whereas in the last 2 a marked increase was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the R, R-isomer of labetalol, SCH 19927, in isolated tissues and in spontaneously hypertensive rats during a repeated treatment.

The alpha 1- and beta 1-adrenoceptor blocking activity of the R, R-isomer of labetalol, SCH 19927, was assessed in isolated tissues and compared with that of labetalol. The antihypertensive actions of both compounds were then evaluated during a 10-day dose regimen in spontaneously hypertensive rats (SHR). SCH 19927 produced a competitive alpha 1- and beta 1-blockade in vitro as indicated by the parallel shift to the right of the dose-response curves for norepinephrine and isoprenaline, respectively. SCH 19927 was found 4 times more potent as beta 1-blocker and 6.5 times less potent as alpha 1-blocker than labetalol. In conscious SHR, both SCH 19927 and labetalol produced long-lasting antihypertensive effects during the 10-day period of repeated administration with 10 mg/kg p.o. No tolerance to the antihypertensive activity occurred during the treatment. These findings suggest that SCH 19927 is more potent as a beta-blocker than as an alpha-blocker in isolated tissues and produces an effective antihypertensive activity during a repeated dose regimen.

Comparative ototoxicity of dibekacin and netilmicin in guinea pigs.

The cochleo- and vestibulotoxicity of dibekacin and netilmicin were compared in a guinea pig model. Both aminoglycosides were administered subcutaneously for 21 days at the dose level of 150 mg/kg/day. Control animals were injected with saline. Dibekacin-treated animals showed a significant (P less than 0.05) increase in the thresholds of the Preyer pinna reflex and the VIIIth nerve compound action potential in response to sound click stimulation. Moreover, a deterioration of the electrophysiologic auditory response and an almost complete suppression of the post-rotatory nystagmus were detected. In contrast, netilmicin did not induce any significant change in auditory and vestibular functions as compared to the control group. Our results demonstrated that netilmicin was devoid of ototoxicity in the guinea pig, while dibekacin provoked mild cochlear and severe vestibulotoxicity.

Comparative pharmacokinetics of aminoglycoside antibiotics in guinea pigs.

The pharmacokinetics of netilmicin, gentamicin, and tobramycin in plasma and in perilymph of guinea pigs were studied after a single intravenous injection of 40 mg/kg. Detailed pharmacokinetic analysis of the plasma drug concentration-time data up to 36 h after the intravenous dose revealed that the pharmacokinetics of the aminoglycoside antibiotics can be best described as a three-compartment open model. The disposition half-lives (t1/2) in plasma of the three antibiotics were comparable and within the following ranges: t1/2 alpha of 0.09 to 0.16 h; t1/2 beta of 0.88 to 1.01 h; and t1/2 gamma of 7.87 to 8.29 h. The volume of distribution in the central compartment and the total body clearance of netilmicin (294 ml/kg, 5.74 ml/min per kg) were greater than those of gentamicin (160 ml/kg, 3.40 ml/min per kg) and tobramycin (204 ml/kg, 4.63 ml/min per kg). Pharmacokinetic analysis of the perilymph drug concentration-time data indicated that all three antibiotics penetrated the perilymph readily, but netilmicin cleared from the perilymph compartment faster than gentamicin and tobramycin. The maximum perilymph drug concentrations were 4.17, 8.05, and 6.78 micrograms/ml and occurred at 1, 2, and 4 h for netilmicin, gentamicin, and tobramycin, respectively. The ratio of area under the curve of perilymph to plasma was lowest for netilmicin (0.27), followed by gentamicin (0.39) and tobramycin (0.57). These results suggest that the differences in pharmacokinetics and concentrations of netilmicin in the perilymph may account for less ototoxic liability of netilmicin compared with gentamicin and tobramycin.

Pharmacological studies with quazepam, a new benzodiazepine hypnotic.

7-Chloro-1-(2,2,2-trifluoroethyl)-5-(o-fluorophenyl)-1, 3-dihydro-2H-1,4-benzodiazepine-2-thione (Sch 16134, quazepam) demonstrated high safety and effective hypnotic properties. Toxicity of quazepam in mice was extremely low at the largest doses administered of 5000 mg/kg p.o. and 1370 mg/kg i.p. as compared to LD50 values for flurazepam of 756 (635-889) mg/kg p.o. and 254 (234-280) mg/kg i.p. In cats, quazepam did not produce overt toxicity even at the highest dose administered, 1000 mg/kg p.o., whereas death occurred after the administration of flurazepam at a median dose of 250 mg/kg p.o. In addition, flurazepam produced central excitation and convulsions. Quazepam did not affect hemodynamic parameters in conscious dogs and anesthetized cats. Autonomic functions were virtually unaffected by the drug in anesthetized cats. In interaction studies in mice, quazepam did not interact with cimetidine while it potentiated the sedative activity of alpha-methyldopa, ethanol and propranolol. The CNS depressant properties of quazepam were further investigated by studying its effects on spontaneous motor activity in mice and EEG pattern in immobilized cats. In mice, quazepam reduced locomotor activity at doses which did not impair motor coordination thus differing from flurazepam which did. In the EEG study, quazepam produced a slow wave EEG pattern comparable to that of physiological sleep, while flurazepam induced a similar EEG activity which alternated with a fast frequency pattern of moderate amplitude. Quazepam also showed potent anticonvulsant activity. These results suggest that quazepam is likely to be a safe and effective sleep-promoting agent.

Effects of physostigmine on benzodiazepine toxicity.

The interactions between physostigmine and chlordiazepoxide, diazepam, flurazepam were experimentally evaluated in rats and mice by the following test: loss of righting reflex (LRR), acute toxicity, cardiovascular toxicity and EEG pattern. Physostigmine did not modify the duration of LRR produced by chlordiazepoxide. Conversely, the recovery after diazepam was significantly longer. The LD50 of diazepam and chlordiazepoxide were not modified by physostigmine administration, but that of flurazepam was significantly decreased. Heart rate and blood pressure did not change significantly with physostigmine pre-treatment. However, the total lethal dose was lowered for chlordiazepoxide and flurazepam. Only the reversal by physostigmine of the EEG pattern due to benzodiazepines, offers experimental support to the claimed usefulness of physostigmine in benzodiazepine intoxication in humans. Furthermore, the potentiation of flurazepam toxicity must be taken into account in the debate concerning the clinical advantages of physostigmine.

Histological evaluation of ototoxic reaction due to some aminoglycoside antibiotics.

Twenty-one days s.c. treatment with netilmicin, gentamicin, sisomicin, and kanamicin at different doses were performed in albino guinea pigs of both sexes. Block surface preparation of Corti's organ was carried out and missing OHCs and IHCs counted in selected areas of each turn. The animals treated with gentamicin and sisomicin showed a dose-depending missing of hair cells, preferably relative to the outer ones and quantitatively the same for both the antibiotics. Furthermore, a characteristic distribution of the damage progressively increasing from the apex to the basal turn of the cochlea was detected. Kanamicin at 267 and 400 mg/kg gave the complete destruction of OHCs and IHCs along the whole cochlea while at 178 mg/kg did not show any significant damage in comparison to the control group. Finally, netilmicin neither damaged Corti's organ nor statistically determined missing OHCs and IHCs at all the doses used. These histological results and the previous electrophysiological and reflexological observations obtained in the guinea pig show a higher safety of netilmicin in comparison to the other aminoglycosides used for the problem relative to ototoxicity.

Auditory function in guinea pigs treated with netilmicin and other aminoglycoside antibiotics.

The following aminoglycoside antibiotics netilmicin, sisomicin, gentamicin, and kanamycin were submitted to a comparative study of their ototoxicity using both reflexological (Preyer's pinnareflex) and electrophysiological (near and far field) methods. The daily s.c. administration of sisomicin, gentamicin, and kanamycin for 21 days provoked a dose-related impairment of the cochlear function, detected with all the employed techniques. On the other hand, a very low ototoxic effect of netilmicin was demonstrated with electrophysiological but not with the reflexological evaluation. The reliability of the methods used in these experiments is also compared.

The neuromuscular blocking activity of a new aminoglycoside antibiotic netilmicin sulphate (SCH 20569).

The neuromuscular blocking activity of netilmicin sulphate (Sch 20569), a new aminoglycoside antibiotic, was studied on the rat sciatic nerve-gastrocnemius muscle preparation. The i.v. administration of netilmicin caused a gradual fall, up to complete blockade, of the muscular contraction elicited by nerve stimulation. Conversely, the muscular response to direct stimulation was not affected. The response pattern was similar to that seen with known aminoglycoside antibiotics. The acute toxic effects (LD50 i.p. in mice) of netilmicin were antagonized by pretreatment with neostigmine; this latter partially prevented netilmicin-induced blockade, but was not able to reverse it. Calcium chloride was the only agent effective both to prevent and to reverse the neuromuscular blocking effects of netilmicin.

Comparison of neuromuscular effects and acute toxicity of some aminoglycoside antibiotics.

The correlation between acute toxicity and the effects occurring at neuromuscular junction level of some aminoglycoside antibiotics was investigated. Netilmicin (Sch 20569), sisomicin, gentamicin and kanamycin were administered i.v. in the rat and the following effects were studied: neuromuscular blocking activity (sciatic-gastrocnemius preparation), and acute toxicity evaluation. Neuromuscular blocking effects were found to be well correlated to acute toxicity data for all test-antibiotics. Comparison of results gave a sequence of relative potency which was as follows: netilmicin = sisomicin greater than gentamicin greater than kanamycin. Our findings confirmed that both respiratory failure, reporter as a side effect of the clinical use of aminoglycosides, and experimental toxicity follow the neuromuscular block.