Effect of certain drugs in perfused human placenta XII: autacoid antagonism by phenothiazines.

The effects of chlorpromazine, prochlorperazine, and trifluoperazine on the pressor actions of serotonin, angiotensin, and bradykinin in the perfused vessels of full-term human placentas were investigated. A significant inhibition of the effect of serotonin was observed with trifluoperazine and chlorpromazine but not with prochlorperazine. The inhibition is attributed to the ability of phenothiazines to cause adrenergic blockade. Because both bradykinin and angiotensin could not be consistently antagonized, it is concluded that they must act primarily via musculotropic mechanisms and only secondarily by stimulation of adrenergic receptors.

Evaluation of teratogenic potential codeine sulfate in CF-1 mice.

The most prominent defect of codeine sulfate, 100 mg/kg sc, was delayed ossification of the supraoccipital bone, paws, xiphoid, and sternebrae as well as other sternebral defects such as checkerboard sternebrae and polysternebrae. Although these anomalies were similar to the minor defects seen in the fetuses of morphine sulfate-treated mice, the major anomalies such as exencephaly, cryptorchid testes, and rib and vertebral fusions produced by morphine were not present in the fetuses of mice challenged with codeine. Thus, codeine sulfate appears to be less teratogenic than morphine sulfate. A review of the incidences of the various defects in mice treated on a single day with codeine showed that there was a range of days on which the mouse fetus was susceptible to codeine's teratogenic effects, with the most critical days of gestation being Days 8-10. Furthermore, a comparison of the defects that occurred in those treated on both Days 8 and 9 with the defects that occurred in those treated on a single day of gestation reveals an additive or cumulative teratogenic response to codeine.

Evaluation of the teratogenicity of morphine sulfate administered via a miniature implantable pump.

A technique has been developed for the implantation of miniature infusion pumps in pregnant mice with minimal teratogenic and toxic side effects. In 7- to 10-day pregnant CF-1 mice receiving constant low doses of morphine sulfate via the infusion pump, the results, including fetal weight reduction and various skeletal and soft tissue abnormalities, were similar to those reported in previous investigations using single injections.

Influence of alpha- and beta-adrenergic antagonists on dopamine-induced responses in the isolated heart of Mercenaria mercenaria.

Agents with predominantly adrenergic antagonistic properties (the alpha-blockers, phentolamine and tolazoline, and the beta-blocker propranolol), and those with suspected alpha-blocking capabilities [hydralazine and 3,3'-(4,4'-biphenylene)bis(2,5-diphenyl-2H-tetrazolium chloride) (neotetrazolium chloride); I] were added individually to a bath containing an isolated Mercenaria mercenaria heart. Two and one-half minutes later, dopamine was added to the bath as the second drug and cardiac responses were noted. Pretreatment with saline controls, followed by dopamine 2.5 min later, produced results that were identical with those which occurred after the administration of dopamine alone, i.e., marked stimulation and cardiac arrest. Pretreatment with phentolamine and I were the only procedures that prevented dopamine-induced cardiac arrest. Phentolamine, tolazoline, and hydralazine generally produced positive inotropic responses when initially added to the bath, whereas propranolol mimicked the effects caused by the addition of dopamine alone or after saline pretreatment. The M. mercenaria heart appears to possess an adrenergic receptor of an alpha-configuration.

Teratogenic potential of cocaine hydrochloride in CF-1 mice.

This investigation revealed that cocaine hydrochloride was teratogenic when administered in nontoxic doses to gravid CF-1 mice on Days 7-12 of gestation. The teratogenic susceptibility of the CF-1 mouse fetus to cocaine hydrochloride was evident throughout this portion of the gestation period. The early appearance of eye defects and the occurrence of skeletal defects later in gestation after cocaine hydrochloride challenge paralleled the sequence of ontogenesis.

Teratogenicity of zinc chloride, 1,10-phenanthroline, and a zinc-1,10-phenanthroline complex in mice.

Zinc chloride, in single doses of 12.5, 20.5 and 25 mg/kg ip on Day 8,9,10, or 11 of gestation in CF-1 albino mice, produced skeletal anomalies without accompanying soft tissue defects. Ripple ribs, the most unusual anomaly, first appeared when the zinc salt was given on Day 9 of gestation in a dose of 20.5 mg/kg, becoming more prevalent when 25 mg/kg of the drug was administered on Day 11.1,10-Phenanthroline, in single doses of 30 mg/kg ip on Day 8,9,10, or 11 of gestation elicited skeletal defects comparable to those caused by zinc chloride as well as soft tissue anomalies, but a significant incidence of the former occurred with this agent only following its injection on Day 8 of gestation. A zinc-1,10-phenanthroline complex in single doses of 50 mg/kg on Day 8,9,10, or 11 of gestation yielded significant incidences of skeletal and soft tissue anomalies only when the complex was administered on Day 8 or 9 of gestation. This dosage level was toxic to both the mother and fetus when given on Day 10 of gestation. However, when the complex was given on Day 8,9,10, or 11 in a dose of 25 mg/kg, neither toxic nor teratogenic effects were observed in the mother or fetus, respectively.

Comparative teratogenicity of cortisone and phenytoin in mice.

Single administrations of cortisone or phenytoin to pregnant mice on Days 11--14 of gestation caused similar skeletal and dissimilar soft tissue fetal anomalies. Cortisone reduced both maternal and fetal weight, whereas phenytoin only reduced fetal weight without adversely affecting maternal weight. A correlation between fetal weight reduction and cleft palate incidence was evident for each drug. Because probit analysis of dose--response regression lines did not deviate from parallelism after drug challenge, it was concluded that cortisone and phenytoin may produce palatal anomalies in the mouse fetus by a similar mechanism.

Influence of cobalt (dietary), cobalamins, and inorganic cobalt salts on phenytoin- and cortisone-induced teratogenesis in mice.

Various cobalt-containing agents (cyanocobalamin, sodium cobaltinitrite, and cobaltous chloride), which formerly had been shown to prevent the onset of cleft palate in CF-1 mice injected with cortisone, were studied to determine whether they would afford similar protection against phenytoin. Phenytoin, however, failed to cause cleft palate in the mouse fetus when given to pregnant animals alone; and cortisone, on the contrary, induced this anomaly in the presence of the so-called cobalt antagonists as well as when administered in their absence. It is suggested from these results that high dietary intake of cobalt prevents cleft palate caused by phenytoin challenge and also negates the protective effects associated with the acute administration of cobalt compounds. Therefore, it is concluded that these well-known teratogens inhibit palatal closure in mice by different mechanisms.

Nonvariance of LD50 values of drugs in gravid and nongravid mice.

This study showed that the LD50 values for morphine sulfate, cobalt chloride, and phenytoin sodium did not vary significantly on Day 9 of gestation in CF-1 mice when compared to values of nongravid animals.