William L. West

A comparative study of the reproductive effects of methadone and benzo [a] pyrene in the pregnant and pseudopregnant rat

Benzo[a]pyrene (BP; 50 mg/kg) or methadone (5 mg/kg) was given subcutaneously to pregnant rats at different stages of gestation. Both BP and methadone affected the reproductive performance of pregnant rats by significantly increasing the number of resorptions and fetal wastage, and by decreasing the fetal weight. The same dosage levels of BP and methadone were also given to pseudopregnant rats (PSP) with an induced decidual cell reaction (DCR) in an attempt to distinguish whether adverse effects occur in the maternal or fetal compartment or both. Since the hormonal requirements for DCR and implantation are similar and the anatomical, histological, cytological, time sequential changes as well as appearance of the vasculature system for DCR and decidua are indistinguishable, PSP with DCR is similar to pregnancy except for the lack of a fetal compartment. BP, in this PSP model, significantly reduced the uterine wet weight and cyclic nucleotide (cAMP) and cGMP) levels whereas methadone was without a detectable effect. Our findings then suggest that BP may exert its effects adversely on both the maternal and fetal compartments, whereas methadone may act primarily in the fetal compartment.

Study of the mechanism of hydralazine-induced myocardial necrosis in the rat

Abstract Hydralazine, 25 mg/kg ip given on 2 consecutive days, causes myocardial necrosis in rats. Propranolol, 10 mg/kg sc twice daily, or verapamil, 10 mg/kg sc twice daily, protected against this effect. Hydralazine alone caused marked tachycardia, but bradycardia occurred when hydralazine and propranolol were given in combination. Verapamil caused a mild tachycardia which was increased further by hydralazine. Pretreatment with dihydrotachysterol, 1 mg/kg po for 3 days, aggravated the hydralazine-induced lesion. 45 Ca measurements indicated increased calcium concentration in the heart 6 hr after hydralazine administration. The data suggest that the lesion is induced by the pharmacological effects of hydralazine and that hypoxia and increased intracellular calcium play a role in the development of necrosis.

Evidence for Hormonal Imbalance after Methadone Treatment in Pregnant and Pseudopregnant Rats

Abstract The effects of methadone (METH) on the plasma estriol level and hormonal target tissues cyclic nucleotides (cAMP and cGMP) were investigated in pregnant and pseudopregnant rats. In the pregnant animals, METH (5 mg/kg/day), given once daily from Days 6 to 15 of gestation, significantly reduced the maternal body weight gain in association with an increase in the number of dams bearing resorptions (56%) and a significant reduction in fetal body weight (33%). An inhibition of the plasma estriol level by METH was observed on Day 9 of gestation. Stimulation of the sympatho-adrenal axis and hypothalamo-pituitary axis by acute METH administration was observed and correlated with a significant increase in the levels of cyclic nucleotides in the uterus and adrenal glands of pregnant rats. However, tolerance to METH effects on cyclic nucleotide levels developed by Day 15 of gestation. METH also depressed the fetal cyclic nucleotide levels on Days 12 and 15 of gestation. These findings suggest that METH had pronounced effects on hormonal secretion during pregnancy, and hormonal transport to or hormonal production by the fetuses. In contrast, METH did not exhibit any adverse effects on the hormonal and cyclic nucleotide levels of pseudopregnant rats with deciduoma formation; a model for the maternal compartment. These latter findings may reflect METHs adverse effects on the fetal compartment, and suggest the use of pseudopregnancy as a model to distinguish adverse drug effects between these compartments.

Hematologic and vitamin status of african american women and their relationships to pregnancy outcome

Abstract A prospective observational study was conducted to investigate the effects of nutrition and related factors on the outcome of pregnancy in nulliparous African American women 16–35 years of age. Blood samples from a subset of these subjects were taken during the first (1st), second (2nd) and third (3rd) trimesters of pregnancy and at delivery. Cord blood samples were also collected at delivery. Levels of selected biochemical variables including serum ferritin, vitamin B 12 and folate as well as whole blood folate, and selected hematologic indices were determined and correlated with pregnancy outcome variables. During the second trimester of pregnancy, values for hematocrit and hemoglobin were less than 30% and 11 g/dL, respectively, in 16% and 30% of the participants, respectively. Serum and whole blood (WB) folate increased sequentially during pregnancy. Cord concentrations of serum folate were significantly higher than maternal concentrations at delivery (P 2 =0.21), while gestational age was inversely correlated with 3rd trimester vitamin B 12 (R 2 =0.34). These data suggest that vitamin B 12 and folate play an important role in the outcome of pregnancy in this population.

Sensitivity of isolated atria from reserpine-treated rats to noradrenaline

SrR,-chronic sympathetic postganglionic denervation reduces the noradrenaline content of smooth or cardiac muscle (Goodall, 1951 ; von Euler & Purkhol, 1951 ; Burn & Rand, 1959) increases its sensitivity to injected noradrenaline and decreases its reactivity to tyramine (Bulbring & Burn, 1938). Pretreatment with reserpine causes similar changes (Burn & Rand, 1958a). Burn & Rand (1959) therefore suggested the possibility of an inverse relationship between tissue stores of noradrenaline and sensitivity to exogenous noradrenaline. Recent observations failed to support such a view, since pretreatment of short duration (24 to 48 hr) with large doses of reserpine failed to cause supersensitivity (Fleming & Trendenburg, 1961). These authors pointed out that the time factor must also be considered, although this factor seemed to be more important for the appearance of supersensitivity of the nictitating membrane than of the cardiovascular system. In the present study, sensitivity to exogenous noradrenaline was reinvestigated in isolated atrial preparations made from rats treated with reserpine at various times. Male albino rats of the Holtzman strain, weighing 225 to 250 g, were used in all experiments. Animals were killed by a blow at the base of the neck, decapitated and the heart rapidly removed. Atria were freed of ventricular muscle, connective tissue, fat and blood vessels, then placed in a modified Tyrodes solution (Bhagat & Shideman, 1963b) maintained at 28 and containing 2.9 x 1 0 8 ~ atropine sulphate. A mixture of 95% oxygen and 5% carbon dioxide was bubbled through the bathing fluid via a sintered glass plate at the bottom of the bath. Isometric contractile amplitude (resting tension of approximately 0.5 g) and rate of spontaneous beat were recorded. Drugs were added to the bath after the preparation had attained a constant amplitude of contraction and responses were calculated as percentage changes relative to the amplitude existing just before the addition of the drug. The concentrations of catecholamines in the ventricular myocardium were determined by the trihydroxyindole fluorimetric procedure of Shore & Olin (1958) and are expressed as pg of noradrenaline per g of fresh tissue. Noradrenaline bitartrate monohydrate and reserpine (Serpasil, Ciba) are expressed as base and cocaine hydrochloride as the salt. In one group, rats were given 1-5 mg/kg of reserpine intramuscularly 24 hr before the experiment, while in another group, 0.5 mg/kg of reserpine was administered every 18 hr and the animals were used 72 hr after the first injection.

Benzo(a)pyrene-induced early cytopathologic changes and peroxidase activity in the endometrium of ovariectomized rats

Abstract The present study was designed to investigate whether benzo(a)pyrene (BP) alone would have cytopathologic effects on the endometrium of ovariectomized rats, and whether DES can modulate or facilitate this cytopathology. The morphology and cytochemically detectable peroxidase activity in the endometrial epithelium of castrated rats were studied 24 hr after sc administration of three to six doses on consecutive days (one dose per day) either of corn oil, BP (50 mg/kg/day), DES (20 μg/kg/day), or a combination of the latter two agents. BP alone induced mitosis, peroxidase activity, and focal squamous cell metaplasia in the endometrial epithelium of castrated rats. Peroxidase activity was weak in the granular endoplasmic reticulum of the normal epithelial cells after three and six doses of BP. However, in the focal metaplasia, the superficial squamous cells contained strong peroxidase activity after six consecutive daily doses of BP. The focal metaplasia present only after six doses of BP consisted of three to four layers of squamous cells and one to two layers of basal cells. DES-treated animals showed no formation of metaplasia or structural alterations in the epithelium, but intense peroxidase activity was present in epithelial cells after three or six daily doses. The castrates treated with three or six combined doses of BP and DES showed significant ultrastructural changes in the epithelial cells. Vacuolization of the cisternae of the granular endoplasmic reticulum was observed in the epithelial cells after three doses of BP-DES. Distinct dilation and degranulation of the granular endoplasmic reticulum as well as enlargement of mitochondria were found in all the epithelial cells of the pseudostratified hyperplastic epithelium after six consecutive daily doses of the combination, BP-DES. These ultrastructural aberrations are clearly indicative of a cytotoxic effect of BP on the endometrial epithelial cells. Collectively these findings suggest that sc administration of BP induces peroxidase activity which may lead indirectly to lesions in the endometrium of ovariectomized rats, and DES may enhance the cytotoxicity of BP by a similar mechanism.

In vitro and in vivo Cytogenetic investigations of tilorone HCl

Summary Tilorone hydrochloride, an orally active antiviral agent, was examined in vitro in the rat-kangaroo cell line and in vivo in rat bone marrow for its ability to produce chromosomal aberrations. A significant increase in aberrations was found in vitro at concentrations of 1.5, 3.0, and 6.0 μ/ml, with significant mitotic inhibition at the latter two levels. In the in vivo studies, the proportion of chromosomal abnormalities did not differ significantly from the control value although inhibition of division was apparent at all dosages tested.