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Biomedical subjects

S T Harris

Publications and source records attributed to S T Harris.

At least 19 recordsLinked to original sources
PubMed1992

Developmental effects of methyl benzimidazolecarbamate following exposure during early pregnancy.

Methyl 2-benzimidazolecarbamate (MBC) and its parent compound benomyl are used as agricultural fungicides. Both chemicals are embryotoxic if administered during organogenesis, and benomyl is teratogenic. Based on a previous study indicating a lack of maternal effects of MBC following exposure during early pregnancy, the current experiments were designed to evaluate the effect of exposure to MBC during early pregnancy on developmental parameters of offspring. Rats were administered MBC at 0, 100, 200, 400, or 600 mg/kg/day during Days 1-8 of pregnancy and killed on Day 11 or Day 20 of gestation. On Day 11, embryos were assessed for survival rate, growth parameters, and anomalies. On Day 20, standard developmental toxicity evaluations were performed. Doses of 200 to 600 mg/kg/day MBC reduced embryonic survival by Day 11; exposure to MBC at 100 to 600 mg/kg/day reduced the number of fetuses surviving on Day 20. Evidence of developmental delay was apparent on Day 11 at all doses, and fetal weight was reduced by Day 20. MBC produced a dose-dependent increase in developmental defects seen on Day 11 and in several malformations observed on Day 20. MBC exposure during the first week of pregnancy was shown to be embryotoxic, resulting in embryonic death, growth retardation, and developmental abnormalities when evaluated on Days 11 or 20 of gestation.

Abnormalities, Drug-Induced↗
PubMed1992

Metabolic acidosis reverses the increase in serum 1,25(OH)2D in phosphorus-restricted normal men.

We tested the hypothesis that in humans, metabolic acidosis can disorder the metabolism of 1,25-dihydroxyvitamin D [1,25(OH)2D] by impairing the capacity for a sustained physiological stimulus to increase renal production of this hormone. Specifically, in seven healthy men in whom restriction of dietary phosphorus had doubled their serum concentration of 1,25(OH)2D, we induced metabolic acidosis of moderate severity with oral NH4Cl, administered for 7 days. With induction of acidosis, the serum concentration of 1,25(OH)2D decreased sharply and remained decreased and near constant throughout the period of acidosis, the decrease amounting to one-half of the increment induced by phosphorus restriction alone. The serum concentration of free 1,25(OH)2D also decreased, since the measured free fraction of 1,25(OH)2D was unaffected by NH4Cl. The decrease in serum 1,25(OH)2D was accounted for by a 16% increase in its metabolic clearance rate and by a 19% decrease in its production rate. Metabolic acidosis induced a modest increase in the concentrations of blood ionized calcium and serum phosphorus. Multiple linear regression analysis revealed that serum levels of 1,25(OH)2D varied inversely and significantly with those of plasma hydrogen ion (R = -0.77, P < 0.001), but not with those of blood ionized calcium or serum phosphorus. These data demonstrate in humans that metabolic acidosis can substantially reverse the increase in serum concentration of 1,25(OH)2D induced by phosphorus restriction. The data provide evidence that acidosis can restrict the increase in renal production and serum concentration of 1,25(OH)2D effected by a sustained physiological stimulus.

Acid-Base Equilibrium↗
PubMed1992

Progestin antagonism of estrogen stimulated 1,25-dihydroxyvitamin D levels.

Progestins are frequently used in combination with estrogen to prevent or treat postmenopausal osteoporosis. Progestins protect against the undesirable hyperplastic effects of estrogen on the endometrium. The possibility that progestins might antagonize the beneficial effects of estrogen on calcium homeostasis has received little attention. In this study we determined whether the addition of progestin to estrogen would alter the ability of estrogen to raise serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels. Women within 5 yr of menopause were treated with three cycles of oral unopposed estrogen [1 or 2 mg/day (3.67 or 7.34 mumol/day) 17 beta-estradiol (E2) for 25/30 days of each cycle] followed by three cycles of E2 plus progestin [10 mg/day (29 mumol/day) medroxyprogesterone on days 12-25]. E2 increased both total and free 1,25-(OH)2D concentrations in a dose-dependent fashion. These levels increased progressively over the three cycles of unopposed estrogen treatment. In contrast the vitamin D binding protein concentration reached maximal levels after one cycle of E2. With the addition of progestin, the levels of total and free 1,25-(OH)2D returned toward baseline although vitamin D binding protein levels remained elevated. PTH levels rose with both doses of E2 as serum calcium levels fell. Progestin did not significantly alter the effects of E2 on PTH or calcium. Our results raise the possibility that progestin may antagonize part of the salubrious effects of estrogen on calcium homeostasis.

Dihydroxycholecalciferols↗
PubMed1991

Validation of protocols for assessing early pregnancy failure in the rat: clomiphene citrate.

A battery of protocols for the assessment of maternally mediated toxicity during early pregnancy in the rat is being evaluated for its utility in detecting and defining mechanisms of early pregnancy failure. In this report, clomiphene citrate (CC), an estrogen agonist/antagonist, was used as a model compound in this evaluation process. The protocols involve dosing rats with CC during, and evaluation of multiple endpoints following, (a) the first 8 days of pregnancy; (b) early pseudopregnancy, accompanied by decidual induction; and (c) the pre- and postimplantation intervals of early pregnancy. In addition, the effect of CC on embryo transport rate was assessed. Eight days of dosing with CC during early pregnancy produced a dose-dependent reduction in the number of implantation sites seen on Day 9, concomitant with alterations in maternal hormonal parameters. No effect on the decidual cell response was found, indicating that the mechanism of fertility reduction was not mediated via compromised uterine decidualization. The preimplantation period was highly vulnerable to the toxic effects of CC while no postimplantation resorptions were seen. When embryo transport rate was measured, a statistically significant embryo transport rate acceleration was detected, but this was insufficient to account for all of the observed preimplantation loss. The data suggest an effect of CC on embryo viability, on the embryo's ability to implant, or on the reproductive tract resulting in compromised embryo survival as the potential mechanism(s) mediating CC-induced early pregnancy failure. The battery of protocols was thus successful in identifying CC as a reproductive toxicant and in elucidating the causes of the observed early pregnancy failure.

Animals↗
PubMed1991

Use of bromoergocryptine in the validation of protocols for the assessment of mechanisms of early pregnancy loss in the rat.

Validated protocols for evaluating maternally mediated mechanisms of early pregnancy failure in rodents are needed for use in the risk assessment process. To supplement previous efforts in the validation of a panel of protocols assembled for this purpose, bromoergocryptine (BEC) was used as a model compound because it is known to inhibit pituitary prolactin secretion. BEC was tested using the early pregnancy protocol (EPP), the decidual cell response technique (DCR), the pre- vs postimplantation protocol (PPP), and embryo transport rate analysis (ETRA). These protocols evaluate the effects of chemicals on multiple endpoints following exposure during (a) the first 8 days of pregnancy, (b) early pseudopregnancy accompanied by decidual induction, (c) the pre- and postimplantation intervals of early pregnancy, or (d) the period of embryo transport. In the EPP, dosing with BEC during Days 1-8 of pregnancy reduced the number of implantation sites found on Day 9 as well as serum progesterone. The DCR technique revealed a dose-dependent inhibition of decidual growth concomitant with decreased serum progesterone as a result of BEC treatment. A modified DCR technique using hormone-supplemented ovariectomized rats demonstrated that BEC did not impair decidual growth in the presence of adequate progestogenic support. Pre- vs postimplantation dosing indicated that implantation is vulnerable to BEC effects at least through Day 4. BEC had no effect on embryo transport rate. Data from these protocols identified BEC as having adverse maternal effects during early pregnancy. While the pituitary was not identified by these protocols as the site of BEC's primary action, the protocols did identify a reduction in serum progesterone and impaired uterine function as toxicological mechanisms mediating the reduced fertility seen following BEC exposure.

Abortion, Veterinary↗
PubMed1991

The effects of estrone (Ogen) on spinal bone density of postmenopausal women.

The effects of cyclical treatment with estrone sulfate (0.3, 0.625, or 1.25 mg), plus calcium carbonate, on spinal trabecular bone density were compared with placebo in 120 postmenopausal women in this 2-year, multicenter, double-blind study. While the placebo and 0.3-mg treatment groups lost bone density (-3.6% and -5.1%), the 0.625- and 1.25-mg treatment groups experienced no significant change from baseline at 24 months (-0.8% and +0.7%). The 1.25-mg treatment group was significantly different from the placebo group at 12, 18, and 24 months. Although the 0.625-mg treatment group was significantly different from the placebo group only at 18 months, the data suggest that 0.625 and 1.25 mg of estrone sulfate had different effects than placebo and 0.3 mg of estrone sulfate and, given with supplemental calcium, are effective doses for the prevention of spinal bone loss.

Bone Density↗
PubMed1990

Intermittent cyclical etidronate treatment of postmenopausal osteoporosis.

BACKGROUND: To determine the effects of etidronate (a bisphosphonate that inhibits osteoclast-mediated bone resorption) in the treatment of postmenopausal osteoporosis, we conducted a prospective, two-year, double-blind, placebo-controlled, multicenter study in 429 women who had one to four vertebral compression fractures plus radiographic evidence of osteopenia. METHODS: The patients were randomly assigned to treatment with phosphate (1.0 g) or placebo twice daily on days 1 through 3, etidronate (400 mg) or placebo daily on days 4 through 17, and supplemental calcium (500 mg) daily on days 18 through 91 (group 1, placebo and placebo; group 2, phosphate and placebo; group 3, placebo and etidronate; and group 4, phosphate and etidronate). The treatment cycles were repeated eight times. The bone density of the spine was measured by dual-photon absorptiometry, and the rates of new vertebral fractures were determined from sequential radiographs. RESULTS: After two years, the patients receiving etidronate (groups 3 and 4) had significant increases in their mean (+/- SE) spinal bone density (4.2 +/- 0.8 percent and 5.2 +/- 0.7 percent, respectively; P less than 0.017). The rate of new vertebral fractures was reduced by half in the etidronate-treated patients (groups 3 and 4 combined) as compared with the patients who did not receive etidronate (groups 1 and 2 combined) (29.5 vs. 62.9 fractures per 1000 patient-years; P = 0.043); the effect of treatment was most striking in the subgroup of patients with the lowest spinal bone mineral density at base line, in whom fracture rates were reduced by two thirds (42.3 vs. 132.7 fractures per 1000 patient-years; P = 0.004). The addition of phosphate provided no apparent benefit. There were no significant adverse effects of treatment. CONCLUSIONS: Intermittent cyclical therapy with etidronate for two years significantly increases spinal bone mass and reduces the incidence of new vertebral fractures in women with postmenopausal osteoporosis.

Aged↗
PubMed1990

Effects of methyl benzimidazolecarbamate during early pregnancy in the rat.

Methyl 2-benzimidizolecarbamate (MBC), an agricultural fungicide, and its parent compound benomyl have adverse reproductive effects on male rats and exhibit embryotoxicity, including teratogenicity, when administered to rats during mid to late pregnancy. This study was designed to assess potential maternal effects of MBC during early pregnancy, to distinguish maternal from embryotoxic effects of the chemical, and to differentiate between early pregnancy failure and late embryonic loss. MBC was administered to rats by gavage at 0, 25, 50, 100, 200, 400, and 1000 mg/kg/day during Days 1 through 8 of pregnancy (Day 0 = sperm positive). A range of maternal and embryonic parameters was assessed following euthanasia on Day 9, including the number of implantation sites, body weight gain, uterine weight, implantation site size, and serum ovarian and pituitary hormones. In a separate experiment, pseudopregnant rats were administered 0 or 400 mg/kg/day MBC during Days 1-8, received bilateral uterine decidual induction on Day 4, and were killed on Day 9 at which time the decidual cell response was evaluated as a measure of uterine competency. When dosages of up to 400 mg/kg/day of MBC were administered during early pregnancy, the chemical had no significant effect on any measured parameter but a trend toward increased resorptions was evident. The 1000 mg/kg/day dosage of MBC produced reductions in body weight gain, implantation site weight, and serum LH and an increase in serum estradiol. When administered during pseudopregnancy, 400 mg/kg/day MBC partially reduced uterine decidual growth but affected no other parameter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Spinal bone mineral density measured with quantitative CT: effect of region of interest, vertebral level, and technique.

This study documents the relationship between different vertebral bone compartments with quantitative computed tomography (CT). Four distinct patient groups were investigated: healthy pre- and early postmenopausal women as well as healthy and osteoporotic late postmenopausal women. Three different regions of interest (ROIs) were employed: the elliptical ROI located in the anterior trabecular portion of the vertebral body, the peeled ROI of irregular shape that circumscribes most of the trabecular bone, and the integral ROI including all bone except for the transverse processes. Both single- and dual-energy quantitative CT techniques were employed at T-12 through L-3. Correlation between measurements in the elliptical and peeled ROIs was high (r = .985). The authors concluded that either ROI is acceptable for clinical use. The decrements in bone mineral density (BMD) for the integral ROI were smaller than those for the elliptical ROI. Dual-energy measurements were consistently higher than single-energy measurements. BMD as a function of vertebral level decreased systematically from T-12 to L-3. However, the average density of T-12 through L-3 can be accurately predicted by the average density of L-1 and L-2 (r = .997). Precision did not deteriorate significantly when BMD was expressed as the average of L-1 and L-2 (1.5%) instead of T-12 through L-3 (1.4%). In this study the data suggest a modified quantitative CT protocol for clinical applications in which BMD of only L-1 and L-2 are measured at a fixed gantry tilt.

Adult↗