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Biomedical subjects

P Leppert

Publications and source records attributed to P Leppert.

16 recordsLinked to original sources
PubMed2002

Differences in the absorption, metabolism and biliary excretion of a diastereomeric pair of alphavbeta3-antagonists in rat: limited role of P-glycoprotein.

1. The study investigated mechanisms underlying the pharmacokinetic differences of two zwitterionic diastereomers ((3S)-3-[(3R or 3S)-2-oxo-3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]pyrrolidin-1-yl]-3-quinolin-3-ylpropanoic acid) with different lipophilicities using a combination of in vivo and in vitro approaches. 2. In rat, both isomers possessed comparable plasma clearances (CL). However, the more lipophilic diastereomer I exhibited a higher metabolic clearance (>2-fold higher than II), whereas the hydrophilic zwitterion II exhibited a higher biliary clearance (approximately 5-fold higher than I). Following oral administration, the bioavailability (F) of I (17%) was much higher than that of II (1%). 3. Consistent with these in vivo observations and the expectation based on their lipophilicity differences, the metabolism in rat liver microsomes was faster and the permeability in Caco-2 and LLC-PK1 cells and in situ rat intestinal loop was better for I than for II. 4. Only the absorption of the more lipophilic diastereomer I was subjected to an efflux system in the Caco-2 and in situ rat intestinal loop models. I was a good substrate for P-glycoprotein (P-gp) in both the human MDR1 and mouse mdr1a transfected cell lines, and in the wild-type mdr1a (-/-) mouse when compared with the P-gp-deficient mdr1a (-/-) mouse. Concomitant administration of I with verapamil in rat caused significant increases in oral AUC, F and Cmax of I without affecting its CL, further supporting the effect of P-gp in limiting the intestinal absorption of I in vivo in this animal model. 5. Since the findings that the lipophilic diastereomer I, but not II, was a good P-gp substrate were not in line with the observations that I was excreted to bile much slower than II and that I was absorbed better than II, the results suggested that P-gp played a minor role to the observed differences in the biliary excretion and intestinal absorption of the diastereomers I and II in rat.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

In vitro and in vivo evaluation of dihydropyrimidinone C-5 amides as potent and selective alpha(1A) receptor antagonists for the treatment of benign prostatic hyperplasia.

alpha(1) Adrenergic receptors mediate both vascular and lower urinary tract tone, and alpha(1) receptor antagonists such as terazosin (1b) are used to treat both hypertension and benign prostatic hyperplasia (BPH). Recently, three different subtypes of this receptor have been identified, with the alpha(1A) receptor being most prevalent in lower urinary tract tissue. This paper explores 4-aryldihydropyrimidinones attached to an aminopropyl-4-arylpiperidine via a C-5 amide as selective alpha(1A) receptor subtype antagonists. In receptor binding assays, these types of compounds generally display K(i) values for the alpha(1a) receptor subtype <1 nM while being greater than 100-fold selective versus the alpha(1b) and alpha(1d) receptor subtypes. Many of these compounds were also evaluated in vivo and found to be more potent than terazosin in both a rat model of prostate tone and a dog model of intra-urethral pressure without significantly affecting blood pressure. While many of the compounds tested displayed poor pharmacokinetics, compound 48 was found to have adequate bioavailability (>20%) and half-life (>6 h) in both rats and dogs. Due to its selectivity for the alpha(1a) over the alpha(1b) and alpha(1d) receptors as well as its favorable pharmacokinetic profile, 48 has the potential to relieve the symptoms of BPH without eliciting effects on the cardiovascular system.

Adrenergic alpha-Antagonists↗
PubMed1995

Epidemiology of uterine leiomyomas. With an etiologic hypothesis.

OBJECTIVE: The few previous epidemiologic studies of uterine myomas have relied on clinical evaluation to select controls, but we previously showed that myomas may be present in more than 75% of such uteri. STUDY DESIGN: We therefore attempted to evaluate risk factors using age-matched controls whose uteri were serially sectioned to exclude the presence of myomas. RESULTS: The small study size precluded a meaningful evaluation of most parameters but tended to confirm the negative association of myomas with cigarette smoking (P = .07). CONCLUSION: Using monoclonal smooth muscle proliferation in human atherosclerotic plaques as a model, we suggest that excessive injury to and repair of the endometrial lining of the uterus may promote monoclonal expansion of smooth muscle cell populations in the uterine wall (i.e., myomas). This theory is largely compatible with the estrogen hypothesis, but fundamental principles of tumorigenesis and previous epidemiologic data on myomas suggest that nutritional factors should be scrutinized as possible initiators (DNA-damaging substances) in the pathogenesis of uterine myomas.

Adult↗
PubMed1990

A comparison of oral and rectal absorption of L-dopa esters in rats and mice.

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration. In most cases, oral administration resulted in nondetectable (less than 0.01 micrograms/ml) levels of the esters in plasma. Correspondingly, the plasma levels of L-dopa itself were consistently higher following rectal administration. At very high oral doses (500 mg L-dopa equivalents/kg body weight), systemic plasma levels of the butyl ester could be detected (1.25 micrograms/ml at 10 min), which might indicate saturation of the esterase activity of the small intestine. These studies indicate that the systemic availability of L-dopa from short-chain alkyl esters of L-dopa may be best optimized by rectal administration, which avoids the relatively high esterase activity characteristic of the small intestine.

Administration, Oral↗
PubMed1989

Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption.

The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable (greater than 360 min) to hydrolysis in physiological buffer. In vitro enzymatic hydrolysis of the esters in plasma was species dependent, with the hydrolytic rate being faster in rat plasma (t 1/2 less than 5 min) than dog plasma (t 1/2 = 68-181 min) or human plasma (t 1/2 = 96-238 min). In vivo hydrolysis in dogs, as indicated by the L-dopa plasma profile following intravenous administration of the esters, was very rapid (high extravascular esterase activity). Significant L-dopa bioavailability was observed in rats following rectal administration of the methyl (46%), ethyl (14%), isopropyl (48%), butyl (100%), and 4-hydroxybutyl (13%) esters of L-dopa (rectal L-dopa absorption, less than 5%). In dogs, significant L-dopa bioavailability was also observed for the methyl (28%), isopropyl (30%), butyl (32%), and 4-hydroxybutyl (34%) esters of L-dopa in the presence of carbidopa. The data indicate that these highly water-soluble (greater than 600 mg/ml) esters of L-dopa are potential candidates for controlled-release rectal delivery systems designed to provide more constant plasma L-dopa levels.

Administration, Rectal↗
PubMed1988

The effect of cocaine abuse on birth weight and gestational age.

A retrospective study of 343 women who lacked prenatal care was conducted to ascertain the effect of recent cocaine abuse on birth weight and gestational age. All pregnant women admitted in labor to a large urban teaching hospital between January 1 and December 31, 1986 who had not received prenatal care were included. The charts of these women were evaluated to obtain information about medical and obstetric complications of pregnancy, labor and delivery, and birth weight and gestational age of the infant. Information about drug use was obtained by urine toxicology at the time of admission. Results of ordinary least-squares multiple regression analyses indicated cocaine abuse to be a significant predictor of low birth weight and early gestational age. No correlation was found between cocaine abuse and abruptio placentae or maternal hypertension.

Adolescent↗
PubMed1981

Comparison of human growth hormone binding to rat liver plasma and Golgi membranes.

The binding characteristics of hGH to Golgi and liver plasma membranes isolated from normal adult female rats have been compared to assess the biological differences between the Golgi and plasma membrane receptor. The effect of cations and the time course of binding were qualitatively similar for both Golgi and plasma membranes. The Golgi membranes from normal rats exhibited maximum binding at pH 6-7 compared to 5-6 for other membrane fractions. The highest apparent affinities (approx. 1 x 10(9) M-1) for hGH were observed in the light Golgi membranes from normal rats and the light and intermediate Golgi membranes from ethanol treated rats. The lowest apparent affinities (0.026 -0.1 x 10(9)M-1 if determined by competitive binding curves or 0.07 - 0.32 x 10(9)M-1 by Scatchard plots) for hGH were observed in plasma membranes isolated by either Neville's or Ray's method or a combination of both methods. The hGH receptors were determined to be lactogenic by competitive binding curves. The affinities of Golgi membranes were not affected by alterations in isolation procedures. Ethanol treatment of the rats prior to sacrifice and membrane isolation resulted in linear Scatchard plots for hGH binding to Golgi membranes compared to curved Scatchard plots for the Golgi membranes of normal rats. The marker enzyme activities of glucose-6-phosphatase and adenylate cyclase were lower in Golgi from ethanol treated rats while the galactosyl transferase activity increased in lighter golgi fractions from ethanol treated rats.

Adenylyl Cyclases↗
PubMed1981

In vivo effect of human growth hormone on hepatic adenylate cyclase activity.

Significant increases in basal, and glucagon and fluoride stimulated adenylate cyclase activity were observed in liver plasma membranes of hypophysectomized rats compared to normal adult and weanling rats. The fluoride stimulated adenylate cyclase activity was 2-3 fold greater in the membranes from hypophysectomized animals while the glucagon stimulated activity was 5-7 fold greater, and the basal activity was approximately double that of membranes from normal adult animals. Administration of growth hormone to hypophysectomized rats by an intramuscular or intravenous route decreased adenylate cyclase activity to levels equivalent to those in normal adult rats. Estradiol and thyroxine replacement did not alter the adenylate cyclase activity of the membranes from hypophysectomized animals. The fluoride or epinephrine stimulated adenylate cyclase activity of rat diaphragm homogenates was not affected by hypophysectomy.

Adenylyl Cyclases↗
PubMed1979

Antecedent renal disease and the outcome of pregnancy.

We assessed the effect of "healed" childhood renal disease on subsequent pregnancies by following-up a cohort of 224 children initially hospitalized with kidney disease. The pregnancy experience in this cohort was compared to two "control" cohorts comprising 81 female siblings and 191 age-matched female patients hospitalized contemporaneously for respiratory infection. The incidence of spontaneous abortion, stillbirth, and pregnancy-associated hypertension was not different among the cohorts; however, the incidence of infants with low birth weights was significantly greater in the renal and respiratory disease groups. Childhood kidney disease followed by impaired renal function (serum creatinine greater than 1.5 mg/dL) was associated with greater maternal and fetal morbidity. Kidney disease in childhood followed by apparent healing and no functional renal impairment does not have an adverse effect on maternal welfare, although the incidence of infants with low birth weight is apparently increased.

Abortion, Spontaneous↗
PubMedDate not supplied

The effect of medroxyprogesterone acetate on blood pressure.

Twenty-four women (21 normotensive and 3 hypertensive) aged 16-35 years received 150-mg injections of medroxyprogesterone acetate (MPA) for contraception. Their blood pressure (BP) was measured under basal conditions by the same nurse before treatment and at 1-, 2- and 3-month intervals. Their mean BP fell from 124.1/79.4 to 119.8/74.6 mm Hg at one month (p less than 0.05 for diastolic pressure) to 117.0/74.9 mm Hg at two months and to 115.6/73.2 mm Hg at three months. When the normotensive patients were analyzed separately, their BP fell, but not significantly. Only one patient had a rise of 20 mm Hg systolic, but she remained normotensive. We conclude that medroxyprogesterone acetate does not raise BP.

Adolescent↗