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Biomedical subjects

R Horton

Publications and source records attributed to R Horton.

At least 271 records · Page 15Linked to original sources
PubMed1985

Increased maternal serum 3 alpha, 17 beta-androstanediol glucuronide concentrations during pregnancy.

Maternal serum concentrations of 3 alpha, 17 beta-androstanediol glucuronide (3 alpha-diol-G), a substance that reflects peripheral androgen action and tissue 5 alpha-reductase activity, were measured in 33 normal men, 51 nonpregnant women, and 51 women with uncomplicated pregnancies. The 3 alpha-diol-G concentrations in men (median, 201 ng/ml) were significantly higher than in nonpregnant women (median, 42 ng/ml) or pregnant women (median, 124 ng/ml). The concentrations in pregnant women were significantly greater than those in nonpregnant women, and there were no significant differences between trimesters in maternal 3 alpha-diol-G concentrations. There were no fetal sex differences found in maternal serum or in third-trimester amniotic fluid. These results indicate that pregnancy is associated with increased androgen production by maternal tissues and that fetal 3 alpha-diol-G production is low.

Androstane-3,17-diol↗
PubMed1985

Tissue production of androgens in women with acne.

Precursor and target tissue-produced androgens were measured in the plasma of eighteen women with mild to moderate acne. Mean plasma levels of the precursor androgens (total testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulfate) wer similar to levels in a group of carefully selected acne-free and hirsute-free, age-matched female controls. In contrast, plasma 3 alpha-androstanediol glucuronide (3 alpha-diol G) values were elevated in 13 of the patients, with a mean value for the entire group nearly threefold that of the normal controls (117 vs 43 ng/dl; p less than 0.001). These results support the concept that target tissue androgen production plays an important hormonal role in the pathogenesis of acne in women and that plasma 3 alpha-diol G may be the most sensitive marker of this process.

Acne Vulgaris↗
PubMed1985

Human pharmacokinetics of temocillin (BRL 17421) side chain epimers.

The pharmacokinetics of the side-chain epimers of temocillin were investigated in four healthy male subjects following a single iv dose of temocillin disodium (1 g pure free acid) containing 64.2% R-epimer. Plasma and urinary concentrations of the epimers were determined by hplc methods. The R-epimer was twice as rapidly cleared, had a 23% larger volume of distribution and a 60% shorter beta half-life than the S-epimer. Intermediate values were obtained for total temocillin (from hplc data). The differences in the pharmacokinetic properties of the epimers are most likely the result of different extents of plasma protein binding. In each plasma sample, the free fraction of the R-epimer was higher (up to two-fold) than that of the S-epimer. In a comparison of temocillin pharmacokinetic parameters derived from hplc and microbiological assay data, the values obtained from the latter analyses reflected most closely those for the R-epimer. Further indications that the R-epimer is more microbiologically active against Pseudomonas aeruginosa NCTC 10701 from other assessments of relative antibacterial activity are discussed.

Adult↗
PubMed1985

Role of extra- and intracellular calcium and calmodulin in renin release from rat kidney.

Renin release from the juxtaglomerular cell appears to be inversely related to calcium concentration. We studied the role of Ca+2 to confirm recent findings and to further explore the role of intracellular calcium as well as the calcium-calmodulin system in renin release. A rat renal cortical slice preparation was used. Isoproterenol (10(-6) M) caused significant stimulation of renin release, whereas angiotensin (AII; 5 X 10(-5) M) suppressed basal as well as isoproterenol-stimulated renin release. Removal of calcium from the buffer reversed AII suppression of renin release. Nifedipine (10(-5) M), a specific calcium channel blocker, induced a marked increase in basal renin release. TMB-8, an inhibitor of intracellular calcium release, also caused a dose-related increase in basal renin release. The calmodulin antagonists trifluoperazine and calmidazolium both caused significant dose-related increases; however, calmidazolium was a more potent stimulator. Low extracellular calcium or nifedipine concentrations did not alter isoproterenol-induced renin release. Isoproterenol further stimulated renin release in the presence of trifluoperazine and calmidazolium. These results suggest that acute beta-adrenergic stimulation of renin in independent of changes in levels of extracellular and intracellular calcium and calmodulin. These studies provide further evidence that unlike most other secretory systems, the reduction of intracellular calcium or inhibition of the calcium-calmodulin system in the juxtaglomerular cells of the kidney acts as a secretogogue.

Angiotensin II↗
PubMed1985

Therapeutic effect of calcium channel blockade in primary aldosteronism.

To determine the potential therapeutic effect of calcium entry blockade in primary aldosteronism, 10 patients (5 adenoma and 5 hyperplasia) documented by endocrine testing and/or surgery were given nifedipine (20 mg, sublingually) in the afternoon. In all patients, nifedipine acutely lowered systolic and diastolic blood pressure to normal for up to 6 h. Plasma cortisol and potassium did not change in the acute study. The basal plasma renin concentration was suppressed and was not altered by nifedipine. However, nifedipine reduced aldosterone within 120 min [22 +/- 5 (+/- SE) to 10 +/- 2 ng/dl; P less than 0.02], including the 5 patients with adenomas (22 +/- 3 to 10 +/- 3; P less than 0.02). In a 4-week study, nifedipine controlled blood pressure (134 +/- 5 mm Hg systolic and 85 +/- 3 mm Hg diastolic) and normalized serum K+ (3.0 +/- 0.1 to 3.7 +/- 0.1 meq/liter; P less than 0.01) while reducing plasma aldosterone levels (46 +/- 8 to 20 +/- 3; P less than 0.02). These results suggest that Ca+2 channel blockers may provide a new medical therapy, both controlling blood pressure and reducing aldosterone levels, for patients with primary aldosteronism.

Adenoma↗
PubMed1985

Evidence that the beta-adrenergic system and prostaglandins stimulate renin release through different mechanisms.

In normal man, converting enzyme inhibition (CEI) acutely increases plasma active renin and decreases plasma inactive renin. This reciprocal relationship suggests that conversion of inactive to active renin may be important in the acute response to stimulation of renin secretion. To determine whether the beta-adrenergic system or prostaglandins (PGs) participate in the acute effect of CEI on renin, we administered captopril (50 mg) alone and with either propranolol (P; 80 mg) or a PG cyclooxygenase inhibitor [PI; indomethacin (50 mg) or ibuprofen (800 mg)] to normal subjects ingesting a 25 meq/day Na diet. Supine blood pressure fell by 12 +/- 2 (+/- SE) mm Hg with CEI alone, 10 +/- 1 mm Hg with CEI plus P, and 7 +/- 1 mm Hg with CEI plus PI. Active renin rose 8-fold (P less than 0.01), with a peak at 1-2 h, after CEI and 3-fold (P less than 0.02) in response to CEI plus P or CEI plus PI. P did not block the fall in acid-activated inactive renin compared to CEI alone. The nadir of the inactive renin response to both CEI or CEI plus P occurred at 1-2 h. PI, however, prevented the fall in inactive renin. To extend this observation, we compared the effects of infusion of a vasodilator PG (PGA1; 0.6 micrograms/kg X min) and a pure beta-agonist (isoproterenol; 0.3 micrograms/kg X min). PGA1 increased active renin 2.5-fold and decreased inactive renin by 80% (both P less than 0.02), while isoproterenol increased active renin 4.1-fold, but did not significantly change inactive renin. These data suggest that the beta-adrenergic system and PGs at least acutely stimulate renin production at different steps of its biosynthesis or secretion.

Adult↗
PubMed1985

Human pharmacokinetics and antimicrobial activities of the temocillin epimers.

The pharmacokinetics of the epimers of temocillin were investigated in 4 healthy male subjects following intravenous administration of 1g of temocillin disodium (free acid) which contains a R : S epimer ratio of approximately 65 : 35. The R epimer had a 2-fold greater total plasma clearance, a 23% larger volume of distribution and a shorter beta half-life than the S epimer. Intermediate values were obtained for total temocillin (R + S) from high pressure liquid chromatography (HPLC) data. In each plasma sample, the unbound fraction of the R epimer was generally 2-fold higher than that of the S epimer, which is suggested as the reason for the differences in the pharmacokinetic properties of the epimers. The temocillin pharmacokinetic parameters obtained from the microbiological assay data reflect most closely those for the R epimer derived from HPLC data. The resolved R epimer exhibited twice the potency of the S epimer against the microbiological assay organism Pseudomonas aeruginosa NCTC 10701. However, in tests for antibacterial susceptibility, for instance minimum inhibitory concentration (MIC) determinations involving prolonged incubation, there was little difference in the inhibitory activities of the resolved R and S epimers compared with temocillin (R + S), presumably as a consequence of the epimerization of the individual epimers. In contrast, in rapid tests for bactericidal activity, which minimise the effect of epimerization, the R epimer exhibited greater bactericidal activity than the S epimer.

Adult↗
PubMed1985

Temocillin concentrations in human tissues.

67 samples of 15 different tissues were obtained from 26 patients who were given an intravenous bolus dose of temocillin approximately 3 to 4 hours prior to surgery. 50 tissue samples were obtained from 19 patients who received 1g temocillin and 17 tissue samples were obtained from 7 patients who received 2g temocillin. The majority of tissue samples were removed 3 to 4 hours after administration of the drug and, at this time, group mean serum concentrations were 53.5 mg/L (1g doses) and 117.3 mg/L (2g doses). Mean tissue concentrations of 8 to 10 mg/kg were seen in muscle, liver and skin samples after 1g doses, and 18, 34 and 9 mg/kg, respectively, after 2g doses. Temocillin concentrations seen in the gallbladder were considerably higher than those in other tissues.

Adult↗
PubMed1985

Augmentin bioavailability following cimetidine, aluminum hydroxide and milk.

Previous studies [Jackson et al. 1980] have shown that the bioavailability of Augmentin is not affected by food. The present work has shown that aluminum hydroxide, milk and cimetidine do have some influence on the bioavailability of a single dose of oral Augmentin, but the small differences observed are unlikely to be of therapeutic importance. It is concluded that Augmentin may be administered in clinical practice with any of these substances.

Administration, Oral↗
PubMed1984

Chronic administration of the GABA-transaminase inhibitor ethanolamine O-sulphate leads to up-regulation of GABA binding sites.

In rats receiving the gamma-aminobutyric acid (GABA)-transaminase inhibitor ethanolamine O-sulphate (EOS) in their drinking water for up to 28 days, the number of GABAA and GABAB binding sites was increased compared to controls. There was no change in binding affinity at GABAA or GABAB sites. One week after EOS withdrawal, the number of GABAA and GABAAB sites in previously treated EOS rats did not differ from controls. There was no difference in the number or affinity of benzodiazepine binding sites between EOS-treated and control rats during EOS administration or withdrawal. There was no difference in the stimulation of benzodiazepine binding by GABA (alone or in the presence of NaCl) during EOS administration. Cortical and cerebellar GABA concentration was increased 3.2- to 4.6-fold and cortical glutamate decarboxylase (GAD) activity reduced 30-42%. The current required to induce electroshock convulsions did not differ between EOS-treated rats and control rats during EOS administration. We speculate that the stimulus for the increased number of GABAA and GABAB binding sites is a reduction in GABA release subsequent to a reduction in GAD activity.

4-Aminobutyrate Transaminase↗
PubMed1984

Aromatization by splanchnic tissue in men.

To measure the rate of aromatization that occurs in splanchnic tissue, four men with normal liver function were infused through an arm vein with [3H]androstenedione/[14C] estrone and four men were infused with [3H]testosterone/[14C] estradiol before indicated cardiac procedures. Catheters were placed under fluoroscopic control in the hepatic vein and descending aorta. Simultaneous blood samples were then obtained from the aorta and the hepatic vein after 90 and 120 min of infusion. The samples were analyzed for radioactivity after multiple chromatographic purification steps. The MCRs, overall aromatization (fraction of androgen infused measured as estrogen in arterial blood), splanchnic extractions, and splanchnic aromatization (fraction of androgen entering the splanchnic tissue which leaves as estrogen) were determined. The mean values for MCRs of androgens and estrogens and overall aromatization for androstenedione and testosterone were similar to those reported previously. The splanchnic extraction values of androstenedione, testosterone, estrone, and estradiol were 0.57 +/- 0.10 (+/- SE), 0.39 +/- 0.12, 0.60 +/- 0.09, and 0.64 +/- 0.18, respectively. The mean splanchnic aromatization of androstenedione to estrone was 0.00086 +/- 0.00072, and the mean splanchnic aromatization of testosterone to estradiol was 0.00059 +/- 0.00020. If one assumes that the splanchnic bed receives 20% of the cardiac output, then the splanchnic bed is responsible for less than 4% of the overall peripheral aromatization of androstenedione or testosterone.

Androgens↗
PubMed1984

Origin of plasma androstanediol glucuronide in men.

The role of testosterone (T) and dihydrotestosterone (DHT) as precursors of the peripheral metabolite androstanediol glucuronide (3 alpha diol G) in plasma from normal men was studied. An apparent steady state of both putative precursors and the steroid glucuronides were attained by 8-h constant iv infusions of 3H-labeled steroid after a loading dose. The unconjugated steroids and the steroid glucuronides (after beta-glucuronidase hydrolysis) with 14C indicator were purified by serial microcolumn and paper chromatography steps previously reported to achieve radiochemical purity. The specific activities of 3 alpha diol and 3 alpha diol G in plasma were widely different in each subject, confirming our earlier suggestion that the two peripheral metabolites are formed in different pools. The conversion ratios (CRPre-Prod BB) varied widely. The CRT-3 alpha diol G was generally less than 5%, while the CRDHT-3 alpha diol G was 10 times higher. These results are compatible with the expected model, T----DHT----3 alpha diol G. In some of the studies, T glucuronide (TG) and DHT glucuronide (DHTG) were isolated after T infusions, and DHTG was isolated after DHT infusion. The major conversion product of blood T was DHTG, not TG, and the major conversion product of DHT was 3 alpha diol G. This suggests that metabolism proceeds through a steroid reduction step and glucuronidation. The peripheral pathway to 3 alpha diol G may involve formation of DHTG and then 3 alpha-reduction to 3 alpha diol G. This may also explain why blood levels of unconjugated 3 alpha diol have not been helpful in elucidating disorders of androgen formation, as this androgen mostly arises from sites different from 3 alpha diol G.

Adult↗
PubMed1984

Parenteral augmentin: pharmacokinetics.

The pharmacokinetics of intravenous Augmentin have been investigated and the data found to fit a two compartment model. In the first study, to a crossover design, a bolus injection of 1.2 g Augmentin was given to 8 healthy volunteers with and without probenecid. It was found that the serum concentrations of amoxycillin were increased in the presence of probenecid, but those of clavulanic acid were unaffected. In a second study a further 8 volunteers received an infusion over 30 min of 2.2 g Augmentin. At the end of the infusion, peak concentrations in excess of 100 micrograms/ml were recorded for amoxycillin and 14 micrograms/ml for clavulanic acid. In both studies the serum and urinary concentrations of amoxycillin and clavulanic acid obtained were well above those considered necessary to achieve a therapeutic effect.

Adult↗