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Biomedical subjects

G Nicolau

Publications and source records attributed to G Nicolau.

At least 19 recordsLinked to original sources
PubMed1989

Skin metabolism and transdermal absorption of viprostol, a synthetic PGE2 analog, in the rat: effect of vehicle.

The effects of three formulations on the transdermal absorption and antihypertensive activity of 14C-viprostol were investigated in the spontaneously hypertensive rat. Single doses of 14C-viprostol were administered topically to rats in three formulations: silicone oil, petrolatum base, and triethyl citrate (TEC). Mean arterial blood pressure (MABP) and blood concentrations of radioactivity were measured over 24 h. Metabolic profiles in the skin were determined by HPLC; in vitro skin metabolism was also investigated. Following topical dosing with 14C-viprostol in petrolatum and silicone oil, substantial systemic concentrations of radioactivity and decreases in MABP were observed. In contrast, administration of 14C-viprostol in TEC led to negligible blood concentrations of radioactivity and the lowering of MABP was diminished. Metabolic profiles in skin at the application site from rats dosed with viprostol in petrolatum and silicone oil indicated rapid hydrolysis of the viprostol methyl ester to the active free acid, CL 115,129. When TEC was used as the dosing vehicle, the conversion of viprostol to the free acid appeared to be slower. TEC (an ester itself) was also found to reduce the rate of hydrolysis of viprostol in rat skin 10,000-g supernatants.

Administration, Topical↗
PubMed1988

Pre-systemic metabolism of viprostol in the monkey following oral and topical administration.

1. 14C-Viprostol, (I), a synthetic PGE2 analogue, was administered to 6 monkeys, orally, topically and intravenously in a three way crossover study. Total radioactivity and the pharmacologically active acid formed by rapid hydrolysis of viprostol in vivo, (II), were measured in plasma to determine absorption and absolute bioavailability. 2. After oral dosing approx. 31% of drug-related radioactivity was absorbed. Systemic bioavailability of unchanged active acid was only 7.3%. This indicates significant first-pass metabolism after oral administration, since only 23% of the absorbed radioactivity was available as 'unchanged' active drug (II). 3. After topical dosing, transdermal absorption of total radioactivity by 48 h averaged only 5% of dose. Absolute bioavailability of II averaged 3.8% of dose. This indicates that after transdermal absorption 74% of the absorbed radioactivity was available systemically as the active acid II, with the remainder being subject to pre-systemic metabolism.

Absorption↗
PubMed1987

Deposition of viprostol (a synthetic PGE2 vasodilator) in the skin following topical administration to laboratory animals.

1. Topical application of 14C-viprostol, a synthetic prostaglandin E2 analogue, to laboratory animals resulted in a significant depot of radioactivity in the skin at the application site in all species studied: mouse, rat, guinea pig, rabbit and monkey, with longer residence times in the larger species. 2. The location of the 14C-label in the skin in mice and monkeys was determined by microscopic autoradiography. Evaluation of the autoradiograms show rapid penetration of the drug into the skin via the hair follicles. 3. In mouse distribution of radioactivity was evident in the stratum corneum and down the hair shafts by 30 min. after dosing. By 2 h radioactivity was also observed throughout the viable epidermis; in the dermis only the hair shafts contained significant radioactivity. At 72 h after dose removal, radioactivity was evident only in the hair follicles and hair shaft. 4. In monkey the residence time of radioactivity in the skin was significantly longer than in mouse, but the general distribution pattern was similar in both species. 5. The presence of viprostol in the hair follicles and epidermal layer after topical administration is consistent with its extensive skin metabolism previously reported.

Administration, Topical↗
PubMed1987

Circannual variations in blood pressure, urinary catecholamine excretion, plasma aldosterone, and serum sodium, potassium, calcium, and magnesium in children 11 +/- 1.5 years of age.

A total of 194 clinically healthy children 11 +/- 1.5 years of age were studied during different seasons. Systolic and diastolic blood pressure were determined by auscultatory endpoints, and blood and urine were collected at 4-hr intervals over a 24-hr span. Urinary norepinephrine, epinephrine, and dopamine were determined by HPLC, plasma aldosterone by RIA, serum sodium and potassium by ion-specific electrode, and calcium and magnesium by colorimetry. The circadian means showed statistically significant circannual variations in all variables except epinephrine. The highest circadian means of systolic and diastolic blood pressure and of urinary norepinephrine occurred during winter; the highest values of plasma aldosterone, serum potassium, and urinary dopamine were found in fall, those of serum calcium and magnesium during the summer, and that of serum sodium in spring. Circannual rhythms characterize functions related to blood pressure regulation in children. The circannual elevation of blood pressure (within the usual range) and of norepinephrine were both found to occur in winter. This time relation may have a functional significance, although a causal relationship is not proven by the temporal coincidence of two rhythms.

Aldosterone↗
PubMed1986

Metabolism of viprostol--a synthetic vasodilator PGE2 analog.

Metabolic studies were done with 14C-Viprostol (I) administered by various routes (I.V., oral and topical) to six animal species and to man. Total radioactivity and metabolic profiles were analyzed in plasma, tissues and excreta. The main metabolites were isolated and identified by capillary GC/MS. Plasma and urinary metabolic profiles were qualitatively similar across species, with two major metabolic reactions being predominant: rapid hydrolysis to the pharmacologically active free acid (II) and oxidation of the alpha-chain to dinor and tetranor acids (III, IV). In the monkey and man, reduction of the 9-keto group lead to PGF2 type metabolites (VI-VIII). In the rat, omega oxidation of the beta-chain occurred as well, resulting in the formation of dicarboxylic acids (V).

Administration, Topical↗
PubMed1986

Tissue deposition of bisantrene in B16 melanoma tumor-bearing mice.

Single doses of 14C-labeled bisantrene, a new antitumor agent, were administered intravenously at 10 and 100 mg/kg to mice bearing intraperitoneally implanted B16 melanoma. At 24 hr after dosing, the tumors contained relatively high drug concentrations as compared to most of the other tissues. The concentrations averaged 2.4 and 28.3 micrograms/g tumor and the tumor/blood concentration ratios were 40/1 and 29/1 for the low and high doses, respectively.

Animals↗
PubMed1985

Radioimmunoassay for mitoxantrone, a new antitumor agent.

A sensitive and specific radioimmunoassay for mitoxantrone in serum has been developed. The procedure allows direct measurement of mitoxantrone in unextracted serum samples, by using antisera from rabbits immunized with mitoxantrone-BSA antigen. Tritiated mitoxantrone of high specific radioactivity (ca. 15 Ci/mmol) was used as a radio-tracer ligand. The assay allows the detection of as little as 50 pg/ml and the quantitation of 75 pg/ml in 0.5 ml serum samples. Standard curves were linear in the concentration range of 75-2500 pg/ml, at antiserum dilutions of 1:15,000. The assay shows good reproducibility: coefficients of variation of 3-6% were obtained by analyzing five samples/concentration at 75, 100, 250, 500, and 1000 pg/ml. There was no cross reactivity with the major metabolite in human serum, having concentrations of up to 10,000 pg/ml. Serum samples collected at various time intervals from rats dosed intravenously with mitoxantrone (0.5 mg/kg), were analyzed for unchanged mitoxantrone by RIA. The drug concentrations decreased from 32 ng/ml at 0.5 h to 0.45 ng/ml by 24 h after dosing. Mitoxantrone, a dihydroxyanthracenedione derivative (1), is an antitumor agent currently used in clinical trials with very encouraging results, especially in metastatic breast cancer, and low incidence of adverse reactions (2-4). The drug is being administered intravenously at doses up to 14 mg/m2. Preliminary pharmacokinetic studies (to be published separately) indicate rapid distribution, followed by slow clearance rates from the tissues. The sensitivity of the currently available (HPLC) methods (5, 6) is of about 5-20 ng/ml in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26.

To examine the defect in side-chain oxidation during the formation of bile acids in cerebrotendinous xanthomatosis, we measured in vitro hepatic microsomal hydroxylations at C-12 and C-25 and mitochondrial hydroxylation at C-26 and related them to the pool size and synthesis rates of cholic acid and chenodeoxycholic acid as determined by the isotope dilution technique. Hepatic microsomes and mitochondria were prepared from seven subjects with cerebrotendinous xanthomatosis and five controls. Primary bile acid synthesis was markedly reduced in cerebrotendinous xanthomatosis as follows: cholic acid, 133 +/- 30 vs. 260 +/- 60 mg/d in controls; and chenodeoxycholic acid, 22 +/- 10 vs. 150 +/- 30 mg/d in controls. As postulated for chenodeoxycholic acid synthesis, mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha-diol was present in all specimens and was 30-fold more active than the corresponding microsomal 25-hydroxylation. However, mean mitochondrial 26-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol was less active in cerebrotendinous xanthomatosis than in controls: 59 +/- 17 compared with 126 +/- 21 pmol/mg protein per min. As for cholic acid synthesis, microsomal 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol was substantially higher in cerebrotendinous xanthomatosis and control preparations (620 +/- 103 and 515 +/- 64 pmol/mg protein per min, respectively) than the corresponding control mitochondrial 26-hydroxylation of the same substrate (165 +/- 25 pmol/mg protein per min). Moreover in cerebrotendinous xanthomatosis, mitochondrial 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol-26-hydroxylase activity was one-seventh as great as in controls. Hepatic microsomal 12 alpha-hydroxylation, which may be rate-controlling for the cholic acid pathway, was three times more active in cerebrotendinous xanthomatosis than in controls: 1,600 vs. 500 pmol/mg protein per min. These results demonstrate severely depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation and pool size disproportionately greater than that for cholic acid. The deficiency of chenodeoxycholic acid can be accounted for by hyperactive microsomal 12 alpha-hydroxylation that diverts precursors into the cholic acid pathway combined with decreased side-chain oxidation (mitochondrial 26-hydroxylation). However, side-chain oxidation in cholic acid biosynthesis may be initiated via microsomal 25-hydroxylation of 5beta-cholestane-3alpha,7alpha,12alpha-triol was substantially lower in control and cerebrotendinous xanthomatosis liver. Thus, separate mechanisms may exist for the cleavage of the cholesterol side chain in cholic acid and chenodeoxycholic acid biosynthesis.

Adult↗
PubMed1981

Testicular function in prepubertal male pseudohermaphroditism.

Testicular function was evaluated in forty-one prepubertal patients with male pseudohermaphroditism by determining serum concentrations of progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone and dihydrotestosterone before and after stimulation with hCG and, in some instances, ACTH. Testosterone response to hCG was normal in all subjects. In one patient, a 4-year-old boy, a deficiency of 17,20-desmolase activity was diagnosed based on the coexistence of elevated levels of pregnenolone, 17-hydroxypregnenolone, progesterone and 17-hydroxyprogesterone and low levels of dehydroepiandrosterone and androstenedione. In three other patients enzymatic blocks were suspected but not confirmed. Congenital deficiency of enzymes necessary for testosterone biosynthesis is an uncommon aetiology of male pseudohermaphroditism.

Adolescent↗
PubMed1980

Testicular function in varicocele.

Testicular testosterone concentration serum testosterone, LH and FSH, sperm count and testicular histology were evaluated in 17 patients with varicocele. Testicular testosterone was either normal or high (mean 906 +/- 723 ng/g of tissue), and serum testosterone was within the normal range in most patients. Serum LH was elevated in half of the patients. The degree of testicular damage observed was extremely variable and correlated with sperm analysis. Testicular testosterone tended to be higher in patients with severe microscopic lesions of the testis. It is concluded that even though Leydig cell function is partially altered, this deficiency is compensated by LH stimulation and therefore, failure of spermatogenesis is not secondary to low testosterone levels.

Adult↗
PubMed1979

Potential antiarthritic agents. 2. Benzoylacetonitriles and beta-aminocinnamonitriles.

Benzoylacetonitrile and beta-aminocinnamonitrile are shown to possess potent antiinflammatory activity in the rat adjuvant arthritis model. In a series of phenyl-substituted analogues, only o-, m-, and p-fluorobenzoylacetonitrile and m- and p-fluoro-beta-aminocinnamonitrile retained activity. Additionally, beta-amino-2- and beta-amino-3-thiopheneacrylonitrile and beta-oxo-2- and beta-oxo-3-thiophenepropionitrile exhibited similar activity. These agents are not believed to be acting via prostaglandin synthetase inhibition. The metabolic profile of benzoylacetonitrile is also described.

Acetonitriles↗
PubMed1979

Testicular function in post pubertal male pseudohermaphroditism.

Testicular endocrine function was studied in twelve post pubertal patients with male pseudohermaphroditism and 46 XY chromosomal constitution. Patients were divided into three groups, four subjects who became feminized during puberty, five who became masculinized during puberty and three who were castrated before puberty. Serum dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, androstendione, testosterone, dihydrotestosterone, LH and FSH were determined by radioimmunoassay. Patients of the first group had the clinical characteristics of testicular feminization secondary to absence of the androgen receptor. One of the five patients of the second group had deficient testosterone secretion but no enzymatic defect could be demonstrated. One of the subjects castrated before puberty had a deficiency in 17,20-desmolase. Therefore, evidence of a failure of the fetal testes could be found in only two of the twelve patients studied.

Adolescent↗
PubMed1979

Metabolism of potential precursors of chenodeoxycholic acid in cerebrotendinous xanthomatosis (CTX).

In patients with cerebrotendinous xanthomatosis (CTX), diminished cholic acid production is associated with incomplete oxidation of the cholesterol side chain and the excretion of C(25)-hydroxy bile alcohols. The aims of this investigation were 1) to provide quantitative information on the pool size and production rate of chenodeoxycholic acid by the isotope dilution technique; and 2) to investigate the possible existence of a block in chenodeoxycholic acid synthesis and explain the absence of chenodeoxycholic acid precursors in CTX. After the injection of [24-(14)C]chenodeoxycholic acid, measurements of chenodeoxycholic acid pool size and production rate in a CTX subject were, respectively, 1/20 and 1/6 as great as controls. Further, three potential precursors of chenodeoxycholic acid, namely [G-(3)H]7alpha-hydroxy-4-cholesten-3-one, [G-(3)H]5beta-cholestane-3alpha,7alpha,25-triol, and [G-(3)H]5beta-cholestane-3alpha,7alpha,26-triol, were administered to the CTX and control subjects and the specific activity curves of [G-(3)H]cholic acid and [G-(3)H]chenodeoxycholic acid were constructed and compared. In the control subjects, the two bile acids decayed exponentially, but in the CTX patient maximum specific activities were abnormally delayed, indicating the hindered transformation of precursor into bile acid. These results show that chenodeoxycholic acid synthesis is small in CTX and that the conversion of 7alpha-hydroxy-4-cholesten-3-one, 5beta-cholestane-3alpha,7alpha,25-triol, and 5beta-cholestane-3alpha,7alpha,26-triol to both chenodeoxycholic acid and cholic acid were similarly impaired.

Adult↗
PubMed1977

Determination of morphine by electron capture gas-liquid chromatography.

We describe a micromethod for determining as little as 0.1 microgram of morphine per liter of human urine. The procedure is about 20-fold more sensitive than are currently used gas-liquid chromatographic methods. It is particularly suitable for use as a confirmatory method for large-scale radioimmunoassay screening tests. The procedure involves extraction of morphine from urine and analysis of its heptafluorobutyryl derivative by gas-liquid chromatography with electron capture detection. Morphine can be determined by this procedure over a range of 0.1-200 microgram/liter of urine, 2 pg of the pure derivative being the lowest amount detectable. Urine samples from patients receiving methadone were analyzed by thin-layer chromatography, radioimmunoassay, and our procedure. The results by our procedure agreed well with those obtained by radioimmunoassay.

Chromatography, Gas↗
PubMed1976

Studies on the 12alpha and 26-hydroxylation of bile alcohols by rabbit liver microsomes.

12Alpha--Hydroxylation of two C27-steroids by rabbit liver microsomes was studied. Optimal assay conditions were determined with 7alpha-hydroxy-4-cholesten-3-one and 5beta-cholestand-3alpha, 7alpha-diol as substrates. The rate of 12alpha-hydroxylation of 7alpha-hydroxy-4-cholesten-3-one was found to be greater than that of 5beta-cholestane-3alpha, 7alpha-diol by ca. 60%. Microsomal 26-hydroxylation of 5beta-cholestane-3alpha7alpha-diol was also measured, and the ratio of 26-hydroxylation to 12alpha-hydroxylation of 5beta-cholestane-3alpha, 7alpha-diol was found to be ca. 0.4. Rabbit liver 12-alphahydroxylase was more active than that of three other species (man, rat, monkey), explaining in part the predominance of cholic acid in rabbit bile.

Alcohols↗