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Biomedical subjects

F Gonzalez

Publications and source records attributed to F Gonzalez.

At least 37 records · Page 2Linked to original sources
PubMed2000

Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing.

Women with polycystic ovary syndrome (PCOS) have chronic anovulation and hyperandrogenism and frequently have abnormalities in their lipid profiles and insulin/insulin-like growth factor axis that increase their lifetime risk for cardiovascular disease. Normal ovulatory women may have polycystic ovaries on ultrasonography and yet lack the clinical features of PCOS. To further explore whether ovulatory women without clinical/biochemical hyperandrogenism but with polycystic appearing ovaries (ov-PAO) have subclinical features of PCOS, we prospectively characterized 26 ov-PAO women and matched them by age and body mass index to 25 ovulatory women with normal appearing ovaries (ov-NAO) and to 22 women with PCOS. After an overnight fast, all women had baseline endocrine and metabolic assessments. In addition, a subset of each group of women underwent GnRH-agonist (leuprolide acetate 1 mg s.c.) testing, ACTH stimulation, and an insulin tolerance test (ITT). At baseline, ov-PAO and ov-NAO women had similar endocrine profiles (LH, LH:FSH, androstenedione, and DHEAS). Compared with ov-NAO, 31% of ov-PAO women had reduced glucose responses after insulin (K(itt)), suggesting mild insulin resistance, and 35% had high density lipoprotein levels below 35 mg/dL, a level considered to represent significant cardiovascular risk. After GnRH-agonist, ov-PAO women had response patterns in LH, total testosterone, and 17-hydroxyprogesterone (17-OHP) that were intermediate between ov-NAO and women with PCOS. Ovarian responses were above the normal range in 30-40% of women with ov-PAO. In ov-PAO, peak responses of LH after leuprolide correlated with triglyceride levels (P < 0.05) and peak responses of 17-OHP correlated inversely with Kitt values (P < 0.05). No significant differences were noted with ACTH testing. In conclusion, occult biochemical ovarian hyperandrogenism may be uncovered using GnRH-agonist in ovulatory women with ov-PAO, while adrenal responses remain normal. Subtle metabolic abnormalities may also be prevalent.

Adrenocorticotropic Hormone↗
PubMed1999

Expression of CYP2A genes in human liver and extrahepatic tissues.

Members of the human cytochrome P450 2A (CYP2A) subfamily are known to metabolize several promutagens, procarcinogens, and pharmaceuticals. In this study, the expression of the three genes found in the human CYP2A gene cluster was investigated in the liver and several extrahepatic tissues by gene-specific reverse transcriptase-polymerase chain reaction (RT-PCR). All three transcripts (CYP2A6, CYP2A7, and CYP2A13) were found to be present in liver. Quantitative RT-PCR analysis showed that CYP2A6 and CYP2A7 mRNAs were present at roughly equal levels in the liver, while CYP2A13 was expressed at very low levels. Two putative splicing variants of CYP2A7 were found in the liver. Nasal mucosa contained a low level of CYP2A6 and a relatively high level of CYP2A13 transcripts. Kidney, duodenum, lung, alveolar macrophages, peripheral lymphocytes, placenta, and uterine endometrium were negative for all transcripts. This survey gives a comprehensive picture of the expression pattern of CYP2A genes in liver and extrahepatic tissues and constitutes a basis for a search for functional CYP2A forms and their roles in chemical toxicity in liver and nasal mucosa.

Aryl Hydrocarbon Hydroxylases↗
PubMed1999

Crystal structure of human bleomycin hydrolase, a self-compartmentalizing cysteine protease.

BACKGROUND: Bleomycin hydrolase (BH) is a cysteine protease that is found in all tissues in mammals as well as in many other eukaryotes and prokaryotes. Although its conserved cellular function is as yet unknown, human bleomycin hydrolase (hBH) has clinical significance in that it is thought to be the major cause of tumor cell resistance to bleomycin chemotherapy. In addition, it has been reported that an allelic variant of hBH is genetically linked to Alzheimer's disease. RESULTS: We have determined the crystal structures of wild-type hBH and of a mutant form of the enzyme. The overall structure is very similar to that of the previously determined yeast homolog, however, there is a striking difference in the charge distribution. The central channel, which has a strong positive electrostatic potential in the yeast protein, is slightly negative in hBH. We have determined that hBH does not have the DNA-binding activity of the yeast protein and that the enzyme is localized to the cytoplasm. CONCLUSIONS: The difference in charge distribution between the yeast and human BH enzymes is most likely responsible for the difference in DNA-binding activity. Nevertheless, the C-terminal autoprocessing activity and the role of the C terminus as a determinant for peptidase activity are conserved between the yeast and human forms. The structure of hBH suggests that the putative Alzheimer's disease linked variation does not directly alter the intrinsic peptidase activity. Rather, the position of the mutation suggests that it could affect interactions with another protein, which may modulate peptidase activity through repositioning of the C terminus.

Alzheimer Disease↗
PubMed1999

Depentylation of [3H-pentyl]methyl-n-amylnitrosamine by rat esophageal and liver microsomes and by rat and human cytochrome P450 isoforms.

Methyl-n-amylnitrosamine (MNAN) induces esophageal cancer in rats, probably involving activation by cytochromes P450. We studied the metabolic depentylation of MNAN. [3H-4,5-pentyl]MNAN and [3H-2,3-pentyl]-MNAN were synthesized, purified, and incubated with rat esophageal microsomes (REM) or rat liver microsomes (RLM) to give [3H]pentaldehyde (depentylation), an indicator of MNAN activation. [3H]Pentaldehyde was determined by high-performance liquid chromatography of its 2,4-dinitrophenylhydrazone. Adding 5 mM semicarbazide to incubations increased the observed depentylation (except that due to CYP2E1) by >60%. MNAN depentylation by REM and uninduced and induced RLM showed Km values of 64, 610, and 170-330 microM, respectively (Vmax: 20, 220, and 160-1270 pmol/mg protein/min, respectively). The depentylation of 100 microM MNAN by REM was inhibited 98% by CO and 65% by coumarin preincubated for 15 min with REM (Ki, 120 microM) but was unaffected by antibodies inhibitory to various P450s. MNAN inhibited coumarin 7-hydroxylation by RLM and CYP2A6 (Ki, 3000 and 320 microM, respectively). REM showed slight coumarin 7-hydroxylase activity. MNAN depentylation by RLM was 41% inhibited by an antibody to CYP2C11. Km for rat CYP2E1, human CYP2E1, and human CYP2A6 was 210, 115, and 17 microM, respectively (Vmax: 900, 570, and 120 pmol/nmol P450/min, respectively). We conclude that MNAN activation by REM is probably due to a P450 related to CYP2A3, a rodent nasal P450.

Animals↗
PubMed1999

Adrenal dynamic responses to physiologic and pharmacologic adrenocorticotropic hormone stimulation before and after ovarian steroid modulation in women with polycystic ovary syndrome.

OBJECTIVE: To test the hypothesis that in women with polycystic ovary syndrome (PCOS), adrenal cytochrome P450c 17alpha activity is different after physiologic vs. pharmacologic ACTH stimulation and that ovarian activity promotes adrenal hyperactivity that is different after physiologic vs. pharmacologic ACTH stimulation. DESIGN: Prospective controlled pilot study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENT(S): Six women with PCOS who had adrenal hyperandrogenism were compared with four women with normal ovulation. INTERVENTION(S): Adrenal dynamic blood sampling was performed before and after 6 months of GnRH agonist administration. MAIN OUTCOME MEASURE(S): Comparison of physiologic and pharmacologic ACTH-stimulated levels of progesterone, 17-hydroxyprogesterone, and androgens before and after ovarian steroid modulation. RESULT(S): In women with PCOS, exaggerated responses of androstenedione and 11beta-hydroxyandrostenedione as well as elevated ratios of 17-hydroxyprogesterone to progesterone and of androstenedione to 17-hydroxyprogesterone after physiologic ACTH stimulation did not persist after GnRH-agonist administration. Three of the six women with PCOS had an increased response of androstenedione and a ratio of androstenedione to 17-hydroxyprogesterone that were >2 SD above the mean of those in the women with normal ovulation after pharmacologic ACTH stimulation; this finding persisted after GnRH-agonist administration. CONCLUSION(S): In women with PCOS, increases in adrenal androgen sensitivity after physiologic ACTH stimulation reflected in both arms of cytochrome P450c 17alpha activity may be influenced by ovarian activity. However, 17,20-lyase hyperactivity in a subset after pharmacologic ACTH stimulation may be an intrinsic adrenal disorder.

Adrenocorticotropic Hormone↗
PubMed1999

Evidence that insulin and androgens may participate in the regulation of serum leptin levels in women.

OBJECTIVE: Although serum leptin is principally influenced by body mass, to understand the role of insulin and androgens in the regulation of serum leptin in normal weight women. DESIGN: Prospective observational study. SETTING: Academic practice in reproductive endocrinology. PATIENT(S): Twenty-one women with polycystic ovary syndrome (PCOS) of normal body weight, 8 apparently normal women with polycystic-appearing ovaries (PAO), and 21 normal women. INTERVENTION(S): Fasting blood levels of luteinizing hormone, follicle-stimulating hormone, testosterone (T), unbound T, dehydroepiandrosterone sulfate (DHEAS), insulin, insulin growth factor-binding protein-1 (IGFBP-1), and leptin. MAIN OUTCOME MEASURE(S): Comparisons of measured hormones in the different groups and correlative analysis RESULT(S): Women with PCOS had higher levels of serum luteinizing hormone, T, unbound T, DHEAS and insulin, and lower levels of IGFBP-1 compared with the normal controls, but they had similar leptin levels. Normal women with PAO had increased levels of insulin and leptin compared with controls, whereas IGFBP-1 was lower in PAO. In normal weight women with PCOS and PAO, leptin correlated positively with body weight and insulin, and negatively with IGFBP-1 and DHEAS. CONCLUSION(S): In normal weight patients serum leptin levels may be regulated in part by insulin. Androgens, on the other hand, may play a role in suppressing serum leptin.

Adult↗
PubMed1999

Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome.

Since an increase in tumor necrosis factor alpha (TNFalpha) expression has been associated with insulin resistance, this study was undertaken to determine the status of circulating TNFalpha and the relationship of TNFalpha with insulin levels, body weight, or both in women with polycystic ovary syndrome (PCOS). Fasting serum samples were analyzed in 34 subjects with PCOS, of whom 22 were obese (body mass index [BMI]>27 kg/m2), and in 40 normal control women, of whom 20 were obese. Women with PCOS exhibited a significantly (P<.02) higher mean serum TNFalpha concentration compared with the controls. The serum TNFalpha level and BMI were directly correlated in women with PCOS (r=.48, P<.005) and highly correlated in controls (r=.78, P<.001). When subjects were classified by body weight, the mean serum TNFalpha concentration was significantly (P<.001) elevated in normal-weight women with PCOS compared with normal-weight controls. On the other hand, mean serum TNFalpha concentrations in obese women with PCOS and obese controls were similar and significantly (P<.02) higher than in normal-weight women with PCOS. A direct correlation between serum fasting insulin and TNFalpha was evident in controls (r=.35, P<.03), but not in women with PCOS. However, in the subgroup of obese women with PCOS, fasting insulin directly correlated (r=.49, P<.03) with TNFalpha and the median fasting serum insulin concentration was significantly (P<.05) higher compared with the level in normal-weight women with PCOS and all controls. Fasting insulin and TNFalpha were no longer correlated in controls as a group and in obese women with PCOS when controlling for body weight. Serum TNFalpha did not correlate with luteinizing hormone (LH), testosterone (T), or dehydroepiandrosterone sulfate (DHEAS) in women with PCOS. However, serum insulin was significantly correlated (r=.49, P<.0004) with T and the BMI exhibited a trend for correlation with serum T (r=.33, P=.05) in women with PCOS. Finally, the mean serum LH concentration was significantly (P<.02) higher in normal-weight women with PCOS versus obese women with PCOS, and serum LH levels exhibited a trend for an inverse correlation with the BMI (r=.31, P=.09) in women with PCOS. We conclude that (1) serum TNFalpha is increased in normal-weight women with PCOS and is even higher in obese individuals regardless of whether they have PCOS; (2) factors other than obesity are the cause of elevated serum TNFalpha in normal-weight women with PCOS; and (3) whereas increased circulating TNFalpha may mediate insulin resistance in obesity, which may in turn promote hyperandrogenism in obese women with PCOS, it remains to be demonstrated whether this is also the case in normal-weight women with PCOS.

Adult↗
PubMed1999

Role of cytochrome P450 2E1 in the metabolism of acrylamide and acrylonitrile in mice.

Acrylonitrile (AN) and acrylamide (AM) are commonly used in the synthesis of plastics and polymers. In rodents, AM and AN are metabolized to the epoxides glycidamide and cyanoethylene oxide, respectively. The aim of this study was to determine the role of cytochrome P450 in the metabolism of AM and AN in vivo. Wild-type (WT) mice, WT mice pretreated with aminobenzotriazole (ABT, 50 mg/kg ip, 2 h pre-exposure), and mice devoid of cytochrome P450 2E1 (P450 2E1-null) were treated with 50 mg/kg [(13)C]AM po. WT mice and P450 2E1-null mice were treated with 2.5 or 10 mg/kg [(13)C]AN po. Urine was collected for 24 h, and metabolites were characterized using (13)C NMR. WT mice excreted metabolites derived from the epoxides and from direct GSH conjugation with AM or AN. Only metabolites derived from direct GSH conjugation with AM or AN were observed in the urine from ABT-pretreated WT mice and P450 2E1-null mice. On the basis of evaluation of urinary metabolites at these doses, these data suggest that P450 2E1 is possibly the only cytochrome P450 enzyme involved in the metabolism of AM and AN in mice, that inhibiting total P450 activity does not result in new pathways of non-P450 metabolism of AM, and that mice devoid of P450 2E1 do not excrete metabolites of AM or AN that would be produced by oxidation by other cytochrome P450s. P450 2E1-null mice may be an appropriate model for the investigation of the role of oxidative metabolism in the toxicity or carcinogenicity of these compounds.

Acrylamide↗
PubMed1999

Pharmacokinetics and bioequivalence of two suxibuzone oral dosage forms in horses.

A disposition and bioequivalence study with a suxibuzone granulated and a suxibuzone paste oral formulation was performed in horses. Suxibuzone (SBZ) is a nonsteroidal anti-inflammatory drug, which was administered to horses (n = 6) at a dosage of 19 mg/kg bwt by the oral route (p.o.) in a two period cross-over design. Suxibuzone is very rapidly transformed into its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ). Therefore plasma and synovial fluid concentrations of SBZ, PBZ and OPBZ were simultaneously measured by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Suxibuzone could not be detected in any plasma and synovial fluid samples (< 0.04 microgram/mL). Plasma PBZ and OPBZ concentrations were detected between 30 min and 72 h after granulate and paste administration. Mean plasma concentration of PBZ peaked at 5 h (34.5 +/- 6.7 micrograms/mL) and at 7 h (38.8 +/- 8.4 micrograms/mL), and mean area under the concentration-time curve (AUC0-->LOQ) was 608.0 +/- 162.2 micrograms.h/mL and 656.6 +/- 149.7 micrograms.h/mL after granulate and paste administration, respectively. Mean plasma concentration of OPBZ increased to 5-6.7 micrograms/mL, with the maximum concentration (Cmax) appearing between 9 and 12 h after administration of both formulations. The AUCs0-->LOQ for OPBZ were also similar (141.8 +/- 48.3 micrograms.h/mL granulate vs. 171.4 +/- 45.0 micrograms.h/mL paste). It was concluded that the suxibuzone products were bioequivalent with respect to PBZ. For OPBZ, the 95% confidence intervals of the pharmacokinetic parameters were within the acceptable range of 80-125%. The paste formulation provided greater bioavailability of PBZ and OPBZ.

Administration, Oral↗
PubMed1999

Long-term (4 year) efficacy and tolerability of doxazosin for the treatment of concurrent benign prostatic hyperplasia and hypertension.

BACKGROUND: The alpha1-adrenoceptor antagonist doxazosin has proved successful in treating patients with concurrent benign prostatic hyperplasia (BPH) and hypertension in short-term studies. However, both conditions are chronic and may worsen over time. The aim of this study was, therefore, to examine the tolerability and efficacy of doxazosin in the long-term treatment of concurrent BPH and hypertension. METHODS: This study was a longitudinal extension of earlier double-blind trials. Patients were enrolled into the study on a rolling basis. From a total of 178 BPH patients with hypertension enrolled into the study, 28 had reached 48 months of open-label treatment with doxazosin at the time of the final data cutoff. RESULTS: Treatment with doxazosin resulted in sustained benefits for BPH patients over the whole study period, with significant improvements in the severity (12.2%, P < 0.001) and bothersomeness (13.2%, P < 0.001) of BPH symptoms, and in the maximum urinary flow rate (26.6%, P < 0.05) from baseline to the end of the 4-year period. There was also a significant and sustained reduction in diastolic blood pressure. The efficacy of doxazosin treatment for both BPH and hypertension was maintained over the 4-year period, despite the tendency of these conditions to worsen with time. Comparison of adverse events in patients with long- and short-term hypertension and BPH demonstrates that the safety of doxazosin is not altered during long-term therapy. CONCLUSIONS: This study demonstrates that doxazosin appears to be well tolerated and efficacious in the long-term management of concurrent BPH and hypertension.

Adrenergic alpha-Antagonists↗
PubMed1999

Interocular temporal delay sensitivity in the visual cortex of the awake monkey.

Due to the separation of the eyes, temporal retinal disparities are created during binocular stimulation and they have been proposed to be the basis of several stereo-visual effects. This paper studies the sensitivity of cortical neurons from area V1 to interocular temporal delay in the awake monkey (Macaca mulatta). Forty-four cells were included in this study. Temporal delay sensitivity was observed in 59% of them. About half of these temporal-delay-sensitive cells were also sensitive to the stimulation sequence of the eyes. The cells that preferred one eye to be stimulated first were termed asymmetrical (46%); those which were not sensitive to the eye sequence of stimulation were termed symmetrical (54%). No clear differences were observed in the distribution of delay-sensitive cells according to their eye dominance. Fifty-six percent of balanced cells and 65% of unbalanced cells were sensitive to interocular delay. These data underline the importance of temporal cues for depth perception.

Animals↗
PubMed1999

The contributions of oestrogen and growth factors to increased adrenal androgen secretion in polycystic ovary syndrome.

Adrenal hyperandrogenism is prevalent in many women with polycystic ovary syndrome (PCOS), although the expression of this enhanced secretion may be heterogeneous. Since no single factor acts in isolation, this study was performed to assess the influence of oestradiol (total and unbound), insulin, insulin-like growth factor (IGF)-I, IGF-II and the binding proteins IGFBP-I, and IGFBP-3, on basal and adrenocorticotrophic hormone (ACTH) stimulated adrenal androgen secretion in 25 women with PCOS and 10 matched ovulatory controls. Women with PCOS exhibited elevations of all androgens as well as unbound oestradiol, insulin and non-IGFBP-1 bound IGF-I. Positive correlations were noted between oestrogen and basal and ACTH stimulated delta 5 adrenal androgens. Serum IGF-I was only correlated with basal dehydroepiandrosterone sulphate (DHEA-S), while insulin exhibited a strong correlation with the delta 4 pathway and androstenedione formation in particular. This correlation was also confirmed by dividing the PCOS group into those women with and without hyperinsulinaemia. The activity of 17,20 lyase favouring androstenedione was increased in the hyperinsulinaemic women. By multivariate analyses, body mass index did not influence these findings. Although there are inherent difficulties in making major conclusions based on correlative analyses, it is suggested that oestrogen may have a greater influence on enhancing delta 5 adrenal androgen secretion, and insulin a greater effect on the delta 4 pathway. In turn, the relative importance of these influences may contribute to the heterogeneous nature of adrenal hyperandrogenism in PCOS.

Adrenal Glands↗
PubMed1999

Disposition and tolerance of suxibuzone in horses.

Suxibuzone (SBZ), a nonsteroidal anti-inflammatory drug, was administered to 6 horses at a dose rate of 7.5 mg/kg bwt by intravenous (i.v.) route. Plasma and synovial fluid concentrations of suxibuzone and its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ), were measured simultaneously by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Plasma SBZ concentrations rapidly decreased and were not detectable beyond 20 min after treatment. The parent drug was not detected in any synovial fluid samples. Average maximum plasma concentrations of PBZ (16.43 microg/ml) and OPBZ (2.37 microg/ml) were attained at 0.76 and 7.17 h, respectively. The mean residence time (MRT) of PBZ was 6.96 h in plasma. Oxyphenbutazone plasma concentrations were below those reached by phenylbutazone during the first 12 h after suxibuzone administration, even though its values were detectable for at least 24 h (MRT = 10.65 h). Plasma concentrations of PBZ and OPBZ exceeding EC50 and IC50 of TXB2 and PGE2 were reached by at least 12 h. Synovial fluid concentrations of PBZ and OPBZ were 2.87+/-0.37 microg/ml and 0.97+/-0.08 microg/ml at 9 h after suxibuzone administration and exceeded IC50 of PGE2 for at least this time. In the present study, suxibuzone was well tolerated following i.v. injection.

Animals↗
PubMed1999

Dorzolamide effect on ocular blood flow.

PURPOSE: To evaluate the effect of dorzolamide on ocular blood flow in normal and glaucomatous eyes. METHODS: Twenty-six eyes with documented open-angle glaucoma of 26 patients and 13 normal control eyes of 8 age-matched subjects were included in this study. All eyes underwent color Doppler imaging for measuring peak-systolic velocity, end-diastolic velocity, and resistance index in the ophthalmic and central retinal arteries and the maximal and minimal velocities in the central retinal vein. Eyes were grouped in control and initial and advanced glaucoma categories. Measurements were made in all groups before and after application of topical dorzolamide. Intragroup comparisons between baseline and dorzolamide conditions were made using paired Student's t-test. Intergroup comparisons under baseline conditions between normal and glaucomatous eyes were made by using the one-way ANOVA test. Statistical significance was set at P < 0.05. RESULTS: The peak-systolic velocity of the central retinal artery in glaucomatous eyes and the end-diastolic velocity of the ophthalmic and central retinal arteries in all groups were significantly higher after application of dorzolamide. The minimal velocity of the central retinal vein showed significantly higher values after dorzolamide, whereas the maximal velocity remained unchanged. The peak-systolic velocity of the ophthalmic artery in all groups and the peak-systolic velocity of the central retinal artery in normal eyes also remained unchanged. The resistance index was significantly lower in the ophthalmic and central retinal arteries in all groups after dorzolamide. The intraocular pressure was significantly reduced in all groups after dorzolamide. Under baseline conditions normal control eyes and glaucomatous eyes showed differences in various measurements. Peak-systolic velocity was significantly lower in glaucomatous eyes than in normal control eyes with the exception of the ophthalmic artery in the initial glaucoma group. End-diastolic velocity was lower in glaucomatous eyes than in control eyes in both arteries. Maximal and minimal velocities of the central retinal vein were lower in glaucomatous eyes than in normal control eyes. Resistance index was higher in glaucomatous eyes than in normal control eyes in the ophthalmic artery but not in the central retinal artery. CONCLUSIONS: Most hemodynamic parameters of intraocular and periocular vessels improve after application of topical dorzolamide in both normal control and glaucomatous eyes. Dorzolamide should be regarded as a useful drug for treatment of glaucoma not only because it reduces intraocular pressure but also because it improves the ocular blood supply.

Aged↗
PubMed1998

Modulation of cell responses to horizontal disparities by ocular vergence in the visual cortex of the awake Macaca mulatta monkey.

Horizontal retinal disparity is the most important cue for stereopsis. However, accurate stereoscopic perception requires additional information on fixation distance. The ocular vergence angle may provide information on fixation distance and therefore may be used to calibrate horizontal disparities. We studied the responses of cells from cortical visual area V1 of one macaca mulatta monkey to dynamic random dot stereograms at different ocular vergence angles. We observed that in about half of cells sensitive to horizontal disparity the vergence angle modifies the cell responses to horizontal disparities. These results suggest that vergence angle may be used to calibrate horizontal disparities for fixation distance.

Animals↗