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Biomedical subjects

J A Ortiz

Publications and source records attributed to J A Ortiz.

At least 19 recordsLinked to original sources
PubMed1995

Molecular cloning and tissue expression of human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase.

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase is a constituent of the HMG-CoA pathway responsible for ketone body synthesis and one of its main regulatory points. We report the isolation and characterization of a 2058-bp cDNA from human liver. This cDNA encodes a polypeptide of 508 residues and 56,635 Da. The homology with previously reported rat mitochondrial and human cytosolic HMG-CoA synthases is 88 and 66%, respectively. mRNA levels were high in liver and colon, low in testis, heart, skeletal muscle, and kidney, and faint in pancreas.

Amino Acid Sequence↗
PubMed1995

Evidence that 5'-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels.

We examined the effects of orally administered 5'-cytidinediphosphocholine (CDP-choline) on arterial plasma choline and cytidine levels and on brain phospholipid composition in rats. Animals receiving a single oral dose of 100, 250, or 500 mg/kg showed peak plasma choline levels 6-8 h after drug administration (from 12 +/- 1 to 17 +/- 2, 19 +/- 2, and 24 +/- 2 microM, respectively). The area under the plasma choline curve at > 14 microM, i.e., at a concentration that induces a net influx of choline into the brain, was significantly correlated with CDP-choline dose. In rats receiving 500 mg/kg this area was 2.3 times that of animals consuming 250 mg/kg, which in turn was 1.8 times that of rats receiving 100 mg/kg. Plasma cytidine concentrations increased 5.4, 6.5, and 15.1 times baseline levels, respectively, 8 h after each of the three doses. When the oral CDP-choline treatment was prolonged for 42 and 90 days, brain phosphatidylcholine concentrations increased significantly (by 22-25%; p < 0.05) in rats consuming 500 mg/kg/day. Brain phosphatidylethanolamine and phosphatidylserine concentrations also increased significantly under some experimental conditions; levels of other phospholipids were unchanged.

Animals↗
PubMed1995

[Mucinous adenocarcinoma of the anal region. Study of 4 cases].

OBJECTIVE: We report 4 cases of a special anal tumor featuring a long history of inflammatory signs and fistulas in that area. DESIGN: A retrospective study from the histologic diagnosis back to the first symptom and up to the last follow-up or death. PATIENTS: We studied all patients with a histologic diagnosis of mucinous adenocarcinoma of the anus admitted to our hospital. RESULTS: All of them showed a long history of anal inflammatory signs and/or fistula before diagnosis. In all cases, the tumors were mucinous adenocarcinomas with minimal cytologic atypia. Of the 4 patients, one is dead, and we have lost the follow-up of another one 13 months after surgery when he had no evidence of recurrence. CONCLUSIONS: In every patient with a long-standing anal fistula or a recurrent anal abscess, a biopsy is mandatory to rule out an underlying low grade mucinous carcinoma and if it shows a low grade mucinous adenocarcinoma, the treatment of choice will be local resection if it is available. If not, an abdominal perineal resection showed be done without hesitation.

Adenocarcinoma, Mucinous↗
PubMed1995

Efficacy and safety of ebrotidine compared with ranitidine in patients with duodenal ulcer.

OBJECTIVE: To compare the efficacy and safety of ebrotidine and ranitidine administered once daily in equimolar doses of 800 and 300 mg, respectively. PATIENTS: A total of 298 duodenal ulcer patients were studied. DESIGN: A multicentre, parallel, randomized clinical trial. METHODS: Of the 298 patients studied, 150 were randomly assigned to ebrotidine and 148 to ranitidine treatment. Digestive endoscopy was performed at enrolment and at weeks 4, 6 and 8 unless the ulcer had healed before. Endoscopic findings were the main parameter for the assessment of treatment efficacy. Plasma gastrin and pancreatic polypeptide concentrations were also measured before and after termination of the therapy. RESULTS: Ebrotidine achieved a duodenal ulcer healing rate comparable to that of ranitidine, and no statistically significant difference was found between the two drugs. The drugs were equally effective in improving ulcerous dyspeptic symptoms and in relieving gastric pain. Both tobacco and ethanol consumption influenced ulcer healing adversely, but healing in smokers was more pronounced in patients treated with ebrotidine, possibly because of its cytoprotective activity. CONCLUSIONS: Ebrotidine 800 mg is as effective and safe as ranitidine 300 mg in healing duodenal ulcer, but ebrotidine appears to be superior in promoting the healing of duodenal ulceration in smokers.

Adult↗
PubMed1994

Transfection of the ketogenic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase cDNA into Mev-1 cells corrects their auxotrophy for mevalonate.

A somatic cell mutant of the Chinese hamster ovary (CHO)-K1 (called Mev-1), auxotrophic for mevalonate by virtue of a complete lack of detectable cytosolic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase activity, was transfected with a plasmid containing the cDNA for ketogenic mitochondrial HMG-CoA synthase under the control of SV40 early promoter. The resulting stable cell line (Mev-SM) was able to grow in the absence of mevalonate. Analysis of Western blot showed that the new cell line strongly expressed mitochondrial HMG-CoA synthase protein. Immunocytochemical studies using specific antibodies against mitochondrial HMG-CoA synthase showed that the protein was located exclusively inside the mitochondria. The prototroph cell line Mev-SM can incorporate labeled acetate into cholesterol in the absence of mevalonate. These results show that the new cell line may circumvent the lack of cytosolic HMG-CoA synthase activity by producing cholesterol-convertible HMG-CoA inside the mitochondria.

Amino Acid Sequence↗
PubMed1994

Toxicity identification evaluations for the investigation of fish kills: a case study.

A large fish-kill was observed in the river Tajo during the Spring-Summer of 1991. The mortality was first detected between Aranjuez and Toledo, affecting several fish species. Then it was slowly going downstream, affecting only carp (Cyprinus carpio), reaching the Spanish-Portuguese border several months later. Short-term toxicity tests on Daphnia magna and in vitro cytotoxicity tests on RTG-2 cells were used as toxicity monitoring systems in water samples and different water fractions. The fish kill was associated to the outbreak of infectious diseases, spring viremia of carp and saprolegniosis, related to an increase in the fish's susceptibility due to the presence of a toxic chemical. Bioassay-directed sample fractionations allowed to detect a toxic chemical. HPLC-MS identified the compound as dehydroabietic acid, a resin acid previously described immunotoxic.

Abietanes↗
PubMed1994

Effects of dotarizine on peripheral and pulmonary circulation and cardiac dynamics in dogs.

The cardiovascular effects of dotarizine in 10-min intravenous infusions were studied in thiopental-anesthetized dogs. The effects of dotarizine 0.024 mg/kg/min almost paralleled those of saline controls; 0.079 mg/kg/min dotarizine significantly raised the stroke index and ejection fraction, and, at a rate of 0.25 mg/kg/min, further effects appeared and were dose-dependent. Dotarizine produced arterial dilation in both systemic and pulmonary circulation: the total peripheral resistance dropped, and femoral artery flow rose; aortic and pulmonary artery mean and diastolic pressures declined, and systolic pressures remained almost stable. A trend of bradycardia and pulmonary artery pressure reduction persisted for 30 min. As compared with the reduced total peripheral resistance, aortic pressure fell only moderately because of rising cardiac output due to a higher ejection fraction and stroke volume. Cardiac preload tended to decline; contractility tended to increase. Cardiac performance remained stable while myocardial oxygen consumption tended to fall, as did the pressure-rate product and the tension time index. Dotarizine exerted direct cardiovascular effects similar to those of the 5-HT2-receptor antagonist ketanserin and, more generally, to calcium channel blockers rather than to alpha-adrenoceptor blockers.

Animals↗
PubMed1993

Oral cytidine 5'-diphosphate choline administration to rats increases brain phospholipid levels.

Exogenous cytidine 5'diphosphocholine (CDP-choline) is completely metabolized to circulating cytidine and choline. Both compounds enter the brain and can be used in phosphatidylcholine (PC) synthesis via the Kennedy (CDP-choline) cycle. We administered oral CDP-choline to 12 month-old rats (500 mg/kg/day) for 21, 42, or 90 days to determine whether this treatment would alter brain levels of PC and the other structural phospholipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE). After 42 days, brain PC levels increased significantly (p < 0.01) by 23.3%; after 90 days PC increased by 30% (p < 0.01), PS by 37.2% (p < 0.01), and PE by 13% (not significant). The ratios of each of the phospholipids to total membrane phospholipids were unchanged. These data demonstrate that repeated oral CDP-choline administration can increase the amounts of phospholipids in brain membranes, thus providing a rationale for using this compound in brain diseases that damage neurons.

Administration, Oral↗
PubMed1992

Relationship between fetal weight and litter size in rats: application to reproductive toxicology studies.

The inverse relationship between mammalian fetal weight and litter size has been discussed by many authors, but their opinions reveal no agreement at all. As in toxicity studies of reproduction, both parameters must be correctly evaluated. We investigated the existence of such a relationship in 2466 fetuses from 203 litters of Sprague-Dawley CD control rats. The frequency distribution of fetal weights had a normal adjustment. From the mean weight of fetuses in each litter, the mean fetal weights in each litter size and correlation coefficient were calculated and the regression line was plotted; the correlation coefficient (r = 0.677) was highly significant (P = 0.002), which made evident that there was an inverse relationship between fetal weight and litter size. If fetal weight/litter size inverse relationship is not taken into account when toxicity on the fetal weight is analyzed, wrong conclusions may be reached if the test substance reduces the litter size, provoking embryofoetal mortality. The iatrogenic decrement in fetal weight can be masked by an increment due to the litter size reduction. We suggest that in all three segments of reproductive toxicity studies, litter size must be considered as a covariate to the effect of the test substance on the fetal weight, in order to perform a correct analysis of covariance (ANCOVA), in addition to the dose factor commonly used in common ANOVA.

Animals↗
PubMed1992

Synthesis and antimycotic activity of (benzo[b]thienyl)methyl ethers of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanol and of (Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone oxime.

A new series of (benzo[b]thienyl)methyl ethers of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol and of (Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone oxime were synthesis and tested for antifungal activity. Series design, synthesis, preliminary antimycotic data and structure-activity relationships are reported. 7-Chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1- yl)ethoxymethyl]benzo[b] (8i, Sertaconazole, FI-7045, CAS 99592-32-2) and its nitrate were selected for further research.

Antifungal Agents↗
PubMed1992

Physico-chemical properties, analytical determinations and stability of sertaconazole nitrate.

Sertaconazole nitrate, the nitrate salt of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy-methyl] benzo[b]thiophene (sertaconazole, FI-7045, CAS 99592-32-2), is a new azole antifungal, which has proved to have a wide spectrum and high activity. This paper describes its physico-chemical properties, structural identification including polymorphism, detection of impurities, determination of related compounds, separation, quantification and purity assays using high-performance liquid chromatography (HPLC) and quantitative assays specially elemental and functional analysis. Stability of sertaconazole nitrate in solid form under accelerated (light, humidity and temperature) and real time conditions and in suspension form at different pH values (acid and basic) was also studied. The results show that sertaconazole nitrate is extremely stable under all the conditions tested, both in solid and in suspension form. Sertaconazole nitrate in solid form packaged in tight sealed amber glass bottles was stable for over 5 years under normal storage conditions.

Antifungal Agents↗
PubMed1992

In vitro activity of sertaconazole.

The activity of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl) ethoxy-methyl]benzo[b]thiophene (sertaconazole, FI 7045, CAS 99592-32-2), a new topical antifungal, was studied in vitro against several infecting organisms. The results obtained show that sertaconazole is a broad-spectrum antifungal against yeasts (C. albicans, C. tropicalis, C. pseudotropicalis, C. krusei, Trichosporon and Cryptococcus), dermatophytes (Microsporum, Trichophyton and Epidermophyton), opportunistic filamentous fungi (Aspergillus) and Gram-positive bacteria. The MIC (minimum inhibitory concentration) values for the fungistatic activity were between 0.35 and 5.04 micrograms/ml for yeasts and between 0.24 and 2 micrograms/ml for dermatophytes; even partial activities (IC25) against these organisms were obtained at concentrations 10 times lower than those mentioned. At concentrations superior to MIC (MFC between 0.5 and 16 micrograms/ml), sertaconazole exhibited fungicidal activity.

Antifungal Agents↗
PubMed1992

In vitro comparative study of the fungistatic and fungicidal activity of sertaconazole and other antifungals against Candida albicans.

The fungistatic and fungicidal activity of 7-chloro-3-[1-(2, 4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy-methyl]benzo[b]thiophene (sertaconazole, FI-7045, CAS 99592-32-2) against Candida albicans was determined and compared with that obtained for other antifungals. The fungistatic activity of sertaconazole, evaluated through the MIC obtained in Sabouraud and YNB media, gave results comparable to those obtained with miconazole and clotrimazole, and superior to those presented by bifonazole and ketoconazole. The fungicidal activity, evaluated by means of the 90% reduction in viable cells, took place at a concentration of 8 micrograms/ml for sertaconazole and at higher concentrations for the other drugs studied.

Antifungal Agents↗
PubMed1992

In vivo activity of sertaconazole in experimental dermatophytosis in guinea pigs.

The comparative curative effect of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H- imidazol-1-yl)ethoxy-methyl]benzo [b]thiophene (sertaconazole, FI-7045, CAS 99592-32-2) (SZ) and miconazole (MZ) 2% creams in a model of dermatomycosis caused by Trichophyton mentagrophytes in guinea pigs was studied. Two treatments of different duration (12 and 3 days) were applied, and their efficacy versus infected and untreated animals (control group) was evaluated according to clinical parameters (degree of alopecia and lesion) and microbiological healing (recovery of T. mentagrophytes from hair pulled from the infected site). The therapeutic effect resulting from the application of the creams for 12 days was excellent and similar for both test creams; however, the application of SZ cream for 3 days had greater therapeutic effect than MZ cream according to the improvement of clinical symptoms and microbiological healing.

Alopecia↗
PubMed1992

Inhibition of ergosterol synthesis by sertaconazole in Candida albicans.

7-Chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl) ethoxy-methyl] benzo [b] thiophene (sertaconazole, FI-7045, CAS 99592-32-2), a new topical antifungal agent, has shown activity against a broad range of clinically relevant yeasts and fungi. In the present study, the molecular basis of the pharmacological action of sertaconazole was examined by investigating the inhibition of ergosterol synthesis in cultures of Candida albicans, ATCC E-10.231, at 6 x 10(5) cells/ml grown aerobically at 37 degrees C, using various concentrations of sertaconazole. Sertaconazole inhibited the ergosterol synthesis with IC50 = 115 nmol/l. The results show that one of the mechanisms of action of sertaconazole consists in the inhibition of ergosterol synthesis.

Antifungal Agents↗
PubMed1992

Direct membrane-damaging effect of sertaconazole on Candida albicans as a mechanism of its fungicidal activity.

The direct action of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy- methyl]benzo[b]thiophene (sertaconazole, FI-7045, CAS 99592-32-2) on the membrane integrity of C. albicans is studied by quantifying the leakage of intracellular adenosine triphosphate (ATP) into the medium as an index of the changes in membrane permeability and integrity and cell viability of the culture used. Sertaconazole caused a dose-dependent decrease in intracellular ATP after only 10-min exposure and a concomitant significant increase in extracellular ATP. This behaviour is characteristic of antifungals which are fungicidal as a result of a direct membrane damage. Thus sertaconazole, in addition to the mechanism of action responsible for its fungistatic activity (inhibition of ergosterol synthesis), has a second mechanism of action providing a significant fungicidal activity due to direct cell membrane damage.

Adenosine Triphosphate↗
PubMed1992

Acute toxicity studies of sertaconazole.

The acute toxicity of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethoxy- methyl]benzo[b]thiophene (sertaconazole, FI-7045, CAS 99592-32-2) was evaluated in mice and rats after single administration by oral, subcutaneous and intraperitoneal routes. The latter intended to ensure maximum blood levels, since intravenous route was unfeasible due to drug insolubility in water. LD50 was indeterminable (greater than 8000 mg/kg) in all routes of dosing. According to these results, and having furthermore proved the absorption of the test substance after oral administration, sertaconazole was concluded to be very safe in the event of overdose or accidental ingestion.

Administration, Oral↗