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Biomedical subjects

A Morales

Publications and source records attributed to A Morales.

At least 91 records · Page 5Linked to original sources
PubMed2000

Yohimbine in erectile dysfunction: the facts.

Yohimbine, a pharmacologically well-characterized alpha-2-adrenoceptor antagonist with activity in the central and peripheral nervous system, has been used for over a century in the treatment of erectile dysfunction. In-depth, systematic studies in animals have shown that the drug has a remarkable positive effect on sexual performance. Meta-analyses of the few controlled, randomized human studies have consistently shown an advantage of yohimbine over placebo. Despite such a long history and encouraging activity, the drug has not yet been subjected to scientifically rigorous human clinical trials. Although relevant basic pharmacological and animal research information has been available for over 15 y, recent studies were designed with a lack of insight and complete disregard of those fundamental studies. Currently, dose-response investigations are not available, alternative routes of administration (i.e. sublingual) have not been investigated, nor has continuous versus 'on-demand' administration been explored. Synergistic activity with other drugs was last studied nearly four decades ago. Assessment of various populations was carried out in very limited cohorts and only in most general terms. In short, properly designed trials in humans have not been done. Why? Yohimbine is an old drug. As such it does not enjoy patent protection or commercial viability. Until molecular/formulation changes can be brought about (as recently happened with two other agents: phentolamine and apomorphine), serious investigations of yohimbine will remain in limbo. It could be that the nay sayers are right and yohimbine, indeed, lacks clinical activity as a treatment for men with erectile dysfunction. As long as it remains an orphan drug, we will never know.

Adrenergic alpha-Antagonists↗
PubMed2000

Yohimbine in erectile dysfunction: the facts.

Yohimbine, a pharmacologically well-characterized alpha-2-adrenoceptor antagonist with activity in the central and peripheral nervous system, has been used for over a century in the treatment of erectile dysfunction. In-depth, systematic studies in animals have shown that the drug has a remarkable positive effect on sexual performance. Meta-analyses of the few controlled, randomized human studies have consistently shown an advantage of yohimbine over placebo. Despite such a long history and encouraging activity, the drug has not yet been subjected to scientifically rigorous human clinical trials. Although relevant basic pharmacological and animal research information has been available for over 15 y, recent studies were designed with a lack of insight and complete disregard of those fundamental studies. Currently, dose-response investigations are not available, alternative routes of administration (i.e. sublingual) have not been investigated, nor has continuous versus 'on-demand' administration been explored. Synergistic activity with other drugs was last studied nearly four decades ago. Assessment of various populations was carried out in very limited cohorts and only in most general terms. In short, properly designed trials in humans have not been done. Why? Yohimbine is an old drug. As such it does not enjoy patent protection or commercial viability. Until molecular/formulation changes can be brought about (as recently happened with two other agents: phentolamine and apomorphine), serious investigations of yohimbine will remain in limbo. It could be that the nay sayers are right and yohimbine, indeed, lacks clinical activity as a treatment for men with erectile dysfunction. As long as it remains an orphan drug, we will never know. International Journal of Impotence Research (2000) 12, Suppl 1, S70-S74

Journal Article↗
PubMed2000

[Effect of alendronate on bone mineral density and incidence of fractures in postmenopausal women with osteoporosis. A meta-analysis of published studies].

BACKGROUND: To perform a systematic review, completed with a meta-analysis, of the published evidences about the effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal women with low bone mass. METHODS: We search for all alendronate clinical trials in postmenopausal women with low bone mass which were randomized, double blind, placebo controlled, with a duration of one year or more and with bone mineral density measurement and/or fractures as outcomes. We used the weighted average of individual study results as an estimation of the global effect. RESULTS: Seven studies meet all the inclusion criteria. Relative Risks (RR) with 95% Confidence Intervals (CI 95%) for the combined effect under fixed effects model were: RR 0.54 (CI 95%: 0.45 to 0.66) for vertebral fractures, RR 0.81 (CI 95%: 0.72 to 0.92) for non vertebral fractures and RR 0.64 (CI 95%: 0.40 to 1.01) for hip fractures. CONCLUSIONS: Our results demonstrate that alendronate reduces the risk of vertebral, non vertebral and hip fractures in postmenopausal women with low bone mass. This meta-analysis allows the classification of alendronate anti-fracture evidences in the highest level.

Alendronate↗
PubMed1999

XLMR database.

The computer database on X-linked mental retardation (XLMR) disorders developed by Arena and Lubs in 1991 has now been updated to include all currently known XLMR disorders and nonspecific (MRX) families. Currently, it includes 123 syndromes, 59 nonspecific XLMR families, and 60 families from the Miami/Greenwood study. The older clinical reports have been reviewed and revised. The search mechanism has also been revised and now includes 740 individual "keywords." Each of these keywords recognizes several of clinical descriptive terms, as used in published literature reports. Searches can be made according to any clinical finding or combination of findings. For each disorder, the database presents a graphic display that contains a revised and more complete set of clinical findings, references, keywords, map localization, molecular information, access to pictures, and OMIM number.

Chromosome Mapping↗
PubMed1999

Overall cardiovascular profile of sildenafil citrate.

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1999

Patterns of diagnosis of Paget's disease in Spain.

To evaluate the incidence of diagnosis of Paget's disease of bone in Spain, a retrospective study was performed from 1991-1997 in four Spanish centers to evaluate the number of diagnosed Paget's disease cases. Information about the age, gender, and year of admission and an estimation of the reference population with the number of discharges at the centers were registered for each calendar year. The relative diagnostic risk of Paget's disease was calculated, using 1991 as the reference by Poisson's regression models. The percentage of males among the diagnosed cases varied from 39% in 1992 to 62% in 1993 without significant difference between the different years (p = 0.31). The great majority of the cases were diagnosed between 50 and 89 years of age, from 89% in 1992 and 94% in 1993. During the first years the main part of the cases corresponded to persons younger than 69 years (57.5% in 1991, 50% in 1992, and 64.7% in 1993), but from 1994 the major percentage was found in individuals over 70 years of age (68.1% in 1994, 53.8% in 1995, 62.3% in 1996, and 58.1% in 1997) (p = 0.045). Once the results were adjusted by the diagnosis center, an increased diagnostic risk of Paget's disease relative to the year of diagnosis was seen. In 1996 the risk was 54% higher than in 1991. This tendency reached statistical significance (p for trend = 0.03). The results of this study demonstrate that there is an increasing diagnostic tendency of Paget's disease along the period of study due to different analyzed variables.

Adult↗
PubMed1999

Safety Evaluation of Transgenic Tilapia with Accelerated Growth.

Recent advances in modern marine biotechnology have permitted the generation of new strains of economically important fish species through the transfer of growth hormone genes. These transgenic fish strains show improved growth performance and therefore constitute a better alternative for aquaculture programs. Recently, we have obtained a transgenic tilapia line with accelerated growth. However, before introducing this line into Cuban aquaculture, environmental and food safety assessment was required by national authorities. Experiments were performed to evaluate the behavior of transgenic tilapia in comparison to wild tilapia as a way to assess the environmental impact of introducing transgenic tilapia into Cuban aquaculture. Studies were also conducted to evaluate, according to the principle of substantial equivalence, the safety of consuming transgenic tilapia as food. Behavior studies showed that transgenic tilapia had a lower feeding motivation and dominance status than controls. Food safety assessment indicated that tilapia growth hormone has no biological activity when administered to nonhuman primates. Furthermore, no effects were detected in human healthy volunteers after the consumption of transgenic tilapia. These results showed, at least under the conditions found in Cuba, no environmental implications for the introduction of this transgenic tilapia line and the safety in the consumption of tiGH-transgenic tilapia as an alternative feeding source for humans. These results support the culture and consumption of these transgenic tilapia.

Journal Article↗
PubMed1999

Mycobacterium phlei cell wall complex directly induces apoptosis in human bladder cancer cells.

Intact mycobacteria and mycobacterial cell wall extracts have been shown to inhibit the growth of human and murine bladder cancer. Their mechanism of action is, however, poorly understood. Mycobacterium phlei mycobacterial cell complex (MCC) is a cell wall preparation that has mycobacterial DNA in the form of short oligonucleotides complexed on the cell wall surface. In this study, we have investigated the possibility that MCC has anti-cancer activity that is mediated by two different mechanisms--a direct effect on cancer cell proliferation and viability and an indirect effect mediated by the production of interleukin 12 (IL-12), a cytokine known to possess anti-cancer activity. We have found that, although MCC is a potent inducer of IL-12 and IL-6 synthesis in monocytes and macrophages either in vitro or in vivo, it is unable to induce the synthesis of either IL-12, IL-6 or granulocyte-macrophage colony-stimulating factor (GM-CSF) by the human transitional bladder cancer cell lines HT-1197 and HT-1376. MCC is not directly cytotoxic towards these cancer cells, but induces apoptosis as determined by nuclear DNA fragmentation and by the release of nuclear mitotic apparatus protein. Mycobacterium phlei DNA associated with MCC is responsible for the induction of apoptosis. Our results indicate that MCC directly effects bladder cancer cells by inhibiting cellular proliferation through the induction of apoptosis, and has the potential for an indirect anti-cancer activity by stimulating cancer-infiltrating monocytes/macrophages to synthesize IL-12.

Apoptosis↗
PubMed1999

Synthesis of steroids in pancreas: evidence of cytochrome P-450scc activity.

In pancreas, the activities of several sex steroid-transforming enzymes have been reported. Data have been obtained in perfused organs, total tissue homogenates, and subcellular organelles. These data, concurrent with the description of the presence of ligand-regulated steroid receptors, as well as the sexually dimorphic behavior of some pancreatic tumors, are clear evidence in support of the participation of steroid hormones in the pancreatic function. In this study, the steroidogenic ability of the pancreas was demonstrated by two different methods: (a) in tissue homogenates, by the identification of cytochrome P-450scc gene (CYP11A) transcripts after reverse transcription-polymerase chain reaction amplification (RT-PCR); and (b) in isolated mitochondria by the glutethimide-dependent inhibition of cholesterol-pregnenolone biotransformation. The results obtained in a series of independent experiments showed that (a) the pancreatic tissue possessed transcriptional activity of the CYP11A gene, although to a lesser extent than the typical steroidogenic tissues, and (b) isolated mitochondria obtained from the pancreas were able consistently to synthesize pregnenolone; furthermore, the addition of the specific inhibitor aminoglutethimide (AMG) blocked its synthesis. On the whole, these findings are interpreted as clear evidences of the activity of the cytochrome P-450scc enzymatic complex (P450scc), responsible for the transformation of cholesterol into pregnenolone and considered the first and limiting step in steroid biosynthesis.

Aminoglutethimide↗
PubMed1999

Glucose-induced preproinsulin gene expression is inhibited by the free fatty acid palmitate.

Prolonged exposure to elevated FFA levels has been shown to induce peripheral insulin resistance and to alter the beta-cell secretory response to glucose. To investigate the effects of FFAs on preproinsulin gene expression, we measured insulin release, cell content, and messenger RNA (mRNA) levels in rat islets after a 24-h exposure to 1 mM palmitate. Insulin release increased at all glucose concentrations studied; in contrast, preproinsulin mRNA levels were specifically reduced by palmitate at high glucose with a decrease in insulin stores, suggesting that palmitate inhibits the glucose-stimulated increase in preproinsulin gene expression. The mechanisms by which palmitate affects preproinsulin gene expression implicate both preproinsulin mRNA stability and transcription, as suggested by an actinomycin D decay assay, quantification of primary preproinsulin transcripts, and transient transfection experiments in Min6 cells. Metabolism of palmitate is not required to obtain these effects, inasmuch as they can be reproduced by 2-bromopalmitate. However, oleate and linoleate did not significantly influence preproinsulin mRNA levels. We conclude that insulin release and preproinsulin gene expression are not coordinately regulated by palmitate and that chronically elevated FFA levels may interfere with beta-cell function and be implicated in the development of noninsulin-dependent diabetes.

Animals↗
PubMed1999

99mTc-labeled antihuman epidermal growth factor receptor antibody in patients with tumors of epithelial origin: Part III. Clinical trials safety and diagnostic efficacy.

UNLABELLED: Monoclonal antibody (moAb) ior egf/r3 is an IgG2a that recognizes the epidermal growth factor receptor (EGF-R). The aim of this study was to evaluate the diagnostic efficacy of the 99mTc-labeled moAb ior egf/r3 for the detection of epithelial-derived tumors, their metastases and recurrences. METHODS: One hundred forty-eight adult patients (51 women, 97 men; mean age 53 +/- 13 y) who were suspected of having cancer of epithelial origin were administered 3 mg/50 mCi (1.85 GBq) 99mTc-labeled moAb ior egf/r3 by intravenous bolus injection. Planar anterior and posterior images of the lesion sites and suspected metastases were acquired at 2, 4, 6 and 24 h after injection, and SPECT images were scanned at 5 h postinjection, using a 360 degrees circular orbit with 64 images. The backprojection method was used for image reconstruction with a Hamming-Hann filter. RESULTS: Labeling efficiency was always greater than 98.5% +/- 2.1 %. No adverse reactions or side effects were observed. Results of the biopsy specimens showed that 85.1% (126/148) of the patients had tumors of epithelial origin, 14.2% (21/148) were negative and 0.7% (1/148) had non-Hodgkin's lymphoma. The sensitivity rate by organ was as follows: brain (8/8, 100%), digestive tract (10/11, 90.9%), head and neck (17/23, 73.9%), lung (52/62, 83.9%) and breast (16/18, 88.9%). Overall sensitivity, specificity, accuracy, and positive and negative predictive values of the immunoscintigraphic imaging were 84.2% (106/126), 100.0% (22/22), 86.5% (128/148), 100% (106/106) and 52.4% (22/42), respectively. New metastases not identified previously by other diagnostic methods were detected in the 50% of the patients. CONCLUSION: Immunoscintigraphy with 99mTc-labeled moAb ior egf/r3 could be a useful procedure for the diagnosis and follow-up of the patients with tumors of epithelial origin.

Animals↗
PubMed1999

Sexual Endocrinopathies.

There is compelling experimental and clinical evidence that for adequate sexual function, there must be complex and efficient cross-communication between the endocrine and nervous systems, both centrally and peripherally. The central nervous system (CNS) controls the release of sex steroids, while at the same time, these hormones are primary modulators of neurologic activity. The investigation and treatment of men suspected of hypogonadism is simple, but careful monitoring is essential. Unfortunately, sexual dysfunction is frequently multifactorial, and in many patients, the dysfunction does not improve with hormonal replacement. However, hypotestosteronemia is associated with a variety of alterations in different organ systems beyond sexual activity. It is important to the practice of urology to be familiar with neuroendocrine interactions and to maintain an adequate knowledge of the evaluation and treatment of hormonal deficiencies, particularly in men beyond middle age, in whom hypogonadism is prevalent.

Journal Article↗
PubMed1998

Tissue-specific modulation of rat glucagon receptor mRNA by thyroid status.

The influence of thyroid status on glucagon receptor mRNA levels was investigated in rats using a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Glucagon receptor mRNA was detected in liver, brown and white adipose tissues (BAT and WAT) and brain. In BAT and WAT, pharmacologically-induced moderate hypothyroidism resulted in a marked reduction in the relative abundance of glucagon receptor mRNA. Short-term treatment of hypothyroid rats with exogenous 3,3',5'-triiodo-L-thyronine (T3), resulting in a marked hyperthyroidism, reversed the phenomenon in BAT while the reversal was only partial in WAT. In the liver, there was no significant effect of mild hypothyroidism while there was a positive effect of hyperthyroidism. In brain, the relative tissue abundance of glucagon receptor mRNA was not affected by the large changes in plasma T3. The present results therefore indicate that thyroid status may modulate the relative abundance of glucagon receptor mRNA in a tissue-specific manner.

Adipose Tissue↗
PubMed1998

Oxidative damage of mitochondrial and nuclear DNA induced by ionizing radiation in human hepatoblastoma cells.

PURPOSE: Since reactive oxygen species (ROS) act as mediators of radiation-induced cellular damage, the aim of our studies was to determine the effects of ionizing radiation on the regulation of hepatocellular reduced glutathione (GSH), survival and integrity of nuclear and mitochondrial DNA (mtDNA) in human hepatoblastoma cells (Hep G2) depleted of GSH prior to radiation. METHODS AND MATERIALS: GSH, oxidized glutathione (GSSG), and generation of ROS were determined in irradiated (50-500 cGy) Hep G2 cells. Clonogenic survival, nuclear DNA fragmentation, and integrity of mtDNA were assessed in cells depleted of GSH prior to radiation. RESULTS: Radiation of Hep G2 cells (50-400 cGy) resulted in a dose-dependent generation of ROS, an effect accompanied by a decrease of reduced GSH, ranging from a 15% decrease for 50 cGy to a 25% decrease for 400 cGy and decreased GSH/GSSG from a ratio of 17 to a ratio of 7 for controls and from 16 to 6 for diethyl maleate (DEM)-treated cells. Depletion of GSH prior to radiation accentuated the increase of ROS by 40-50%. The depletion of GSH by radiation was apparent in different subcellular sites, being particularly significant in mitochondria. Furthermore, depletion of nuclear GSH to 50-60% of initial values prior to irradiation (400 cGy) resulted in DNA fragmentation and apoptosis. Consequently, the survival of Hep G2 to radiation was reduced from 25% of cells not depleted of GSH to 10% of GSH-depleted cells. Fitting the survival rate of cells as a function of GSH using a theoretical model confirmed cellular GSH as a key factor in determining intrinsic sensitivity of Hep G2 cells to radiation. mtDNA displayed an increased susceptibility to the radiation-induced loss of integrity compared to nuclear DNA, an effect that was potentiated by GSH depletion in mitochondria (10-15% intact mtDNA in GSH-depleted cells vs. 25-30% of repleted cells). CONCLUSION: GSH plays a critical protective role in maintaining nuclear and mtDNA functional integrity, determining the intrinsic radiosensitivity of Hep G2. Although the DNA repair is a complex process that is not yet completely understood, the protective role of GSH probably does not seem to involve the repair of classical DNA damage but may relate to modification of DNA damage dependent signaling.

Apoptosis↗