RESUMEN
BACKGROUND: The objective of the present trial was to assess the difference in pharmacokinetics (PK) of an oral test preparation containing 4 mg drospirenone (DRSP) under fasting conditions compared to PK upon food intake after single dose administration. METHODS: Open label, single centre, two-treatment, two-sequence, crossover study in 24 healthy female volunteers, with duration of 1 day per sequence and with a real wash-out period of 14 days to investigate the relative bioavailability of DRSP with both forms of administration. The 90% confidence intervals (CI) were calculated for the intra-individual ratio (test with food vs. without food) of the PK endpoints Area under the curve; 0-72 h [AUC(0-72 h)] and maximal plasma concentration [Cmax] of DRSP. RESULTS: The 90% CI calculated by analysis of variance using logistic transformation (ANOVA-log) for the endpoint, intra-individual ratio (Test 'A' = with food intake) vs. Test 'B' = without food intake) of AUC(0-72 h) of drospirenone was between 104.72 and 111.36%. The 90% CI calculated by means of ANOVA- log for the endpoint intra-individual ratio (Test 'A' vs. Test 'B') of Cmax of DRSP was between 118.58 and 141.10%. The mean relative bioavailability of the test with food 'A' compared to the Test without food 'B' after single dose administration based on the endpoints AUC(0-72 h) was 107.99%; for the endpoint Cmax it was 129.35%. CONCLUSIONS: The rate of absorption, based on the endpoint Cmax of DRSP was increased by about 30% under fed conditions. With respect to consumer habits, this may represent a relevant benefit for contraceptive safety, as the time span between food consumption and pill intake does not play a role. IMPLICATIONS: Our results suggest that the food intake has no impact on the absorption of 4 mg DRSP in the management of contraception. This increases the contraceptive efficacy as no interference with food is expected when consuming the oral formulation under real life conditions. TRAIL REGISTRATION: Trial registration number: EudraCT-No: 2012-004,309-28.
Asunto(s)
Androstenos , Desayuno , Anticonceptivos , Grasas de la Dieta , Androstenos/farmacocinética , Desayuno/efectos de los fármacos , Anticonceptivos/farmacocinética , Estudios Cruzados , Grasas de la Dieta/administración & dosificación , Femenino , HumanosRESUMEN
Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity through binding to specific progesterone receptors. New estrogen-free contraceptive and its possible implication on bone turnover are discussed in this review. Insufficient bone acquisition during development and/or accelerated bone loss after attainment of peak bone mass (PBM) are 2 processes that may predispose to fragility fractures in later life. The relative importance of bone acquisition during growth versus bone loss during adulthood for fracture risk has been explored by examining the variability of areal bone mineral density (BMD) (aBMD) values in relation to age. Bone mass acquired at the end of the growth period appears to be more important than bone loss occurring during adult life. The major physiological effect of estrogen is the inhibition of bone resorption. When estrogen transcription possesses binds to the receptors, various genes are activated, and a variety modified. Interleukin 6 (IL-6) stimulates bone resorption, and estrogen blocks osteoblast synthesis of IL-6. Estrogen may also antagonize the IL-6 receptors. Additionally, estrogen inhibits bone resorption by inducing small but cumulative changes in multiple estrogen-dependent regulatory factors including TNF-α and the OPG/RANKL/RANK system. Review on existing data including information about new estrogen-free contraceptives. All progestins exert activity through binding to specific progesterone receptors; hereby, three different groups of progestins exist: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progestogens is known to bind with more affinity to androgen receptors than the C21 progestins. This article reviews the effect of estrogens and progestogens on bone and presents new data of the currently approved drospirenone-only pill. The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml does not seem to lead to an accelerate bone loss.
Asunto(s)
Remodelación Ósea/efectos de los fármacos , Anticonceptivos Hormonales Orales/farmacología , Factores de Edad , Androstenos/farmacología , Densidad Ósea/efectos de los fármacos , Densidad Ósea/fisiología , Desarrollo Óseo/fisiología , Remodelación Ósea/fisiología , Resorción Ósea/sangre , Resorción Ósea/fisiopatología , Anticonceptivos Orales Combinados/farmacología , Anticonceptivos Hormonales Orales/química , Estradiol/sangre , Estrógenos/fisiología , Femenino , Humanos , Progestinas/farmacologíaRESUMEN
Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.
Asunto(s)
Calcinosis/genética , Hiperostosis Cortical Congénita/genética , Hiperfosfatemia/genética , Mutación , N-Acetilgalactosaminiltransferasas/genética , Osteoblastos/patología , Secuencia de Bases , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular , Niño , Femenino , Factor-23 de Crecimiento de Fibroblastos , Citometría de Flujo , Humanos , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Células Madre/patología , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
OBJECTIVE: The current study evaluated menstrual bleeding profiles, compliance and tolerability in women using a drospirenone (DRSP)-only pill. PATIENTS AND METHODS: This is a non-interventional, retrospective, multi-center study on healthy female adults [n=276, aged between 18 and 53 years and premenopausal using a DRSP-only pill for at least six months with a mean duration of 10.4 months (+/-SD 4.0) months]. 75.6% used other contraceptives than POP before starting with the DRSP-only pill. A questionnaire was used to evaluate the bleeding profile. 56.5% of the women had associated cardiovascular risk factors. RESULTS: Two hundred and sixty-two (262) women (mean age of 32.5 ± 9.1 years; mean BMI of 23.1 ± 3.8 kg/m²) were eligible for analysis. 42.6% of the users had a scheduled bleeding, 33,3% unscheduled bleeding and 48% no bleeding during the last evaluable cycle. 75.4% evaluated the bleeding profile in the last cycle as very good or good, 13.8% said there was no change since starting the medication, 8.4% declared the profile was bad and 2.3% as very bad. 87.8% of the users evaluated the general satisfaction of the contraception as very good or good, whereas only 8.8% and 3.4% said there was no change or that it was bad. No women evaluated the general satisfaction as very bad. CONCLUSIONS: These data demonstrate that the DRSP-only pill is associated with a very high satisfaction as a contraceptive in general and in the individual bleeding profile. These aspects reaffirm the acceptability not only in women with cardiovascular risk factors.
Asunto(s)
Antagonistas de Receptores de Mineralocorticoides , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/administración & dosificación , Antagonistas de Receptores de Mineralocorticoides/farmacología , Estudios Retrospectivos , Menstruación , Factores de Riesgo de Enfermedad Cardiaca , Tolerancia a MedicamentosRESUMEN
This review focuses on the pharmacological and inhibition of the ovulation of progestin-only, estrogen-free contraceptive containing drospirenone in a dosage of 4 mg in a regimen 24/4. The USA and European regulatory authorities have approved it. The molecule has anti-gonadotropic, anti-mineralocorticoid, anti-estrogenic, and antiandrogenic properties. This regime improves the bleeding profile, maintains the plasma E2 levels comparable to the menstrual cycle's early follicular phase, avoids hypoestrogenism, and preserves efficacy despite forgetting the tablet intake as drospirenone has a half lifetime of 30-34 hours. Clinical studies have shown good efficacy, very low cardiovascular side effects, and high acceptability and maintenance of ovulation inhibition after scheduled 24-h delays in pill intake. The molecule is compared to other POP like levonorgestrel or desogestrel.
Asunto(s)
Androstenos , Progestinas , Androstenos/efectos adversos , Femenino , Humanos , Ovulación , Inhibición de la Ovulación , Progestinas/farmacologíaRESUMEN
OBJECTIVE: The current post-market study aimed at analyzing women's menstrual bleeding intensity, vaginal infections, and quality of life parameters using the contraceptive vaginal ring Ornibel®. PATIENTS AND METHODS: In Germany and Spain, a multicenter study of healthy female adults (n=211) aged 18 to 45 used the vaginal ring Ornibel® for at least six months. Data collection was conducted using a patient questionnaire. The menstrual bleeding intensity was analyzed using visual analog scales (VAS). A Chi-square linear trend test assessed associations between quality-of-life parameters and continuation and recommendation of vaginal ring use. RESULTS: Three out of four women experienced six menstrual bleedings during the first six months of using the vaginal ring, with a median duration of four days during the study. The use of the vaginal ring led to a significant reduction in menstrual flow intensity (from 60 VAS points to 40 VAS points, p<0.001). In the German cohort, it was shown that dysmenorrhea and unscheduled bleeding and spotting were reduced with the use of Ornibel® as well. Most women (93.7%) agreed or strongly agreed that the vaginal ring was easy to insert, and its use was rated as comfortable or very comfortable by 97.5%. Both parameters were significantly associated with the continuation of the ring (easy to insert p=0.01, feeling comfortable: p=0.002) or its recommendation (easy to insert p=0.002, feeling comfortable: p=0.002). CONCLUSIONS: The observational data demonstrate that the contraceptive vaginal ring provides high acceptability and comfort. It is a well-accepted contraceptive method characterized by high efficacy and positive effects on cycle control.
Asunto(s)
Anticonceptivos Femeninos , Dispositivos Anticonceptivos Femeninos , Adulto , Femenino , Humanos , Etinilestradiol/efectos adversos , Calidad de VidaRESUMEN
AIMS: Since glucose levels during oral glucose tolerance test (OGTT) are determined both by insulin sensitivity and insulin secretion, we investigated whether the percentage increment (PG%) of 2-h plasma glucose (2hPG) over fasting plasma glucose (FPG) is related to validated indexes of insulin sensitivity and insulin secretion. METHODS: Using Stumvoll's formulas we calculated estimated insulin sensitivity index and first-phase insulin secretion in 1281 subjects who underwent a standard OGTT. The ratio first-phase insulin secretion/(1/estimated insulin sensitivity index) was considered a surrogate index of ß-cell function. For each subject we calculated PG% using the formula: [(2hPG - FPG)/FPG] × 100. For each glucose tolerance group we formed tertiles based on PG% values. RESULTS: In each glucose tolerance group, ß-cell function was better preserved in lower PG% tertiles, demonstrating a correlation between PG% and insulin resistance. CONCLUSIONS: By a simple calculation, our study allows, expansion of the clinical use of OGTT to recognize subjects liable to further worsening of glucose homeostasis, independent from glucose tolerance groupings.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Ayuno/sangre , Prueba de Tolerancia a la Glucosa , Células Secretoras de Insulina/fisiología , Diabetes Mellitus Tipo 2/etiología , Humanos , Insulina/sangre , Insulina/metabolismo , Resistencia a la Insulina , Secreción de InsulinaRESUMEN
Loss of function of the retinoblastoma protein, pRB, leads to lack of differentiation, hyperproliferation and apoptosis. Inactivation of pRB results in deregulated E2F activity, which in turn induces entry to S-phase and apoptosis. Induction of apoptosis by either the loss of pRB or the deregulation of E2F activity occurs via both p53-dependent and p53-independent mechanisms. The mechanism by which E2F induces apoptosis is still unclear. Here we show that E2F1 directly regulates the expression of Apaf-1, the gene for apoptosis protease-activating factor 1. These results provide a direct link between the deregulation of the pRB pathway and apoptosis. Furthermore, because the pRB pathway is functionally inactivated in most cancers, the identification of Apaf-1 as a transcriptional target for E2F might explain the increased sensitivity of tumour cells to chemotherapy. We also show that, independently of the pRB pathway, Apaf-1 is a direct transcriptional target of p53, suggesting that p53 might sensitize cells to apoptosis by increasing Apaf-1 levels.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Regiones Promotoras Genéticas/genética , Proteínas/genética , Factores de Transcripción/fisiología , Proteína p53 Supresora de Tumor/fisiología , Animales , Factor Apoptótico 1 Activador de Proteasas , Factores de Transcripción E2F , Factor de Transcripción E2F1 , Embrión de Mamíferos/metabolismo , Humanos , Ratones , Proteínas/metabolismo , Proteína de Retinoblastoma/metabolismo , Transcripción Genética , Activación TranscripcionalRESUMEN
BACKGROUND AND AIMS: Cardiovascular (CV) events occur even when LDL-C are <100mg/dL. To improve the detection of CV risk we investigated the apoB/apoA-I ratio versus LDL-C in subjects considered normal glucose tolerant (NGT) by oral glucose tolerance test (OGTT). METHODS AND RESULTS: We enrolled 616 NGT (273 men and 343 women), and we measured insulin resistance, lipid profile, apoB/apoA-I and the factors compounding the metabolic syndrome (MetS). An unfavourable apoB/apoA-I (≥0.9 for males and ≥0.8 for females) was present in 13.9% of 108 patients with LDL-C <100mg/dL: compared to subjects with lower apoB/apoA-I (<0.9 for males and <0.8 for females), they had more elements of MetS and their lipid profile strongly correlated with high CV risk. Out of 314 patients with lower apoB/apoA-I, 40.12% had LDL-C ≥130mg/dL: these retained a more favourable lipid profile than corresponding subjects with elevated apoB/apoA-I ratio. Finally, we found a significant correlation between LDL-C and apoB/apoA-I ratio (r=0.48, p<0.0001). CONCLUSIONS: In NGT with LDL-C <100mg/dL, a higher apoB/apoA-I exhibited an atherogenic lipid profile, indicating that LDL-C alone is insufficient to define CV risk. Independent from LDL-level, when apoB/apoA-I is lower, the lipid profile is, in fact, less atherogenic. This study demonstrates that apoB/apoA-I is at least complementary to LDL-C in identifying the "effective" CV risk profile of asymptomatic NGT subjects.
Asunto(s)
Apolipoproteína A-I/sangre , Apolipoproteínas B/sangre , Enfermedades Cardiovasculares/diagnóstico , LDL-Colesterol/sangre , Adulto , Glucemia/análisis , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/patología , Estudios de Cohortes , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Masculino , Síndrome Metabólico/sangre , Persona de Mediana Edad , Factores de RiesgoRESUMEN
BACKGROUND: Progestin-only pills are associated with irregular bleeding pattern including amenorrhea. Desogestrel 75mcg even being a pill that inhibits ovulation shows a poor cycle control that limits a more common use. A drospirenone (DRSP)-only pill was developed to improve the bleeding profile. METHODS: A phase III study in healthy women aged 18 to 45 years was performed to compare the bleeding profile and safety of women taking a DRSP only pill in a regime of 24 days of 4 mg of DRSP tablets followed by 4 days of placebo versus desogestrel 0.075 mg per day continuously over 9 cycles. A total of 858 women with 6691 drospirenone and 332 women with 2487 desogestrel treatment cycles were analyzed. The primary endpoint was the proportion of women with bleeding/spotting days in each cycle from cycles 2 to 9 and cumulative in cycles 2 to 4 and cycles 7 to 9 including and excluding those with amenorrhea. FINDINGS: In each cycle, up to cycle 7, the proportion of women with unscheduled bleeding including those which did not bleed was statistically significantly lower in the DRSP group than in the DSG group (p = 0.0001, chi-square test). The mean [SD] number of unscheduled bleeding and spotting days during cycles 2-9 was statistically significantly lower in the DRSP group than in the DSG group (21.5 [22.86] days vs. 34.7 [33.73] days, p = 0.0003, Wilcoxon-rank-sum-test). Excluding amenorrhoeic women following results were obtained: In the cycles 2-6, the proportion of women with unscheduled bleeding was statistically significantly lower in the DRSP group than in the DSG group (p = 0.0001, chi-square test). The mean [SD] number of bleeding days was 8.6 [8.52] days vs. 12.9 [16.47] days, p = 0.0233. CONCLUSIONS: This report describes the improvement in bleeding profile of women using the new DRSP only oral contraceptive in comparison to DSG providing a better quality of live and adherence to the contraceptive method. EudraCT registration number: 2011-002396-42.
Asunto(s)
Androstenos/efectos adversos , Anticonceptivos Orales Combinados/efectos adversos , Desogestrel/efectos adversos , Hemorragia Uterina/etiología , Adolescente , Adulto , Androstenos/administración & dosificación , Anticonceptivos Orales Combinados/administración & dosificación , Desogestrel/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Efecto Placebo , Adulto JovenRESUMEN
Combined contraceptive vaginal rings (CVR) are increasingly appreciated due to several beneficial properties like avoidance of the hepatic first-pass effect, a comparatively low dosage of hormones and comfortable use. A further development of the widely used CVR releasing 0.12 mg etonogestrel (ETO) and 0.015 mg ethinylestradiol (EE) per 24 hours has been marketed since 2017. The 11.00/3.474 mg ETO/EE CVR Ornibel® is bioequivalent to the former product but differs in its polymer composition leading to improved stability. Here, results from recent studies on the novel CVR Ornibel® are reviewed including clinical trials on bleeding profile, acceptability, sexual function and other quality of life (QoL) parameters as well as in vitro studies on microbial adhesion to the CVR and the influence of ring rupture on hormone release. Findings are complemented with new data on contraceptive efficacy and safety of the new CVR that were assessed during 3 years of real-life experience.
Asunto(s)
Dispositivos Anticonceptivos Femeninos , Desogestrel , Etinilestradiol , Dispositivos Anticonceptivos Femeninos/efectos adversos , Desogestrel/efectos adversos , Relación Dosis-Respuesta a Droga , Etinilestradiol/efectos adversos , Femenino , Humanos , Calidad de Vida , Factores de TiempoRESUMEN
OBJECTIVE: To determine the pharmacokinetics (PK) of drospirenone (DRSP), alone versus in combination with ethinyl estradiol (EE), after single and repeated administration. STUDY DESIGN: We conducted a single-centre, open-label, crossover, 2-treatment, 2-period, 2-sequence study in which non-micronized DRSP 4â¯mg or a combination of DRSP 3â¯mg and EE 0.02â¯mg were administered to healthy female subjects on day 1 to obtain a single-dose kinetic profile, and from day 4 to day 15 to obtain a repeated-dose kinetic profile. The maximum observed concentration (Cmax) and area under the concentration/time curve (AUC) were determined in a model-independent way using non dose corrected data. Statistical analysis was based on a parametric method (ANOVA-log). RESULTS: A total of 24 healthy female subjects were randomized 1:1 into the study. The mean relative, non-dose-corrected PK estimates after single-dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 543.5â¯ng*h/mL, 296.1â¯ng*h/mL and 27.3â¯ng/mL for DRSP alone, and 442.0â¯ng*h/mL, 264.7â¯ng*h/mL and 37.5â¯ng/mL for the DRSP/EE combination; pâ¯<â¯0.001. The mean relative, non-dose-corrected PK estimates after repeated dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 1066.8â¯ng*h/ml, 570.2â¯ng*h/mL and 41.0â¯ng/mL for DRSP alone, and 1394.5â¯ng*h/mL, 732.8â¯ng*h/mL and 61.4â¯ng/mL for the DRSP/EE combination; pâ¯<â¯0.001. CONCLUSIONS: DRSP alone exhibits a lower accumulation ratio than together with EE. The extent of systemic exposure at steady-state is about 32% less with the new formulation (AUC(0-24h), steady-state geometric mean ratio: 77.8%; 90% confidence interval: 74.6%-81.1%). This PK profile may be caused by EE. IMPLICATIONS: Our results suggest that metabolic pathways of DRSP can be inhibited by EE resulting in higher DRSP plasma concentrations in DRSP/EE formulations than in a DRSP-alone formulation. The enzymes CYP3A4 and SULT1A1 may play a role. Additional drug-drug-interaction studies are needed to better understand these metabolic pathways and their future clinical implications.
Asunto(s)
Androstenos/farmacocinética , Etinilestradiol/farmacocinética , Sustancias para el Control de la Reproducción/farmacocinética , Administración Oral , Adulto , Androstenos/administración & dosificación , Bulgaria , Estudios Cruzados , Esquema de Medicación , Interacciones Farmacológicas , Etinilestradiol/administración & dosificación , Femenino , Humanos , Adulto JovenRESUMEN
OBJECTIVE: Our objective was to analyze the prevalence and risk factors for erectile dysfunction (ED) in men with diabetes in Italy in a cross-sectional study. RESEARCH DESIGN AND METHODS: Eligible for the study were men aged 20-69 years with a diagnosis of IDDM or NIDDM who were observed on randomly selected days in 178 diabetes centers in Italy. ED was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance. RESULTS: Of the 9,868 diabetic men interviewed, 3,534 (35.8%) reported ED. The prevalence increased with age, from 4.6% in men aged 20-29 to 45.5% in those aged > or =60 years (test for trend, P = 0.0001). After taking into account the confounding role of age, men with NIDDM reported ED less frequently than did men with IDDM (odds ratio [OR], 0.7; 95% CI 0.6-0.8). In comparison with men reporting diabetes lasting < or =5 years, the ORs for ED were 1.3 and 2.0 for subjects with diabetes lasting 6-10 and 11-30 years, respectively. In comparison with men with good metabolic control, the ORs for ED were 1.7 and 2.3 in men with fair and poor control, respectively. A history of diabetes-related arterial, retinal, or renal diseases and neuropathy was associated with an increased risk of ED. Finally, in comparison with never-smokers, the ORs for ED were 1.5 (95% CI 1.3-1.6) for current smokers and 1.4 (95% CI 1.3-1.6) for ex-smokers. The OR increased with number of cigarettes smoked per day: in comparison with men smoking <12 cigarettes per day, the OR was 1.5 (95% CI 1.3-1.7) for those smoking > or =30 cigarettes day. CONCLUSIONS: The study offers a quantitative estimate of the prevalence of ED and of its main risk factors in Italian men with diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Disfunción Eréctil/etiología , Adulto , Anciano , Estudios Transversales , Disfunción Eréctil/epidemiología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
A novel T/C polymorphism (ATG to ACG) at the translation initiation site of the vitamin D receptor (VDR) gene, defined by FokI restriction endonuclease, has been recently associated with variation in bone mineral density (BMD) and rates of bone loss in a group of postmenopausal Mexican-American women. The presence of the restriction site, designated as f, allows protein translation to initiate from the first ATG, while the allele lacking the site, indicated as F, initiates translation at a second ATG. In this study, we investigated the role of FokI polymorphism in a group of 400 postmenopausal women of Italian descent stratified for BMD into osteoporotic (n = 164), osteopenic (n = 117), and normal (n = 119) groups. There were 159 (41%) FF homozygotes, 55 (14%) ff homozygotes, and 186 (45%) Ff heterozygotes. In the whole population, we observed a weak association between FokI polymorphism and lumbar BMD (p = 0.06, analysis of covariance [ANCOVA]) but not with femoral neck BMD (p = 0.5, ANCOVA). Interestingly, the effect of FokI genotypes on lumbar BMD was influenced by the years since menopause such that differences in BMD related to different VDR allelic variants were greater among women in the first 5 years of menopause (p = 0.04, ANCOVA), progressively declining afterward. In addition, a significantly higher prevalence of ff genotype in osteoporotic than in osteopenic and normal women was observed (p = 0.04, Chi-square test). Finally, ff genotype resulted significantly over-represented in the group of women with a vertebral fracture as compared with controls (p = 0.003, Chi-square test), equivalent to a relative risk of 2.58 (95% confidence intervals 1.36-4.91). We conclude that in this population, FokI polymorphism at the VDR gene locus accounts for a part of the heritable component of BMD at the lumbar spine.
Asunto(s)
Densidad Ósea/fisiología , Desoxirribonucleasas de Localización Especificada Tipo II/genética , Iniciación de la Cadena Peptídica Traduccional/genética , Polimorfismo Genético , Posmenopausia/fisiología , Receptores de Calcitriol/genética , Fracturas de la Columna Vertebral/genética , Anciano , Análisis de Varianza , Enfermedades Óseas Metabólicas/genética , Femenino , Genotipo , Humanos , Italia , Persona de Mediana Edad , Osteoporosis Posmenopáusica/genéticaRESUMEN
Conversion of C(19) steroids to estrogens is catalyzed by the aromatase enzyme. Inactivating mutations of the aromatase gene are associated with decreased bone mineral density in both men and women. Genetic studies suggest that several genes contribute to the regulation of bone mass via interaction with the modeling and remodeling processes. Among these genes, the aromatase gene is a potential candidate to be evaluated for segregation with bone metabolism and bone mass. A tetranucleotide simple tandem repeat polymorphism in intron 4 at the human aromatase cytochrome P-450 gene has been recently described. In the present study we evaluated the distribution of this polymorphism in a cohort of Italian postmenopausal women, both normal and osteoporotic. We observed that the NN genotype was significantly more frequent in nonosteoporotic women than in osteoporotic women (72.7% vs. 27.2%), whereas the DN genotype was significantly more represented in osteoporotic women (90.48% vs. 9.5%; Pearson's chi(2) test = 42.8; df = 10; P = or < 0.01). The allele containing the longer TTTA repeats was statistically more represented in nonosteoporotic women (Pearson's chi(2) test = 19.14; df = 2; P = 0.00007). In addition, women with a high number of TTTA repeats had a significantly higher lumbar bone mineral density than women with alleles containing 8-11 TTTA repeats (P = 0.03). Finally, considering the spine fractures, a significantly higher incidence was observed in women with shorter TTTA repeats than in those with longer TTTA repeats (Pearson's chi(2) test = 7.3; df = 2; P = 0.02), equivalent to a relative risk of 4.1 (95% confidence interval, 1.19-13.87). In conclusion, the aromatase gene can be one of the several genes potentially involved in the maintenance of bone mass and in the regulation of bone mass loss.
Asunto(s)
Aromatasa/genética , Densidad Ósea , Fracturas Óseas/etiología , Polimorfismo Genético , Posmenopausia/genética , Anciano , Estudios de Cohortes , Femenino , Genotipo , Humanos , Repeticiones de Microsatélite , Persona de Mediana Edad , RiesgoRESUMEN
We investigated whether D1 dopaminergic receptors modulate in vivo acetylcholine output in the shell and core areas of rat nucleus accumbens using the microdialysis technique. Subcutaneous injection (1, 2 and 3 mg/kg) of the D1 agonist SKF 82958 enhanced acetylcholine output in both areas of the nucleus accumbens while the selective D1 antagonist SCH 39166 (0.15 and 0.30 mg/kg, s.c.) lowered it. Both SKF 82958 and SCH 39166 were more effective in the shell than in the core region. The increase in acetylcholine release induced by SKF 82958 in the shell was tetrodotoxin-sensitive. The dopamine release inducer d-amphetamine (1 and 2mg/kg, s.c.) and the dopamine uptake inhibitor cocaine (10 and 20 mg/kg, i.p.) dose-dependently raised acetylcholine release in the shell and core areas. The dopaminergic stimulants, like the direct-acting D1 compounds, were more effective in the shell than in the core compartment of the nucleus accumbens. The acetylcholine increases in the shell induced by d-amphetamine (2 mg/kg), cocaine (20 mg/kg) and SKF 82958 (3 mg/kg) were antagonized by the D1 antagonists SCH 39166 (5 microM) and SCH 23390 (10 microM), applied locally by reverse dialysis. The results suggest that dopamine acting at the D1 receptors exerts a tonic stimulatory control over the cholinergic function of the shell and core compartments of the nucleus accumbens with the shell being more strongly influenced.
Asunto(s)
Acetilcolina/fisiología , Benzazepinas/farmacología , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Núcleo Accumbens/fisiología , Receptores de Dopamina D1/fisiología , Transmisión Sináptica/fisiología , Animales , Cocaína/farmacología , Dextroanfetamina/farmacología , Femenino , Microdiálisis , Núcleo Accumbens/efectos de los fármacos , Ratas , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inhibidores , Transmisión Sináptica/efectos de los fármacos , Tetrodotoxina/farmacologíaRESUMEN
OBJECTIVE: Calcitriol analogues might represent an interesting new therapy for benign prostate hyperplasia (BPH). We here report the preclinical characterization of BXL-628, an analogue selected for an ongoing double-blind, randomized, placebo-controlled phase II trial in BPH. DESIGN: Experiments with BXL-628 were carried out in human BPH cells and in the ventral prostate of intact and castrated rats. METHODS: BPH cell and rat prostate growth were evaluated along with morphological and biochemical hallmarks of apoptosis. RESULTS: BXL-628 inhibited human BPH cell proliferation and induced apoptosis even in the presence of androgens or growth factors. It also decreased prostate growth to an extent similar to finasteride, inducing DNA fragmentation and apoptosis, both in intact and in testosterone-supplemented castrated rats. Accordingly, BXL-628, like finasteride, increased the expression of clusterin, a prostatic atrophy marker. However, BXL-628 did not inhibit 5 alpha-reductase 1 and 2, did not bind to the androgen receptor (AR) in BPH homogenates and did not affect AR-coupled luciferase activity. In addition, BXL-628 did not affect rat pituitary and testis activity or calcemia. CONCLUSIONS: BXL-628 inhibited in vitro and in vivo prostate cell proliferation, and therefore might represent a novel, interesting option for the treatment of BPH.
Asunto(s)
Calcitriol/análogos & derivados , Calcitriol/administración & dosificación , Próstata/efectos de los fármacos , Hiperplasia Prostática/tratamiento farmacológico , Animales , División Celular/efectos de los fármacos , Ensayos Clínicos Fase II como Asunto , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Orquiectomía , Próstata/patología , Hiperplasia Prostática/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Ratas Sprague-Dawley , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
BACKGROUND: Several studies reported data on the increased risk of erectile dysfunction (ED) in populations of diabetic men, but few presented data separately for Type 1 and Type 2 subjects. No comparison data for these diabetic subgroups are available with regard to risk factors for ED. METHODS: Eligible for the study were men aged 20-69 years with a diagnosis of insulin-dependent (Type 1) or non-insulin-dependent (Type 2) diabetes who were observed on randomly selected days in 178 diabetes centres in Italy. Erectile dysfunction was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance. RESULTS: The study population consisted of 1383 Type 1 and 8373 Type 2 men. The prevalence of ED increased with age for both groups. After taking into account the effect of age Type 2 men (37/100 men) tend to report ED less frequently than Type 1 men (51/100 men). A significant positive relationship was reported between ED and poor metabolic control and smoking for both Type 1 and Type 2 men, whereas high body mass index (BMI) increased only the risk of ED in Type 1 cases. CONCLUSIONS: The study offers a quantitative estimate of the prevalence of ED and its main risk factors in Type 1 and Type 2 diabetic subgroups.
Asunto(s)
Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Disfunción Eréctil/etiología , Adulto , Anciano , Estudios Transversales , Disfunción Eréctil/epidemiología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
PURPOSE: MMDX [3'-deamino-3'-[2(S)-methoxy-4-morpholinyl] doxorubicin], an anthracycline derivative active in vitro and in vivo against multidrug-resistant tumors, is currently under investigation in phase I clinical trials. In vivo it is metabolically activated, resulting in more cytotoxic compounds. We determined in vitro the toxic concentration of a 1-h period of exposure to doxorubicin (DX), MMDX, and bioactivated MMDX on hematopoietic progenitors and tumor cell lines. METHODS: DX and MMDX were tested on both bone marrow- (BM) and cord blood (hCB)-derived clonogenic cells, whereas the metabolites were tested on hCB only. All substances were tested on seven tumor cell lines. RESULTS: BM cells proved to be twice as sensitive as hCB cells to cytotoxics, and MMDX was twice as toxic as DX against hCB cells; MMDX activated with normal rat-liver microsomes and with dexamethasone-induced rat microsomes were, respectively, 70 and 230 times more toxic than MMDX. A comparison of the cytotoxic concentrations on hematopoietic progenitors and tumor cells, revealed that DX and MMDX had 5-fold stronger activity on tumor cell lines than on granulocyte/macrophage colony-forming cells (GM-CFCs), whereas bioactivated MMDX showed comparable cytotoxicity against tumor cells and hematopoietic progenitors. CONCLUSIONS: MMDX metabolites are very potent but display a lower degree of tumor selectivity than MMDX. Strategies to reduce MMDX metabolization should be developed to optimize the therapeutic index of this new anthracycline.