[Relation between hypogonadism and malocclusion in beta-thalassemia major patients: analysis of 122 subjects]. / Relazione tra ipogonadismo e malocclusione dentaria in pazienti affetti da beta-talassemia major. Studio su 122 pazienti.

AIM: The type of malocclusion most often seen in beta thalassemic patients is represented by Angle's II class, which however cannot be considered significant in the patients studied in this research. The only causal factor indicated by medical literature for this pathology is medullary hyperplasia due to inefficient erythropoiesis which occurs in patients transfused at low hemoglobin levels. The aim of this research is to evaluate the influence of other factors as well, particularly sexual development, the level of seric ferritin, ALT, and age at first transfusion. METHODS: One-hundred and twenty-two b thalassemic patients and 39 homozygotes, aged between 16 and 27, undergoing treatment at the "Ospedale Regionale per le Microcitemie di Cagliari", have been analysed. RESULTS: The results of the statistic analysis have shown that hypogonadism can play an important role in determining malocclusions in male beta thalassemic patients (Odds ratio 4,5; CI 1,5-13). No other factor has shown any statistically relevant influence on dental occlusion. CONCLUSION: It would therefore be interesting to further investigate the hormonal mechanisms that can alter bone development in thalassemic youngsters: the prevention of such alterations will surely contribute to improving the quality of life in these patients, particularly now that their life expectancy has been significantly extended by the progress made in transfusional therapy and ferrochelation.

Complexation of zolpidem with 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin: effect on aqueous solubility, dissolution rate, and ataxic activity in rat.

The effect of some chemically modified cyclodextrins [namely, 2-hydroxypropyl-beta-, methyl-beta-, and 2-hydroxypropyl-gamma-cyclodextrin (HP-beta-CD, Me-beta-CD, and HP-gamma-CD, respectively)] on the aqueous solubility and dissolution rate of the hypnotic agent Zolpidem (ZP) was investigated. Solid complexes were prepared by freeze drying and characterized by infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. The solubility and dissolution rate of the drug were significantly improved by complexation with HP-beta-CD or Me-beta-CD. The structure of the inclusion complex ZP-HP-beta-CD in CH(3)COOD/D(2)O was investigated by (1)H and (13)C NMR spectroscopy, including NOE measurements. These measurements revealing a weak interaction between the tolyl moiety of the guest molecule and the HP-beta-CD cavity. The ataxic activity in rat was also investigated and it was found that ZP-HP-beta-CD and ZP-Me-beta-CD complexes showed almost 2-fold longer ataxic induction times than controls.

Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain.

The effects of social isolation on behavior, neuroactive steroid concentrations, and GABA(A) receptor function were investigated in rats. Animals isolated for 30 days immediately after weaning exhibited an anxiety-like behavioral profile in the elevated plus-maze and Vogel conflict tests. This behavior was associated with marked decreases in the cerebrocortical, hippocampal, and plasma concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone compared with those apparent for group-housed rats; in contrast, the plasma concentration of corticosterone was increased in the isolated animals. Acute footshock stress induced greater percentage increases in the cortical concentrations of neuroactive steroids in isolated rats than in group-housed rats. Social isolation also reduced brain GABA(A) receptor function, as evaluated by measuring both GABA-evoked Cl(-) currents in Xenopus oocytes expressing the rat receptors and tert-[(35)S]butylbicyclophosphorothionate ([(35)S]TBPS) binding to rat brain membranes. Whereas the amplitude of GABA-induced Cl(-) currents did not differ significantly between group-housed and isolated animals, the potentiation of these currents by diazepam was reduced at cortical or hippocampal GABA(A) receptors from isolated rats compared with that apparent at receptors from group-housed animals. Moreover, the inhibitory effect of ethyl-beta-carboline-3-carboxylate, a negative allosteric modulator of GABA(A) receptors, on these currents was greater at cortical GABA(A) receptors from socially isolated animals than at those from group-housed rats. Finally, social isolation increased the extent of [(35)S]TBPS binding to both cortical and hippocampal membranes. The results further suggest a psychological role for neurosteroids and GABA(A) receptors in the modulation of emotional behavior and mood.

Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions.

The thienobenzodiazepine derivative etizolam (CAS 40054-69-1, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo-(3,4-c)thienol(1 ,4) diazepine) is a potent anxiolytic with a pharmacological profile similar to that of classical benzodiazepines. In order to rationalize the therapeutic use of etizolam, its pharmacodynamics properties on GABAA receptors were investigated by a comparative study with other ligands on human recombinant GABAA as well as rat brain native receptors. Etizolam inhibited in a concentration-dependent manner [3H]flunitrazepam (CAS 1622-62-4) binding to rat cortical membranes, with an affinity of 4.5 nmol/l greater than that of alprazolam (CAS 28981-97-7) (7.9 nmol/l). Ethizolam enhanced GABA-induced Cl- currents in oocytes expressing human cloned GABAA receptors. With alpha 1 beta 2 gamma 2S subunit combination, etizolam produced a 73% increase in GABA-induced currents with an EC50 of 92 nmol/l. At the same receptor type, alprazolam showed a higher degree of potentiation and potency (98%, EC50 56 nmol/l). At alpha 2 beta 2 gamma 2S or alpha 3 beta 2 gamma 2S subunit constructs, the effects of etizolam were similar to those of alprazolam. Flumazenil (CAS 78755-81-4) completely blocked both etizolam and alprazolam effects on GABA-induced currents. Etizolam, administered i.p., was uneffective in changing ex vivo t-[35S]butylbicyclophosphorothionate ([35S]-TBPS) binding to rat cerebral cortex, whereas alprazolam and abecarnil (CAS 111841-85-1) significantly reduced this parameter. However, etizolam similarly to abecarnil and alprazolam, antagonized isoniazid-induced increase (61%) in [35S]-TBPS binding to rat cortical membranes. Further, etizolam inhibited in a dose-dependent manner basal acetylcholine release from both hippocampus and prefrontal cortex, and reversed foot-shock-induced increase of basal acetylcholine release to a control level. Altogether, these results suggest that etizolam may have a reduced intrinsic activity, at least at specific subpopulations of GABAA receptors. This property, together with the pharmacokinetic indication of a short-acting drug, may characterize etizolam as a ligand endowed with less side-effects typical of full agonits such as diazepam (CAS 439-14-5) and alprazolam. Finally, given its marked efficacy under conditions of GABAergic deficit, etizolam may represent a possible drug of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.

Synthesis and binding affinity of 2-phenylimidazo[1,2-alpha]pyridine derivatives for both central and peripheral benzodiazepine receptors. A new series of high-affinity and selective ligands for the peripheral type.

A number of 6-substituted or 6,8-disubstituted alkyl 2-phenylimidazo[1,2-alpha]pyridine-3-carboxylates 5a-h, -acetates 5i-s, 6a-g, and -propionates 5t, 6h and of N,N-dialkyl-2-phenylimidazo[1,2-alpha]pyridine-3-carboxamides 7a-d,-acetamides 7e-t or -propionamide 7u were prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PBR) benzodiazepine receptors evaluated. The compounds of the ester series displayed low affinity for both receptor types. Conversely, most of N,N-dialkyl(2-phenylimidazo[1,2-alpha]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR depending on the nature of substituents at C(6)- and/or C(8) on the heterocyclic ring system. In particular, the 6-substituted compounds 7f-n displayed ratios of IC50 values (IC50(CBR)/IC50(PBR)) ranging from 0.32 (7m) to 232 (7k), while the 6,8-disubstituted compounds 7o-t were more than 1000-fold more selective for PBR versus CBR. Compounds 7f,m were examined in several different benzodiazepine receptor subtypes. Expression of specific GABAA, receptor subunit assemblies in Xenopus oocytes was utilized to evaluate functionally both the efficacy and potency of the positive modulation of GABA-evoked Cl- currents by 7f and 7m in comparison with Zolpidem. The rank order of potencies of these drugs was 7f (EC50 = 3.2 x 10(-8) M) > Zolpidem (EC50 = 3.6 x 10(-8) M) > 7m (EC50 = 2.2 x 10(-7) M). The actions of these compounds were also tested on alpha 2 beta 2 gamma 2s, receptors. However, the EC50 of these compounds was increased, compared to alpha 1 beta 2 gamma 2s receptors, by 30-, 4-, and 5-fold for 7m, 7f, and Zolpidem, respectively. Finally, these compounds were almost completely devoid of activity at receptors containing the alpha 5 subunit.

Effect of tibolone on glucose and lipid metabolism in postmenopausal women.

The effect of tibolone, a new therapeutic agent for menopause, on glucose and lipid metabolism was investigated in 11 healthy postmenopausal women. At baseline and after 3 months of tibolone administration (2.5 mg/day), glucose metabolism was evaluated in each subject using both an oral glucose tolerance test (75 g) and the minimal model method of a frequently sampled intravenous glucose tolerance test. Frequently sampled intravenous glucose tolerance test allows the calculation of insulin sensitivity and peripheral glucose use independent of insulin. High-density lipoprotein-cholesterol, total cholesterol, apoprotein-A, and apoprotein-B measured in fasting conditions were not modified by tibolone, whereas triglycerides were reduced significantly (P < 0.01). Fasting levels of glucose were reduced significantly (P < 0.025), whereas those of insulin, C-peptide, and the C-peptide/insulin ratio were not modified. Glucose, insulin, C-peptide, and the C-peptide/insulin ratio responses to oral or iv glucose were not modified. Insulin sensitivity was inversely correlated to body mass index, and independent on that body mass index was significantly enhanced (P < 0.01). Glucose utilization independent of insulin was not modified. The present data indicate that tibolone does not negatively influence glucose metabolism and may indeed improve both the peripheral tissue sensitivity to insulin and the lipid profile.

The effect of transdermal 17-beta-estradiol on glucose metabolism of postmenopausal women is evident during the oral but not the intravenous glucose administration.

OBJECTIVES: To evaluate the effect of transdermal 17-beta-estradiol (50 micrograms/day) on glucose metabolism of postmenopausal women. STUDY DESIGN: A frequently sampled intravenous glucose tolerance test (FSIGT), to calculate insulin sensitivity (SI) and peripheral glucose utilization independent of insulin (SG), and an oral glucose tolerance test (75 g; OGTT), were performed in nine postmenopausal women prior to, and after 2 months of, treatment. RESULTS: Estradiol decreased insulin and increased the C-peptide/insulin ratio both during fasting (P < 0.02) and OGTT (insulin levels, P < 0.01; C-peptide/insulin ratio, P < 0.05), but not FSIGT. Glucose levels, C-peptide levels, SI and SG were not affected. CONCLUSIONS: In spite of unmodified SI, the reduction of insulin levels and the increase of the C-peptide/insulin ratio, observed during fasting and OGTT, support a beneficial effect of estradiol on glucose metabolism. This effect probably requires the interplay of estradiol with gastrointestinal factors.

Prolonged opioid blockade does not influence luteinizing hormone modifications of the follicular and luteal menstrual phases.

Although an acute opioid withdrawal markedly modifies LH secretion in the different phases of the menstrual cycle, whether a sustained opioid blockade imbalances spontaneous LH modifications associated with the progression of the follicular or luteal menstrual phases is presently unknown. Accordingly, normal cycling women during either the follicular (n = 14) or luteal (n = 14) menstrual phase, randomly and in double blind fashion, received either placebo (n = 7 for each phase) or 50 mg/day of the oral opioid antagonist naltrexone (n = 7 for each phase). In each subject, LH pulsatility (10-min blood drawing for 8 h) and the pituitary LH response to a 10-micrograms GnRH stimulus were investigated at baseline and on the fifth day of placebo/naltrexone administration. In the follicular phase, after placebo treatment, the number and amplitude of LH pulses did not significantly vary, whereas mean LH levels (P < 0.01) and the LH response to GnRH (P < 0.05) were significantly increased. The same occurred after naltrexone treatment, when significant increases in both mean LH levels (P < 0.02) and LH response to GnRH (P < 0.025) were observed. In the luteal phase, after placebo administration, the frequency of LH pulses and mean LH levels were not modified, but both the amplitude of LH pulses (P < 0.025) and the LH response to GnRH were reduced (P < 0.02). The same occurred after naltrexone treatment, when significant decreases in both the amplitude of LH pulses (P < 0.05) and the LH response to GnRH (P < 0.05) were observed. During both phases of the menstrual cycle, the modifications observed during naltrexone treatment were similar and not significantly different from those observed during placebo. The present data do not support important modulatory functions for endogenous opioid peptides on spontaneous LH modifications occurring with the progression of the follicular or the luteal menstrual phases.