Intermittent low-dose finasteride is as effective as daily administration for the treatment of hirsute women

In a prospective randomized study 38 women with idiopathic hirsutism or polycystic ovary syndrome (PCOS) received 2.5 mg of finasteride every day or every 3 days. Intermittent low-dose administration of finasteride was as effective as continuous administration in reducing hirsutism score and was accompanied by a lower incidence of side effects.     

Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients

BACKGROUND: Guidelines for treating anemia in dialysis patients accept, as high-end range of serum ferritin useful to optimize erythropoietin therapy, values high as 500 to 900 microg/L, on the hypothesis that ferritin might be not representative of iron overload. METHODS: A superconducting quantum interference device (SQUID) was used to make direct noninvasive magnetic measurements of nonheme hepatic iron content in 40 dialysis patients treated with intravenous iron, and liver iron content was compared with biochemical markers of iron status. RESULTS: Only 12/40 (30%) patients showed normal hepatic iron content (SQUID <400 microg/g), while 32.5% had mild (400 to 1000 microg/g) and 37.5% severe (>1000 microg/g) iron overload, although 28/40 patients (70%) had serum ferritin below 500 microg/L. Among many parameters, hepatic iron content was only correlated with ferritin (r= 0.324, P= 0.04). The receiver operating characteristic (ROC) analysis showed the best specificity/sensitivity ratio to identify iron overload for ferritin >340 microg/L (W = 0.716). Multivariate logistic regression analysis demonstrated that an increase in serum ferritin of 100 microg/L and female gender were independent variables associated with moderate to severe hepatic iron overload: OR 1.71 (95% CI 1.10 to 2.67) and OR 10.68 (95% CI 1.81 to 63.15), respectively. CONCLUSION: Hepatic iron overload is frequent in dialysis patients with ferritin below currently proposed high-end ranges, and the diagnostic power of ferritin in indicating true iron stores is better than presumed. Safety concerns should prompt a reevaluation of acceptable iron parameters, focusing on potential gender-specific differences, to avoid potentially harmful iron overload in a majority of dialysis patients, mainly females.     

Males with subnormal hypo-osmotic swelling test scores have lower pregnancy rates than those with normal scores when ovulation induction and timed intercourse is used as a treatment for mild problems with sperm count, motility, or morphology

This study was designed to evaluate the effectiveness and clinical usefulness of the hypo-osmotic swelling (HOS) test in predicting successful conception in couples in which men with mild male-factor infertility criteria were undergoing a timed vaginal inter-course protocol. One hundred couples, in which mild male infertility was the only abnormality, were included in the study. Semen was analyzed according to standard World Health Organization (WHO) criteria and subjected to the HOS test. Patients were divided into 2 groups: group 1 (n=39) with normal HOS test and group 2 (n=61) with abnormal HOS test. All women underwent three consecutive cycles of follicular growth ultrasound monitoring and timed intercourse. Ten couples were exclude from the study. Ten clinical pregnancies were achieved in group 1 with a pregnancy rate per patient and per cycle of 28.5% and 9.5%, respectively. In group 2, 6 pregnancies were achieved, with a pregnancy rate per patient and per cycle of 10.9% and 3.6%, respectively. Both pregnancy rates per patients and per cycle was significantly higher (P <.05) in group 1 than in group 2. The HOS test may be considered an easy and reliable test in identifying among subfertile men those who have a greater possibility of causing pregnancy.     

Homocysteine metabolism in renal failure

PURPOSE OF REVIEW: This review focuses on recent findings (June 2002-July 2003) on the topic of homocysteine, a sulfur amino acid associated with cardiovascular disease, and its metabolism in renal failure, a condition with a high prevalence of both hyperhomocysteinemia and cardiovascular disease. RECENT FINDINGS: A large meta-analysis of prospective studies in the general population established that hyperhomocysteinemia is a risk factor for cardiovascular disease. The results of intervention trials, once available, will also have to be tested in a meta-analysis, because of predicted problems with their statistical power. In kidney patients, intervention trials, still in the recruiting stage, target transplant patients, because of their unique characteristics related to folate responsiveness. As for the cause of hyperhomocysteinemia, new findings show that in humans, renal metabolic extraction depends on renal plasma flow in the post-absorptive state. Folate absorption or interconversion seems not to be affected. Riboflavin is a determinant of plasma homocysteine levels in uraemia. The consequences of hyperhomocysteinemia in uraemia are DNA hypomethylation and altered gene expression. SUMMARY: The causes of hyperhomocysteinemia in renal failure are still not clear. However, the possibilities include defective renal or extrarenal metabolism as a result of uraemic toxicity. Renal plasma flow is important in homocysteine renal metabolism. Among the consequences of hyperhomocysteinemia in renal failure are impaired protein and DNA methylation, with an alteration in the allelic expression of genes regulated through methylation. Intervention trials are under way to test whether hyperhomocysteinemia is causally related to cardiovascular disease in this patient population.     

New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse

The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.     

t(10;16)(q22;p13) and MORF-CREBBP fusion is a recurrent event in acute myeloid leukemia

Recently, it was shown that t(10;16)(q22;p13) fuses the MORF and CREBBP genes in a case of childhood acute myeloid leukemia (AML) M5a, with a complex karyotype containing other rearrangements. Here, we report a new case with the MORF-CREBBP fusion in an 84-year-old patient diagnosed with AML M5b, in which the t(10;16)(q22;p13) was the only cytogenetic aberration. This supports that this is a recurrent pathogenic translocation in AML.     

Outpatient Parenteral Antibiotic Therapy (OPAT): the Italian registry

In the early eighties, in the US the advantages (reduced costs, no hospitalisation trauma in children, no immobilization syndrome in elderly, reduction of nosocomial and acquired infections by multi-resistant organisms) of OPAT were identified and suitable therapeutic programs were established. Following the US experience, other countries set up their own OPAT programs which vary considerably from country to country because of different ways in which infections are managed in different parts of the world and because of different reimbursement systems. In order to understand the ways of managing OPAT and its results, a National OPAT Registry was set up in 1999 in Italy belonging to a wider International OPAT database, which collects data also from USA, Canada, Spain, Uruguay and Argentina. Up to now 396 patients and as many antibiotic courses have been included in the National Registry by eight different centres. The analysis of data permits to get information about the criteria of patient's selection, treatment (route of administration, site of care, choice of antibiotic, dosage and duration), outcomes and possible side-effects. Italian results offer a quite peculiar picture of OPAT in this country when comparing data with those of other countries. In contrast with other countries where soft tissue infections and osteomyelitis are the most frequent diagnoses for including patients in OPAT programmes, in Italy pneumonia and bronchitis are the top two amenable infections. Ceftriaxone, Teicoplanin and Amikacin are absolutely the top three antibiotics selected for OPAT in Italy which confirm that a single daily dose regimen represents a great advantage in terms of compliance. Finally, a large percentage of antibiotic courses (50%) are carried out by using the i.m. administration route, which is very unusual in other countries. OPAT Registry is still ongoing and it will give us more detailed information in the future about the management of infections in the outpatient setting, but it already permits to define an actual picture of OPAT in our country and/or to compare and correlate data and information from different countries.     

Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds

Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (INa) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position alpha [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or beta [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a proline-like cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). INa were elicited with pulses to -20 mV from different holding potentials (-140, -100, and -70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3- and 10-fold more effective than Toc in blocking INa at the holding potential of -140 and -70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 >/= Benzyl-Toc > Benzyl-To5. At a holding potential of -100 mV and 10-Hz stimulation, Benzyl-To9 blocked INa with a half-maximal concentration of 0.5 microM, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pKa value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.     

Interactive role of adenosine and dopamine in the opiate withdrawal syndrome

Adenosine reduces opioid withdrawal symptoms by activating A₁ adenosine receptors, probably by inhibiting excitatory amino acid release. Since blockade of A_2A adenosine receptors seems to enhance dopaminergic striatopallidal transmission, we evaluated the role of the purinergic system in the opiate withdrawal syndrome by using two A₁ receptor agonists [N⁶-cyclohexyladenosine, CHA and 2-chloro-N⁶-cyclopentyladenosine, CCPA], and two A_2A receptor antagonists (SCH 58261 and 8-(3-chlorostyryl)caffeine, CSC).Male adult rats received increasing doses of morphine sulphate suspended in 5 ml/kg of a sustained release preparation (40–100 mg/kg s.c.) daily for 4 days and 20 h after the last administration, the withdrawal syndrome was evoked by naloxone (5 mg/kg i.p.). Animals were observed for 30 min for signs of opiate withdrawal. Other groups of rats were implanted with concentric probes for microdialysis and dopamine levels were measured in the nucleus accumbens. CHA and CCPA (0.05, 0.1 or 0.5 mg/kg i.p.) significantly reduced "wet-dog" shakes, diarrhoea, teeth chattering, jumping and writhing. SCH 58261 and CSC (0.1, 0.5 or 1 mg/kg i.p.), given 10 min before naloxone, also reduced signs of opiate withdrawal. CHA plus SCH 58261 and CCPA plus CSC greatly enhanced the reduction of withdrawal signs observed with CHA and CCPA or CSC and SCH 58261 alone. In vivo microdialysis showed that naloxone significantly decreased DA release; this effect was prevented by pretreatment with systemic SCH 58261 and CSC, but not with CHA and CCPA. Our results demonstrate that A₁ and A_2A adenosine receptors mediate the effect induced by adenosine in opiate withdrawal syndrome and suggest that adenosine A₁ agonists and adenosine A_2A antagonists may be beneficial in the treatment of this syndrome.L. Stella and V. de Novellis share first authorship