Monitoring testosterone replacement therapy with transdermal gel: when and how?

PURPOSE: Testosterone replacement therapy (TRT) is recommended for the treatment of most cases of male hypogonadism. Transdermal testosterone (T) gels are commonly used in clinical practice; however, there is little evidence concerning how to monitor dosage to bring and maintain serum T levels in the normal physiologic range. METHODS: We examined 30 hypogonadal patients undergoing treatment with 40 mg/day transdermal 2% testosterone gel. After a week from treatment onset, all patients underwent a total of four measurements to assess serum total T, bioavailable T and free T at + 2 h (samples A and A') and + 23 h (samples B and B'). RESULTS: No significant difference was found concerning total, free and bioavailable T between the two samples taken at the same time points (A vs A' and B vs B'). A repeated-measures mixed effects regression model showed significantly lower serum levels of total, free and bioavailable T at + 23 h compared to + 2 h (total T, ß = - 3.050 ± 0.704, p < 0.001; free T, ß = - 85.187 ± 22.746, p < 0.001; bioavailable T, ß = - 1.519 ± 0.497, p = 0.003) without a significant between-sample variability. Serum T > 3.5 ng/ml at + 2 h was reached in 21/30 patients (70%), but only 11 (36.7%) still had adequate serum T at + 23 h. CONCLUSION: Assessment of TRT with transdermal gels at its peak and at its minimum could be useful in providing a finely tailored treatment for hypogonadal men, both preventing supra-physiological levels and maintaining adequate concentrations through the day.

Psychopathology of first-episode psychosis in HIV-positive persons in comparison to first-episode schizophrenia: a neglected issue.

This study aims to detect different psychopathological dimensions in first-episode psychoses with different underlying causes. We evaluated 22 subjects with first-episode psychosis, who differed in biological variables (HIV-positive versus HIV-negative) and who were compared by using the Structured Clinical Interview for DSM-III-Reviewer, the 18-item Brief Psychiatric Rating Scale (BPRS), the 17-item Hamilton Depression Rating Scale, the 14-item Hamilton Anxiety Rating Scale and the Mini-Mental State Examination. HIV-positive subjects had higher mean scores on the global BPRS and on the paranoid Positive and Negative Syndrome Scale subscale compared with HIV-negative subjects. Conversely, higher prevalence of affective and anxious symptoms was found in the HIV-negative patients in comparison to HIV-positives. HIV-positives had significantly greater attention/concentration impairment than HIV-negative persons. In conclusion, taking into account psychopathological dimensions may help psychiatrists in clinical decision-making regarding the differential diagnosis of psychotic symptoms. The psychopathological pattern of first-episode psychosis in HIV-positive patients may represent an 'elementary model' of acute psychosis characterized by paranoid delusions in the absence of the usual affective symptoms.

Changes in residual volume during induced bronchoconstriction in healthy and asthmatic subjects.

The increase of residual volume (RV) was investigated during acute bronchoconstriction induced in healthy subjects by methacholine (MCh) (Group 1, n = 13) and in asthmatics by MCh (Group 2, n = 21), or housemite dust (Group 3, n = 11) during early and late airway responses (EAR and LAR), or a series of deep breaths (Group 4, n = 7). In all subjects the difference between residual volume after partial (RVp) and maximal maneuver (RV), expressed as a percentage of control FVC, increased during bronchoconstriction and was correlated with the percent increase of maximal to partial flow ratio at 50% of control FVC (M/P50) (r = 0.854, p < 0.0001). At comparable reduction of partial expiratory flow at 50% of control FVC (VP50), the decreases of FEV1 and FVC were less in healthy than asthmatic subjects, whereas the change of FEV1/FVC was similar in all groups, reflecting similar change in slope of flow-volume curves. The increase of RVp was similar in all groups (range: 15 to 19%), but the increase of RV was 6 +/- 1% (SEM) in healthy subjects and significantly greater (range: 11.1 to 13.3%) in all groups of asthmatics (p < 0.02, analysis of variance [ANOVA]). The effect of deep inhalation (DI) on the airway caliber as assessed by the increase of M/P50 was higher in normal subjects than in all groups of asthmatics (p < 0.0001). A negative correlation was found between the increases of RV and M/P50 in all groups (r = -0.358, p < 0.01), suggesting that healthy subjects had a limited increase of RV because of a marked bronchodilator effect of DI.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of aminophylline and salbutamol to improve respiratory muscle function and exercise tolerance in healthy humans.

We investigated the effects of intravenously administered aminophylline (A; 6 mg/kg over 20 min, followed by 0.9 mg/kg/h), salbutamol (S; 4 micrograms/kg over 20 min, followed by 3 micrograms/kg/h) and placebo (P; saline solution) on the strength of the respiratory muscles, the ventilatory endurance and the exercise tolerance in 7 healthy humans. Neither A nor S caused bronchodilation, as shown by the lack of change in FEV1. The strength of respiratory muscles, as measured by maximal inspiratory pressure (MIP), and the ventilatory endurance, as measured by sustainable inspiratory pressure (SIP), were not statistically different after A (MIP: 136.5 +/- SE 11.6 cm H2O; SIP: 104.2 +/- 8.4 cm H2O or after S (MIP: 135.7 +/- 11.5; SIP: 107.1 +/- 10.4) compared to after P (MIP: 127.1 +/- 10.1; SIP: 105.0 +/- 5.9). Significant changes in 12-min walking distance, perceived exertion rate, anaerobic threshold, maximal work output, maximal O2 uptake were observed neither after A nor after S. The exchange ratio and heart rate were higher after A and S than after P at some steps of a progressive, symptom-limited, treadmill-based exercise test. This might be the result of metabolic or cardiovascular adaptations elicited by these drugs. We conclude that A or S at therapeutic concentrations have no clinically relevant beneficial effects on ventilatory muscle function and exercise tolerance in healthy subjects.

Anti-inflammatory agents: determination of ibuproxam and its metabolite humans. Correlation between bioavailability, tolerance and chemico-physical characteristics.

A study on absorption and elimination in the urine of 2-(4-isobutylphenyl)-propiohydroxamic acid (ibuproxam, Ibudros) (400 mg film tablets) after administration to healthy volunteers is reported. In the plasma, only a minimum concentration of ibuproxam as such could be found: instead its chief metabolite ibuprofen mainly present, with top peaks at 45 min. The maximum ibuprofen concentration in the plasma--when obtained through metabolization of ibuproxam--is significantly higher than after administration of an equal dose of ibuprofen. This phenomenon is related to the chemico-physical characteristics of the two compounds.

Ibuproxam and ibuprofen. A pharmacological comparison.

The anti-inflammatory, analgesic and antipyretic effects and the tolerability of 2-(4-isobutylphenyl)-propionic acid (ibuprofen) were compared with those of its derivative 2-(4-isobutylphenyl)-propiohydroxamic acid (ibuproxam, Ibudros. Our experiments show that the interfering action of the two drugs with the reactive processes of the tibio-tarsic articulation, brought about by carrageenin, serotonin, dextrane and formalin is of the same intensity. Also, the analgesic activity is perfectly consistent with the antipyretic one. However, the tolerability of the two molecules is different; the acute toxicity is consistent in the case of the single parenteral administration and it differs in the case of a single or repeated oral treatment. When used under these conditions, ibuproxam is considerably less damaging to the gastroenteric tube than is ibuprofen. The hypothesis is put forth that the greater tolerability of ibuproxam is due to its pharmacokinetics: it is, as such, little or not toxic for the mucous membrane of the digestive apparatus, and it progressively releases ibuprofen, whose concentrations in the blood would remain below those levels that cause systemic lesions in the gastroenteric tract.

Determination of ibuproxam and its metabolites in the plasma and urine of rats.

The metabolism of 2-(4-isobutylphenyl)-propio-hydroxamic acid (ibuproxam, Ibudros), a new molecule with anti-inflammatory, antipyretic and analgesic activity was studied by its administration orally and rectally to the rat. The analysis, carried out with gas chromatographic method and thin-layer chromatography, showed that the drug is present in blood as 2-(4-isobutylphenyl)-propionic acid (ibuprofen), an anti-inflammatory drug which is commonly used and the metabolites of which are already known. Using the same methods, it was observed that only a few traces of the hydroxamic acid appear in the urines of rats treated with ibuproxam, whilst the ibuprofen metabolite is absent. Therefore, we conclude that the drug ibuproxam changes rapidly into ibuprofen, following afterwards the same known metabolic process as the latter drug.

Chemistry and pharmacology of arginine pyroglutamate. Analysis of its effects on the CNS.

By studying the influence of the arginine pyroglutamate on the CNS its variations were evidenced which are clearly identifiable through the analysis of the interaction with molecules having either a depressive or excitatory action. In the case of pentobarbital the antagonistic effect of the compound on the general anaesthesia is very intense and is equally present even when medazepam and flurazepam are associated. Equally obvious is the antagonism with barbiturate in the case of spontaneous motility but much less so with the two benzodiazepines. As far as the specialized behaviour is concerned, arginine pyroglutamate does not alter the sound discrimination capacity (responses in Sdelta punished) at fixed intervals (F.I.) nor does it influence the learning of a sound discrimination (responses in Sdelta punished) at varied intervals (V.I.). The process of learning is instead moderately accelerated in the case of a temporal discrimination and of a conditioned avoidance response (CAR) in the shuttle-box. No effect was found when the same amino acids were introduced alone or in random association. The hypothesis is proposed that the phenomena described depend on the different pharmacokinetics of arginine pyroglutamate that ensures brain concentrations sufficient to block the activity of depressive compounds but is not capable of influencing in a significant way the spontaneous and specialized behaviour of normal animals.

[Some new derivatives of aromatic oximes with beta-blocking activity]. / Su alcuni nuovi derivati di eteri di ossime aromatiche con attività beta-bloccante

Because of the great importance assumed by beta-blocking agents in recent years, some new derivatives of aromatic oxime ethers, in the syn form, have been synthesized, having the following general structure: The above compounds were obtained by two different methods designed to demonstrate their structure. The results of some pharmacological tests are also reported, in order to give an indication of the real activity of the new compounds synthesized.