Co-trimoxazole effect on human alveolar macrophages of AIDS patients.

Compelling evidence suggests that co-trimoxazole prophylaxis reduces mortality in HIV-infected patients, although it is unclear whether these effects are directly related to antimicrobial activities. We evaluated in vitro phagocytosis and killing of Staphylococcus aureus in alveolar macrophages (AM) obtained from AIDS patients who smoke, treated (n=19) or not treated (n=13) with co-trimoxazole, as compared to non-HIV-infected healthy smokers (n=15). Phagocytosis and killing of Staphylococcus aureus by AM obtained from non-co-trimoxazole treated AIDS patients were significantly lower compared to non-HIV-infected healthy smokers. In contrast, AIDS patients treated with co-trimoxazole prophylaxis showed phagocytosis and killing levels similar to those of healthy controls. These results might help to clarify the observed positive effect of co-trimoxazole on survival in HIV-infected patients.

Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome.

OBJECTIVE: To reverse the profile of abnormal intracortical excitability in patients with restless legs syndrome (RLS) by administering the dopaminergic agonist cabergoline. METHODS: The effects of this drug on motor cortex excitability were examined with a range of transcranial magnetic stimulation (TMS) protocols before and after administration of cabergoline over a period of 4 weeks in 14 patients with RLS and in 15 healthy volunteers. Measures of cortical excitability included central motor conduction time; resting and active motor threshold to TMS; duration of the cortical silent period; short latency intracortical inhibition (SICI) and intracortical facilitation using a paired-pulse TMS technique. RESULTS: Short latency intracortical inhibition was significantly reduced in RLS patients compared with the controls and this abnormal profile was reversed by treatment with cabergoline; the other TMS parameters did not differ significantly from the controls and remained unaffected after treatment with cabergoline. Cabergoline had no effect on cortical excitability of the normal subjects. CONCLUSIONS: As dopaminergic drugs are known to increase SICI, our findings suggest that RLS may be caused by a central nervous system dopaminergic dysfunction. This study demonstrates that the cortical hyperexcitability of RLS is reversed by cabergoline, and provides physiological evidence that this dopamine agonist may be a potentially efficacious option for the treatment of RLS.

Transcranial magnetic stimulation shows impaired transcallosal inhibition in Marchiafava-Bignami syndrome.

A case of Marchiafava-Bignami (MB) syndrome with selective callosal involvement was evaluated by clinical examination and magnetic resonance imaging (MRI) in the acute phase and 6 months after the onset of symptoms; at the same time, the corticospinally and transcallosally mediated effects elicited by transcranial magnetic stimulation (TMS) were investigated. The first MRI study showed the presence of extensive abnormal signal intensity throughout the entire corpus callosum. After high-dose corticosteroid administration her symptoms rapidly resolved, in parallel with the reversion of MRI changes, except for severe cognitive impairment. Follow-up TMS examination revealed persistent transcallosal inhibition (TI) abnormalities. This report indicates that the measurement of TI during the course of MB syndrome is useful for evaluating functional changes to the corpus callosum, including their evaluation with time and after treatment and for elucidating the pathophysiology of MB syndrome.

Transient ischaemic attacks in two cases of internal carotid artery hypoplasia.

Congenital anomalies of the internal carotid arteries (ICA) and cerebral arteries have not been frequently reported. Moreover, in the literature there is no clear association between hypoplastic carotid and cerebral vessel systems and the occurrence of cerebral ischaemia. We report two cases of unilateral hypoplasia of the ICA affecting two young patients suffering from an episode of minor stroke and from recurrent transient ischaemic attacks, respectively. Congenital variations in the configuration and size of the carotid and cerebral arteries should not always be considered benign conditions and may predispose to cerebral ischaemia in young adults.

Changes in motor cortical excitability in humans following orally administered theophylline.

The effects of theophylline on human corticospinal excitability were studied using transcranial magnetic stimulation (TMS) before and after double-blind oral administration of theophylline or placebo in 20 healthy volunteers. TMS measurements included resting and active motor threshold, silent period, intracortical inhibition (ICI), and intracortical facilitation. F-wave and compound muscle action potential (CMAP) were also measured. Theophylline produces a reduction in ICI, while other parameters of corticospinal excitability remained unaffected. Since ICI is thought to depend on GABAA intracortical inhibitory mechanisms, our data suggest that the increase of human motor cortex excitability is the result of a decrease in GABAergic transmission. Our results further support the hypothesis that theophylline might induce convulsions by inhibiting GABAA receptor binding.

Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis.

Multidrug-resistant (MDR) tuberculosis (TB) is a form of TB that is resistant to some of the first-line drugs used for the treatment of the disease. It is associated both with a higher incidence of treatment failures and of disease recurrence, as well as with higher mortality than forms of TB sensitive to first-line drugs. Levofloxacin (LFX) represents one of the few second-line drugs recently introduced in the therapeutic regimens for MDR TB. We report our experience concerning in vitro activity and clinical safety of LFX in long term second-line regimens for MDR TB. IN VITRO ACTIVITY ON MYCOBACTERIA: The in vitro activity of ciprofloxacin, ofloxacin and LFX was studied on 28 strains belonging to different species of Mycobacteria. In Dubos medium, LFX inhibited the growth of both library and MDR clinical Mycobacteria strains in a range of 0.25-1 mcg/ml. In International Union Tuberculosis Medium (IUTM) the minimum inhibitory concentrations (MIC) were slightly higher, but LFX activity was not affected by the higher complexity of the medium. CLINICAL EXPERIENCE: Four patients with MDR TB were treated with a second-line regimen comprising oral LFX 500 mg twice daily, for at least 9 months. Two isolates obtained from the patients reported here showed multi resistance to isoniazid and rifampin, one to rifampin and streptomycin and one to isoniazid and ethambutol. During therapy, no significant alteration of either liver function tests, blood tests or any other described side effect of the fluoroquinolone class was observed. The 3 patients with pulmonary MDR TB showed radiologic and clinical improvement. CONCLUSION: We confirm the higher in vitro activity of LFX compared to older fluoroquinolones. Furthermore, in a limited number of MDR TB patients, second-line regimens comprising LFX 500 mg b.i.d. administered in a range of 9-24 months were well tolerated and safe.

Comparison of the efficacy and safety of isepamicin and amikacin in the treatment of acute lower respiratory tract infections caused by gram-negative organisms.

In a prospective multicentre open trial, hospitalised adult patients with acute lower respiratory tract infections, mainly pneumonia or bronchitis, were randomised to receive either isepamicin 8 or 15 mg/kg once daily depending on the severity of the infection or amikacin 7.5 mg/kg twice daily. Patients with infections known to be caused by Pseudomonas aeruginosa were to be given concomitant treatment with ceftazidime. In the intent-to-treat population, i.e. patients who received at least one dose randomised treatment, a clinical cure or improvement at the end of treatment was seen in 112/125 (90%) isepamicin patients and 55/60 (92%) amikacin patients. The corresponding rates for patients with a primary diagnosis of pneumonia were 45/52 (87%) and 25/28 (89%). Cure/improvement rates for patients with P. aeruginosa as the causative pathogen (34 of whom also received ceftazidime) were 28/30 (93%) and 16/18 (89%), respectively. In the efficacy population (patients who had a valid pretreatment culture and who met other evaluability criteria), total elimination (documented or presumed if infection had resolved) of target pathogens occurred in 54/63 (86%) of isepamicin patients and 25/30 (83%) of amikacin patients. P. aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus were commonly isolated pathogens. Treatment-related adverse were mainly mild or moderate in severity and occurred in 10% of isepamicin patients and 13% of amikacin patients. Four patients (3 isepamicin and 1 amikacin) discontinued treatment because of severe adverse events and a further isepamicin patient withdrew because of a mild adverse event. Nephrotoxicity and ototoxicity occurred infrequently.

Activity of aztreonam in pneumology, Part 2: Influence on phagocytosis and intracellular killing of human alveolar macrophages.

The study aim was to evaluate the activity of aztreonam on phagocytosis and intracellular killing of Staphylococcus aureus ATCC6538 by human alveolar macrophages. Drug concentrations of 1, 10, 25, 100 micrograms/ml were assayed in culture medium. Aztreonam induces dose-dependent phagocytosis up to 25 micrograms/ml concentrations; with a phagocytosis index (PIa) of 1.18 +/- 0.2 at 1 microgram/ml; of 1.27 +/- 0.2 at 10 micrograms/ml; of 1.42 +/- 0.3 at 25 micrograms/ml. No phagocytosis increase or inhibition, with unchanged cell viability compared to controls, is shown at 100 micrograms/ml aztreonam (PI 1.03 +/- 0.3). Intracellular killing acts in a similar way: the killing index (KIa) is 1.27 +/- 0.3 at 1 microgram/ml concentrations; 1.38 +/- 0.3 at 10 micrograms/ml; 1.61 +/- 0.4 at 25 micrograms/ml whereas at 100 micrograms/ml the KIa is 1.03 +/- 0.3. This study shows aztreonam's ability to stimulate macrophages' functional activity against a microorganism (S. aureus) which is not susceptible to its antibacterial activity.

BAL modifications after antiblastic and immunomodulant therapy in lung cancer.

The bronchoalveolar compartment can be easily investigated with BAL (bronchoalveolar lavage) before and after antiblastic therapy. We studied 50 patients affected by primary lung cancer, of whom 31 served as a control group and 19 were submitted to BAL after chemo- and/or radiotherapy. Data from BAL performed in an unaffected lung area show that antiblastic therapy can produce alterations in the terminal airways without clinical evidence. Chemotherapy causes a significant impairment of the alveolo-capillary barrier. Radiotherapy is able to affect lymphocytes, with a CD4/CD8 reduction. The concomitance of both therapies produces synergistic effects. Immunomodulant therapy with thymostimulin in otherwise untreated lung cancer patients seems able to modify alveolar lymphocyte number and subsets, but these are preliminary data which need further substantiation.

Aztreonam activity in pneumology. Part 1: Clinical activity and pulmonary bioavailability of two different administration regimens.

Twenty-three patients suffering from lower respiratory tract infections caused by Gram-negative germs were treated with aztreonam (AZT) administered according to two different regimens: 17 subjects (Group A) with 2 g i.v. every 12 h and 6 patients (Group B) with 4 g in 100 ml of saline every 24 hours. Group A included 8 cases of superinfected bronchiectasis, 8 purulent bronchitis and 1 gangrene caused by Gram-negative and anaerobic agents. Group B comprised 6 patients with severe bronchiectasis infection. Pseudomonas aeruginosa was isolated from the sputum in 10/23 cases. The treatment was performed for 10 days on the average. The local and systemic tolerability was good. Group B, with higher antibiotic sputum concentrations for at least 12 hours, attained a better response than Group A: with clinical cure in 100% vs 76% cured plus 18% improved patients; therapy lasted 9.5 days for Group B vs 10.8 days for Group A. Moreover, in 14 subjects affected by pulmonary interstitial diseases who underwent diagnostic broncho-alveolar lavage, we dosed AZT in lavage fluids about 1 hour after the injection of a 2 g dose (Group C: 8 cases) or a 4 g dose (Group D: 6 cases). In group D antibiotic concentrations were significantly higher (P less than 0.005) than group C, while all the parameters that usually define the intensity of the alveolar alterations were not significantly different. Therefore, aztreonam administration in a daily monodose seems able to assure higher and longer lasting concentrations at the site of infection.

[Treatment of tuberculosis]. / Terapia della tubercolosi.

Tuberculosis appears to be a diagnostic challenge and an important therapeutical problem in industrialized and in developing countries, where most infections occur. Besides several rifamycin derivatives, new molecules (fluorinated quinolones, macrolides, beta-lactam antibiotics) are being explored in the face of increasing bacterial-resistance with the aim of improving the efficacy and safety of anti-tuberculous drugs, shortening the period of treatment or allowing intermittent regimens. At present, in severe forms of the disease three or more of the available anti-tuberculous agents must be administered simultaneously for at least 3-4 months and two for the following 6-7 months. Nevertheless, a variety of highly effective 6 months regimens are currently used for the treatment of less severe tuberculosis.

[Treatment of mycobacteriosis]. / Terapia delle micobatteriosi.

At present the increased incidence of infections with mycobacteria other than tuberculosis and leprae bacilli seems to be correlated with several causes: improved diagnostic techniques, prolonged life expectancy, immunodepression. Rational chemotherapy depends upon the identification of the etiologic mycobacterium and the determination of its drug susceptibility. Besides the "classic" treatment with 3 or 4 antituberculous and, sometimes, nonantituberculous chemotherapics, clinical trials are in progress to assess the effectiveness of new molecules: rifamycin derivatives, fluorinated quinolones, anti-lepromatous drugs, and the latest macrolides. Yet at present, national and international data do not permit to define a standard treatment for every mycobacteriosis; in fact, the drug resistance is high and varies not only between different strains but also within the same strain; moreover, there are discrepancies between in vitro and in vivo results. When possible, appropriated surgery for circumscribed disease is recommended.

Effect of graded doses of PGE2 on pancreatic exocrine secretion of bicarbonate, chymotrypsin and cyclic nucleotides during i.v. infusion of secretin in man.

We have previously reported that PGE2 inhibits pancreatic enzyme secretion during Secretin-Caerulein infusion, but differing results have also been reported. In this study 10 tests were performed in 5 healthy volunteers as follows: each subject received secretin (GIH) 2 CU/Kg-h by continuous infusion for 2 hours and, several days later, Secretin at the same dose plus PGE2 (Upjohn) in step-wise doses (0.04-0.08-0.12 gamma/Kg min) increasing every thirty min form 30' to 120' min. Duodenal juice was collected in 10 min samples. The volume of each sample was recorded and bicarbonate, chymotrypsin, cAMP and cGMP contents were determined. Statistical evaluation was performed by Student's "t" test for paired data and the regression test. PGE2 significantly decreased chymotrypsin concentration under Secretin. Both cyclic AMP and GMP Secretin-induced secretions were significantly increased by the highest dose of PGE2. No correlation was found in the behaviour of bicarbonate, chymotrypsin and cyclic nucleotides, but it must be noted that our data concern duodenal contents and not pure pancreatic secretion.

Concentrations of semi-synthetic penicillins in the plasma and in the expectoration, administered by means of intermittent vein perfusion.

We report the levels of concentration of ampicillin, dicloxacillin, and carbenicillin reached in the blood and in the expectoration following the administration of these drugs by rapid venous infusion, once every 24 h. The concentration of ampicillin in the blood serum varied from 150 to 180 micrograms/ml at the end of the infusion and from 30 to 3 micrograms/ml 4 afterwards and the dicloxacillin concentration from 150 to 120 micrograms/ml, and from 24 to 6 micrograms/ml. The concentration of ampicillin in purulent expectoration was 5-7 micrograms/ml and that of dicloxacillin 2.5-4 micrograms/ml. The concentration of carbenicillin in the plasma varied from 1,040 to 130 micrograms/ml, and in the expectoration it was around 15 micrograms/ml. Several cases of acute and chronic lung and bronchial diseases caused by bacteria have been treated by means of venous infusion once every 24 h and results were excellent.