A crossover trial of oxdralazine in hypertension.

Twenty-nine moderate and severe essential hypertensive patients completed a crossover study aimed at evaluating efficacy and tolerability of a double combination (chlorthalidone plus propranolol) and of a triple combination (chlorthalidone plus oxdralazine plus propranolol). After one month on 25 mg/day chlorthalidone, which caused nonsignificant reduction in blood pressure of 7/4 mm Hg, patients were randomized to receive either the double or triple regimen for a three-month period. Then, after another month on chlorthalidone alone at the same dose of 25 mg/day, treatments were crossed over and the study continued for another three-month period. The double regimen caused a drop in pressure of 16/11 mm Hg after one month (daily doses 25 mg chlorthalidone, 103 +/- 25 mg propranolol), and this reduction did not change at the third month in spite of dosage increases (daily doses 25 mg chlorthalidone, 222 +/- 77 mg propranolol). The triple regimen reduced blood pressure 35/15 mm Hg after one month (daily doses 25 mg chlorthalidone, 20 mg oxdralazine, 40 mg propranolol), and further increase in dosages caused a reduction of 45/24 mm Hg at the third month (daily doses 25 mg chlorthalidone, 56 +/- 20 mg oxdralazine, 112 +/- 40 mg propranolol). Both treatments were well tolerated; in particular, at the end of the third month of each treatment period, 25 patients on the triple regimen achieved a stable diastolic blood pressure of 90 mm Hg or less, as compared to 10 patients on the double regimen (P less than 0.01).

Efficacy and tolerability of glaucine as an antitussive agent.

One hundred and thirty out-patients, affected by acute and chronic cough caused by upper respiratory tract inflammation, took part in two clinical studies aimed at evaluating the efficacy and tolerability of glaucine , a new antitussive agent. The first study involved 90 patients in a double-blind comparative trial of glaucine and codeine: both treatments were administered as a syrup at a dosage of 30 mg 3-times daily for 7 days. The cough suppressant effect of the two treatments was checked by the physician and the patient using a 4-point scale (from absent to severe), and by the patient using a visual analogue scale. Mean scores of the physician's evaluation decreased from 3.0 to 1.10 after codeine and from 3.0 to 0.47 after glaucine (p less than 0.001 between treatments). Mean values of the patients' visual analogue scales decreased from 83 mm to 17 mm after codeine, and from 85 mm to 7 mm after glaucine (p less than 0.001 between treatments). Constipation and nausea were reported by 9 patients on codeine and by no patient on glaucine (p less than 0.01). One patient on codeine was withdrawn from the study after 3 days because of vomiting, constipation and nausea. The second study was an open trial in 40 patients who received glaucine capsules at a dosage of 30 mg 3-times daily for 28 days. The antitussive effect of the treatment was evaluated on the basis of the same criteria as in the first study. The mean score of the physician's evaluation decreased from 3.0 to 0.15 (p less than 0.001); the mean value of the patients' visual analogue scales decreased from 93 mm to 1 mm (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Multi-institutional phase II randomized trial of integrated therapy with cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2, interferon alpha2a and tamoxifen in metastatic melanoma. BREMIM (Biological Response Modifiers in Melanoma).

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma. Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months. According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.

Interferon alfa 2a in superficial bladder cancer prophylaxis: toleration and long-term follow-up. A phase I-II study.

Twenty patients (17 M., 3F., -mean age 61.5 yrs) affected by superficial bladder tumors (TINOMO) were included in the study. All patients had cold mucosa biopsy to exclude the presence of dysplasia or CIS; the histopathological grade was G1 in 19 cases and G2 in 1. The treatment was started between 3 to 7 days after radical TUR with intravesical instillations of recombinant Interferon alfa 2a, at the daily dose of 54 million/Units for 5 days for 2 consecutive weeks. No systemic adverse effects were observed. Local toleration and efficacy were assessed by cystoscopy, performed at the end of treatment after 6 weeks and then at three month intervals. At the first control 15% of patients showed an early local reaction with bollous oedema surrounding the resected area (with spontaneously disappeared after few days). No other abnormal findings were observed at the 6-week control. After a median follow-up of 98 weeks, 15 of the 19 evaluable patients (79%, C.I. 60-91) were disease-free. The median relapse time was 39.9 weeks, while clinical and local tolerance were optimal. These preliminary data confirm the complete absence of toxicity of Interferon alfa 2a administered at relatively high doses intravesically and indicate that this compound has some effect on superficial bladder cancer.

Recombinant leukocyte interferon alfa-2a in the treatment of mycosis fungoides.

This study was designed to evaluate the efficacy and tolerability of recombinant leukocyte interferon alfa-2a (Hoffmann-LaRoche) as single agent in patients with histologically confirmed Mycosis Fungoides. The protocol consisted of a 12 week induction with subcutaneous interferon, escalating from 3 up to 18 million units daily, and a 6 or 9 month maintenance phase for complete or partial responses, respectively, with 18 million units 3 times weekly. 12 patients are evaluable: 5 are in complete remissions, 6 are partial remissions, and one had disease progression. Alfa-2a interferon was well tolerated: only 3 patients had WHO grade IV organ toxicity. Our study documents that recombinant leukocyte alfa 2a is a highly active agent in untreated patients with Mycosis Fungoides. Finally, the dose schedule chosen in this study allows alfa-2a interferon administration on an outpatient basis.

Neuroendocrine effects of interferon alpha 2-a in healthy human subjects.

The acute effects of interferon alpha-2a (3 x 10 IU im) on catecholamine and immunoreactive beta endorphin plasma levels, cortisol serum levels and lymphocyte beta 2-adrenoceptor density were evaluated in ten healthy volunteers. Interferon induced a significant increase in plasma norepinephrine; there was an increased norepinephrine standing response, too. On the contrary, epinephrine standing response was reduced by interferon. Lymphocyte beta 2-adrenoceptors decreased significantly after interferon administration; dissociation constant of binding was unchanged. Cortisol serum levels increased significantly with respect to control test, whereas immunoreactive beta endorphin did not change. These results support the hypothesis of functional relationships between neuroendocrine and immune systems; moreover they may be useful in clinical trials given the administration of interferon alpha in an increasing number of diseases.

Ceftriaxone plus amikacin in a single daily dose as empiric antibiotic therapy in granulocytopenic patients.

In our study ceftriaxone plus amikacin were employed as empirical antibiotic therapy. This antibiotic treatment allows for a once daily administration and has a broad spectrum of activity. 21 febrile episodes were treated with an antibiotic regimen of ceftriaxone 50 mg/kg/day and amikacin 30-35 mg/kg/day i.v. An earlier pilot study was carried out in which 47 febrile episodes were treated with an antibiotic regimen of ceftriaxone 80-100 mg/kg/day i.v. and amikacin 30-35 mg/kg/day i.v. in a single dose. The overall response rate was 76% (16/21) and 79% (37/47) for the pilot study. During the treatment no side effects were observed and aminoglycoside related toxicity did not occur. In conclusion, this empiric antibiotic therapy gives a high response rate and allows for a single daily administration.

Objective assessment of cough suppressants under normal and pathological experimental conditions.

The influences of the antitussive activity of glaucine were studied in 56 non-anaesthetized cats under normal and pathological conditions. Cough was induced by mechanical stimulation of the airways with a nylon fibre. The authors found that if glaucine was administered at a dose of 5.0, 7.5 and 10.0 mg/kg b.w., i.p., it evoked statistically significant suppression on single cough components. After inflammation of the airways was induced with unsoluted croton oil, no decrease in antitussive activity of glaucine could be observed, according to the number of cough efforts, frequency, intensity of maximal cough effort, and intensity of cough attack during expiration. Glaucine used under such conditions was not found to be powerful enough to suppress either the intensity of maximal cough effort or the intensity of cough attack during inspiration. The antitussive effect of glaucine was stronger under pathological conditions (Staphylococcus-induced inflammation). The antitussive effect of glaucine was approximately the same as with codeine if administered in equal doses.

Cutaneous adverse reactions following the administration of nonsteroidal antiinflammatory drugs and antibiotics: an Italian survey.

The Italian Group for Epidemiological Research in Dermatology (GISED) collected a series of cutaneous adverse reactions following NSAID and/or antibiotics administered by topical and/or systemic route. Dermatologists from North and Central Italy took part in this survey by filling in 1457 case report forms during a four-month observation time in 1988-89. The main purpose of our epidemiological study aimed at evaluating a post-marketing surveillance program by examining spontaneous reports of cutaneous adverse reactions. This result seems to be noteworthy, considering the difficulties encountered in Italy to develop such a program.

Pharmacodynamic studies in man of the beta-adrenoceptor antagonist DL 071 IT.

DL 071 IT, a new potent non-selective beta-adrenergic blocking drug with intrinsic sympathomimetic activity and weak membrane stabilizing activity, was evaluated alone and in comparison with oxprenolol, in six volunteers, at rest and during an exercise test. Heart rate and systolic pressure were monitored for up to 7 h after oral administration of the drugs. Exercise heart rate and systolic pressure were significantly reduced by both drugs, but only DL 071 IT caused a significant reduction in resting heart rate. As compared to oxprenolol, DL 071 IT has a longer duration of action and is from 5.0 to 13.5 times more potent.

Long-term study of oxdralazine in hypertensive patients.

56 moderate and severe hypertensive patients entered an open long-term trial aimed at evaluating the efficacy and tolerability of a combined treatment consisting of 3-hydrazino-6-[N,N-bis-(2-hydroxyethyl)amino]pyridazine (oxdralazine, L 6150), propranolol and chlorthalidone. The mean basal blood pressure was 186.9/111.8 mmHg: after one month of treatment, the mean value was 149.7/95.5 mmHg (p less than 0.01). The heart rate was practically unaffected by treatment, the mean value changing from 75.4 b.p.m. (basal) to 73.3 b.p.m. (one month). The significant reduction in the blood pressure observed at the end of the first month remained unchanged in the following months of therapy, and only minor variations occurred. The combined treatment was well tolerated. Five patients were withdrawn from the trial during the first month; three of them because of side-effects and two of them for personal reasons.

Double-blind study of glaucine in chronic cough.

Thirty-eight patients, affected by chronic cough and hospitalized in 14 different rooms, entered a double-blind cross-over trial aimed at evaluating efficacy and tolerance of single oral doses of glaucine (eo mg) versus single oral doses of codeine (30 mg) and placebo. Patients occupying the same room were administered on 3 consecutive nights, and an objective evaluation of efficacy was ensured by means of a tape recorded. The mean cough counts during the 8-h interval after drug administration were 269.3 after placebo, 241.8 after glaucine, and 201.9 after codeine (p less than 0.05). The antitussive effects of glaucine and codeine were practically superimposable up to the 6th h, when glaucine effect declined. Treatments were well tolerated by all the patients, they themselves were not able to detect any difference in cough suppression among the three treatments.

In vitro enhancement of the proliferative response of human T cells to autologous non-T cells by hydralazine.

While high doses of hydralazine inhibit the proliferative response of T lymphocytes to mitogens and antigens, low doses (0.15 microgram/ml) selectively enhance the proliferative response of T cells to autologous non-T cells. The effect is especially pronounced on lymphocytes which express the HLA-DR4 allospecificity. These results suggest that the autologous mixed lymphocyte response with non-T cells may represent a useful in vitro model to analyse the mechanism(s) of the immunologic abnormalities induced by hydralazine.

The effects of a new phthalazine derivative (MDL 899) on human lymphocyte functions.

MDL-899 is new phthalazine derivative which has been developed as a substitute for hydralazine, which has several undesirable effects, in the treatment of hypertension. The effects of MDL-899 on human lymphocyte functions are analyzed. This drug inhibited in a dose-related fashion the blastogenesis of lymphocytes upon PHA and Con A activation and down-regulated the activation of allogeneic mixed lymphocyte reactions (MLR). On the contrary the drug enhanced the activation of autologous MLR of non T/T type. This effect was five times higher on cells which carried the HLA DR 4 phenotype. The above reported observations suggest that MDL-899, as well as hydralazine, affects the in vitro responsiveness of human lymphocytes mostly in subjects with HLA-DR 4 phenotype. Whether the impact of MDL-899 on immune function gives rise to a lupus like syndrome is not known. For this reason further studies are warranted to assess its long-term in vivo effects.

Interferon alpha-2a and vinblastine in the treatment of metastatic renal carcinoma.

Twenty patients with measurable metastatic renal cell carcinoma (RCC) were treated with interferon alpha-2a (18 X 10(6) IU i.m. 3 times weekly) in combination with vinblastine sulfate (0.1 mg/kg i.v. every 3 weeks). Objective responses in the lungs, bone and liver metastases were observed in 5 of 18 evaluable patients. Dose reduction of interferon alpha-2a (to 9 X 10(6) IU i.m. 3 times weekly) was necessary in 7 patients due to intolerable flu-like side effects and leukopenia (nadir 3,500 leukocytes/mm3). Tolerance was good in 55% of cases. Objective clinical response was observed in 27.7% of patients, and only 38.8% progressed. It is necessary to perform further studies, varying the therapeutic schedules, in order to elicit a better control of the toxic effects and a greater objectiveness of the clinical response.

Deflazacort in thrombocytopenia: a comparison with prednisone.

Deflazacort is a new glucocorticoid which in previous studies was found to be about 0.8 times as potent as prednisone. Twelve outpatients affected by chronic idiopathic thrombocytopenic purpura, in whom the maintenance dose of corticosteroid had already been established, were given 6 mg deflazacort for each 5 mg prednisone equivalent. Effectiveness of deflazacort therapy was estimated on the basis of the results of platelet count, bleeding time, tourniquet test, and physical signs related to platelet function. Tolerability was evaluated on the basis of laboratory data, side effects, and body weight. Deflazacort was administered for 54--263 days (mean 114.5) and, at the same mean daily dose of prednisone, succeeded in keeping platelet number unchanged. As far as bleeding time, tourniquet test, and physical signs are concerned, deflazacort therapy gave a further improvement compared to prednisone. Both treatments were very well tolerated. The high number of white blood cells and neutrophils during prednisone therapy was restored to the normal range by deflazacort.

Effects of a new glucocorticoid, deflazacort, on pituitary-adrenal function in man: a comparison with prednisone.

The influence on plasma ACTH and cortisol and on blood sugar have been evaluated in seven volunteers after single oral doses of prednisone 4 mg and 8 mg and deflazacort 5 mg and 10 mg. Drugs were administered at midnight to achieve a maximum inhibitory effect on the hypothalamic-pituitary-adrenal axis. No difference was detected in the majority of cases between the high and the low dose of each drug. In particular, the results obtained with the higher doses show a significant effect of both drugs on ACTH (at hour 4 after drug administration) and on cortisol (at hours 4, 8, 12 and 16). As for blood sugar, the hyperglycemic activity of deflazacort appears to be lower than prednisone at hours 12 and 16. On the whole, the potency of deflazacort appears similar to that of prednisone.

Objective evaluation of dextromethorphan and glaucine as antitussive agents.

Twenty-four inpatients affected by chronic cough completed a single-dose double-blind cross-over study of placebo, glaucine 30 mg and dextromethorphan 30 mg. The study was carried out using a balanced incomplete block design, each patient receiving two of the three experimental treatments. Objective evaluation of cough was ensured by means of a writing cough recorder. Coughs after dextromethorphan and glaucine were fewer than coughs after placebo: however only glaucine was significantly different from placebo in reducing coughs. Treatments were well tolerated: clinical results included a reduction in pulse rate after both dextromethorphan and glaucine , and a large number of patients reporting side effects after dextromethorphan administration.