Phase I Study in Healthy Women of a Novel Antimycotic Vaginal Ovule Combining Econazole and Benzydamine.

Purpose: A novel fixed-dose combination of 150 mg of econazole with 6 mg of benzydamine formulated in vaginal ovules was investigated in a randomised, double-blind, four-parallel group, tolerability, and pharmacokinetic Phase I study in healthy women. Methods: The fixed-dose combination was compared to econazole and benzydamine single-drug formulations and with placebo after daily applications for 3 consecutive days. Safety and tolerability were evaluated recording the adverse drug reactions, local and general tolerability scores, clinical laboratory assays, and vital signs. Econazole, benzydamine, and its metabolite benzydamine N-oxide pharmacokinetics were investigated after single and multiple applications. Results: Local reactions were generally absent. Pruritus and pain at the application site were infrequently reported. According to the subjects' evaluations, the overall tolerability of the ovules was rated as excellent or good. No significant effect of any treatment on laboratory parameters, vital signs, body weight, vaginal pH, or ECG was observed. Very low econazole, benzydamine, and benzydamine-N-oxide concentrations were measured in plasma, though quantifiable in almost all samples. Conclusion: The tested fixed-dose combination showed a good safety profile consistently with the known tolerability of both active substances. In addition, the confirmed low bioavailability of the drugs excludes the possibility of any accumulation effects and limits the risk of undesired systemic effects. This trial is registered at ClinicalTrials.gov with the identifier NCT02720783 last updated on 07 February 2017.

Prulifloxacin versus levofloxacin in the treatment of severe COPD patients with acute exacerbations of chronic bronchitis.

RATIONALE: Antimicrobial therapy of chronic bronchitis exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) is based on empiric antibiotic treatment. OBJECTIVES: To evaluate the efficacy of prulifloxacin versus levofloxacin therapy in severe COPD patients with exacerbations of chronic bronchitis. METHODS: This study involved a multicenter, parallel, double-blind, randomized clinical trial. Patients aged 40 years or older, smokers, or ex-smokers (>10 pack-years) with spirometrically confirmed severe COPD (FEV1 ≤ 50% predicted and FEV1/FVC ratio < 0.7) and diagnosed with an acute exacerbation of chronic bronchitis were enrolled in the study. Patients were randomized to receive prulifloxacin 600 mg once a day or levofloxacin 500 mg once a day for 7 days. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was clinical assessment at the TOC visit (7-10 days after the end of treatment) of signs and symptoms of exacerbation, namely sputum purulence, sputum volume, dyspnoea, cough and body temperature assessed through semi-quantitative scales. The ITT population included 346 (174 prulifloxacin, 172 levofloxacin) out of 351 treated subjects. A total of 161 patients with prulifloxacin (92.5%) and 166 with levofloxacin (96.5%) were considered cured at TOC (the difference in the percentage of cured patients was -3.98 with 95%CI of -8.76; 0.79). At the 6-month follow-up, the rates of patients with no relapse of AECB were higher than 95% in both the prulifloxacin and levofloxacin groups. CONCLUSIONS: Both prulifloxacin and levofloxacin showed efficacy rates higher than 90% in the treatment of severe COPD patients with exacerbations of chronic bronchitis, with no statistically significant differences between the two antibiotics. The long-term follow-up confirmed a very low incidence of relapse, endorsing the appropriateness of this therapeutic approach. EUDRACT no. 2006-004167-56.

Prulifloxacin versus ciprofloxacin in the treatment of adults with complicated urinary tract infections.

INTRODUCTION: The present study was performed to evaluate the efficacy and safety of a 10-day regimen of prulifloxacin 600 mg once daily as compared to ciprofloxacin 500 mg twice daily in the treatment of patients with complicated urinary tract infections (UTIs). MATERIALS AND METHODS: 257 patients (mean age +/- SD 62.3 +/- 16.5) were enrolled and orally treated with prulifloxacin (127 patients) or ciprofloxacin (130 patients). The study was designed as a randomized, double-blind, double-dummy, controlled clinical trial. The primary efficacy parameter was the eradication of infecting strains (<10(3) cfu/ml). The clinical outcome and tolerability were also assessed. RESULTS: At baseline, the most common infecting strains were Escherichia coli (62.8%), Proteus mirabilis (7.1%) and Klebsiella pneumoniae (4.1%). At the early follow-up, the rate of patients showing successful treatment was 90.8% in the prulifloxacin group, and 77.8% in the ciprofloxacin group (p = 0.008). A positive clinical outcome was observed in 94.8 and 93.3% of prulifloxacin- and ciprofloxacin-treated patients. Both drugs were well tolerated. Two patients dropped out for treatment-related adverse events. CONCLUSIONS: The high urinary concentrations of prulifloxacin, combined with a broad-spectrum antimicrobial activity, allow its use in the empiric therapy of UTIs.

Effects of ibopamine eye drops on intraocular pressure and aqueous humor flow in healthy volunteers and patients with open-angle glaucoma.

PURPOSE: On the basis of intraocular pressure measurements and fluorophotometry we assessed the effects of 2% ibopamine eye drops on aqueous humor production in normal and glaucomatous eyes. METHODS: Thirty subjects (15 healthy volunteers and 15 open-angle glaucoma patients with ocular hypertension) were included in a placebo-controlled study with random assignment of treatment from masked containers. All subjects underwent ophthalmologic examinations and intraocular pressure (IOP) measurements. Fluorophotometry was done in both eyes at baseline (without treatment) and during treatment. Each subject was treated with 1 drop of 2% ibopamine in one eye and 1 drop of placebo in the fellow eye 30 minutes before fluorophotometric scans and every hour after the first instillation (for a total of 4 times). Safety was evaluated by recording adverse events and ocular symptoms and signs. Aqueous humor flow data were analyzed using the paired t-test, comparing ibopamine and placebo-treated eyes. RESULTS: No changes in IOP were detected in normal eyes, whereas glaucomatous eyes showed a mean increase of 4 mmHg (95% CI 3.46-4.51) from baseline. The difference in IOP between healthy eyes and those with glaucoma was significant (p < 0.0001). In normal eyes and patients with glaucoma ibopamine led to a significant increase in aqueous humor flow compared with placebo-treated eyes (p < 0.01). The safety profile of ibopamine was very good. CONCLUSIONS: The results seem to confirm that ibopamine increases aqueous humor production in normal and glaucomatous eyes, raising IOP only in eyes with glaucoma.

Comparative bioavailability study of two oral formulations of ibuprofen.

The pharmacokinetic profile of ibuprofen (CAS 15687-27-1) in a Fast Melting Tablet (FMT), a modified release formulation (encapsulation of the active ingredient in gastroresistant microcapsules), was compared with that of sugar coated tablets (SCT; Moment 200). In the following paper an open, single dose, cross-over study in eighteen healthy volunteers (9 males and 9 females--mean age 27 years) is reported. The results of the study demonstrated that the rate of absorption of the FMT was markedly slower than that of the SCT. In fact, the geometric mean peak plasma concentration (Cmax) and median peak time (tmax) were 12.04 micrograms/ml at 3.5 h with the new formulation, and 18.71 micrograms/ml at 1 h with the SCT, respectively. The longer absorption time and diminished peak plasma concentration did not affect the extent of absorption of the two formulations, expressed by AUCo-t and AUC (90% confidence interval: 0.89-1.00 for AUCo-t and 0.92-1.03 for AUC). The safety profile of both drugs proved to be very good and no clinically significant adverse events were observed.

Bindarit prolongs survival and reduces renal damage in NZB/W lupus mice.

OBJECTIVE: The present study was designed to investigate the effects of bindarit on animal survival and renal damage in murine lupus autoimmune disease. METHODS: Female NZB/W mice were used. Bindarit was administered, as a 0.5% medicated diet, starting either before the onset of the pathology or early in the course of the disease, in order to assess the effects of age upon the response. Furthermore, the effects of combined administration of bindarit with low dose i.p. cyclophosphamide bolus were also studied. Proteinuria and anti-dsDNA antibody levels were determined during the course of the study. Renal damage was evaluated by light microscopy. RESULTS: Bindarit markedly prolonged the NZB/W mouse life span (p < 0.001 vs. controls), showing a significant difference even against high dose cyclophosphamide (90 mg/kg ip bolus) chosen as the reference (p < 0.01). Bindarit significantly reduced the degree of renal damage, delayed proteinuria and did not prevent autoantibody development, thus confirming the lack of immunosuppressive activity. CONCLUSION: The present results and other experimental data demonstrating the capacity of the drug to interfere with the inflammatory and immune response cross-talking, indicate that bindarit exerts its action in murine lupus through a novel and original mechanism. These findings, coupled with the evidence that the drug possesses a very safe toxicological profile, suggest that further investigations to assess the potential value of bindarit in the treatment of SLE are warranted.

Benzydamine protection in a mouse model of endotoxemia.

OBJECTIVE: Previous studies have shown that benzydamine (40 mg/kg s.c.) is able to inhibit tumor necrosis factor (TNF) production and to reduce mouse lethality when administered before or concomitantly with LPS. The present study was designed to further investigate benzydamine activity against LPS-induced toxicity in terms of potency and therapeutic effects. METHODS: Female Balb/c mice were used. A dose-response curve of animal lethality versus endotoxin dose was performed (LD50 = 45 micrograms/mouse). Therapeutic effects were studied selecting the dose of LPS to achieve an LD100 (160 micrograms/mouse). Mortality was assessed daily and mice were followed for 8 days. The potential mode of action of therapeutically administered benzydamine was also investigated. TNF alpha and IL-1 beta levels were measured, at 5 h after LPS injection, both in sera and in lungs. Moreover, the drug was assayed in a TNF-dependent cytoxicity test. RESULTS: Benzydamine, administered at 20 mg/kg s.c. simultaneously with the endotoxin, significantly increased LPS LD50 up to 230 micrograms/mouse (p < 0.05). Moreover, the drug significantly protected mice against LPS-induced lethality when administered either 30 min or 4 h after endotoxin injection (p < 0.001). Benzydamine, therapeutically administered at 20 mg/kg s.c., significantly reduced TNF alpha and IL-1 beta production induced by LPS both in serum and lungs and it was shown to inhibit TNF-dependent cytoxicity on L929 cells. CONCLUSIONS: These results clearly demonstrate the therapeutic activity of benzydamine in a simple model of endotoxic shock. Available data confirm the potential role of benzydamine as an anti-cytokine agent and provide suggestions for novel therapeutic applications of this anti-inflammatory drug.

Double-blind randomized study of lonidamine and radiotherapy in head and neck cancer.

PURPOSE: Preclinical studies showed lonidamine to potentiate the effects of x-irradiation by inhibiting the repair of potentially lethal damage. This Phase III double blind, placebo-controlled study was performed to evaluate whether lonidamine can increase the tumor control of radiotherapy in the treatment of advanced head and neck cancer without any synergistic toxic effects on the exposed normal tissues. METHODS AND MATERIALS: Ninety-seven patients with Stages II-IV squamous cell carcinoma of the head and neck were enrolled. Separate analyses were done on the 96 eligible patients and the 90 patients who completed the prescribed treatment regimen. Patients received radiotherapy up to a planned total of 60-66 Gy, in 2 daily fractions of 1.5 Gy each and either lonidamine (450 mg p.o. in three divided daily doses) or placebo, given continuously for 3 months or up to 1 month after the end of radiotherapy. RESULTS: The rate of tumor clearance was 66% (32/48) in the lonidamine group and 65% (31/48) in the placebo group, while the subsequent failure rate was 50% and 77%, respectively (p < 0.05). The 3 and 5 year locoregional control rates in the adequately treated patients achieving complete tumor clearance were 66% and 63% for lonidamine vs. 41% and 37% for placebo. The disease-free survival in adequately treated patients was significantly better in the lonidamine group (p < 0.03), with 3 and 5 year rates of 44% and 40%, respectively, vs. 23% and 19% in the placebo group. The overall survival rate for all eligible patients at both 3 and 5 years was 44% in the lonidamine group and 44% and 31%, respectively, in the placebo group. Both acute and late radiation reactions were similar in the two groups. Myalgia and testicular pain were the most frequent side effects of lonidamine with an incidence of 8.5% and 4.2%, respectively. CONCLUSION: The addition of lonidamine to hyperfractionated radiotherapy was correlated with a statistically and clinically significant proportion of long-term disease-free patients. The toxicity of radiotherapy was not aggravated by the drug and the overall tolerance of the combined regimen was acceptable.