Cost-effectiveness analysis of oral N-acetylcysteine as a preventive treatment in chronic bronchitis.

UNLABELLED: Chronic bronchitis has a prevalence of approximately 11% in the population aged over 35 years and its frequent acute exacerbations (AECBs) are an important cause of morbidity and costs in health-care resources. Oral N -acetylcysteine (NAC) is administered during the winter months as a way of reducing AECBs. This cost-effectiveness analysis was done from the payers' point of view in the Swiss health-care system, based on a retrospective analysis of published placebo-controlled studies. The pooled data show that continuous administration of 400 mg day(-1)per os of NAC leads to a significant reduction in the number of AECBs (NAC: 16.2 vs 25.2% AECBs per month); a significantly smaller percentage of days of sick leave (NAC: 3.6 vs 5.3%) and a lower rate of hospitalizations (NAC: 1.5 vs 3.5% over a period of 6 months). Taking into account the poor compliance of these patients, calculations assumed a compliance of 80%. Direct costs were those of an NAC treatment, the management of an AECB (biological tests in 59%, X-rays in 65% and pulmonary function tests in 45%; antibiotics 70%, bronchodilators in 89%, corticosteroids in 24% and 'others' in 25% of the patients), and of hospitalizations (estimated at 10 days per case). Based on these figures, the mean direct costs of an untreated patient were CHF 869 vs CHF 700 in the NAC-treated patient. Univariate sensitivity analysis indicated that cost neutrality is reached with 0.6 (<0.25-1. 94, 95% CI) AECBs per 6 months. Indirect costs (based on sick leave) were also significantly different; the mean in untreated patients was CHF 1324 vs CHF 779 in the NAC-treated patients. CONCLUSION: Treating chronic bronchitis patients with NAC during the winter months is cost-effective both from the payer's and a social point of view.

Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials.

OBJECTIVE: This meta-analysis was performed to assess the possible prophylactic benefit of prolonged treatment with oral N-acetylcysteine (NAC) in chronic bronchitis (CB) based on qualifying clinical trials. Treatment of acute exacerbations with NAC was not investigated. BACKGROUND: Prolonged treatment with oral NAC has been investigated in a number of studies of patients with CB. NAC prevented acute exacerbations and symptoms of CB in some but not all trials. METHODS: The trials included in this analysis were selected from a MEDLINE search of the period from January 1, 1980, through June 30, 1995; references in the articles retrieved in the initial search; and consultation with 2 experts. Selection was based on the following criteria: published, double-blind, placebo-controlled, chronic bronchopulmonary disease, duration of therapy > or =2 months, and data sufficient to calculate an outcome variable permitting direct comparison of studies (effect size) for both NAC and placebo groups. The primary end point was the incidence of acute exacerbations in 7 of 8 trials and clinical assessment in the other. In 7 studies, inclusion criteria were based on Medical Research Council criteria for CB, with an additional criterion in some trials. For the meta-analysis, the end points of individual trials were transformed into an effect size as a common outcome. RESULTS: Of 21 trials initially identified, 8 qualified for inclusion. References from the 8 papers and consultation with the experts produced 8 additional publications, 1 of which qualified for inclusion. NAC was administered orally at a daily dose of 400 mg (1 study), 600 mg (5 studies), or 1200 mg (1 study). One other trial used a dose of 600 mg 3 times per week. The duration of treatment was 3 months (1 study), > or =5 months (2 studies), or 6 months (7 studies). The results of this meta-analysis showed a statistically significant effect size for NAC compared with placebo. The overall value of effect size was -1.37 (95% CI, -1.5 to -1.25). Sensitivity analyses did not significantly alter these results. In a subset analysis of trials with the number of acute exacerbations as a clinical end point, a mean difference of -0.32 clinical event (95% CI, -0.50 to -0.18) was found (ie, a 23% decrease in the number of acute exacerbations compared with placebo). CONCLUSION: These findings suggest that a prolonged course of oral NAC prevents acute exacerbations of CB, thus possibly decreasing morbidity and health care costs.

GSH rescue by N-acetylcysteine.

Reduced glutathione (GSH) is the main intracellular low molecular weight thiol. GSH acts as a nucleophilic scavenger and as an enzyme-catalyzed antioxidant in the event of electrophilic/oxidative tissue injury. Therefore, GSH has a major role as a protector of biological structures and functions. GSH depletion has been recognized as a hazardous condition during paracetamol intoxication. Conversely, GSH rescue, meaning recovery of the protective potential of GSH by early administration of N-acetylcysteine (NAC), has been found to be life-saving. Lack of GSH and electrophilic/oxidative injury have been identified among the causes of the adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and the acquired immunodeficiency syndrome (AIDS). Experimental and early clinical data (in ARDS) point to the role of NAC in the treatment of these conditions. Recently, orally given NAC has been shown to enhance the levels of GSH in the liver, in plasma, and notably in the bronchoalveolar lavage fluid. Rescue of GSH through NAC needs to be appreciated as an independent treatment modality for an array of different disease, all of which have one feature in common: pathogenetically relevant loss of GSH.

Antispasmodic effects of flavoxate, MFCA, and REC 15/2053 on smooth muscle of human prostate and urinary bladder.

The antispasmodic effects of the flavone compounds flavoxate hydrochloride, 3-methylflavone carboxylic acid (MFCA), and REC 15/2053 (and in the case of the detrusor, oxybutynin), on the human detrusor, prostatic adenoma, prostatic capsule, and bladder neck, were studied by the in vitro isometric method. All the compounds inhibited, in different orders of potency, potassium-induced contractions of the tissues. Flavoxate showed a slightly greater activity than the other two compounds in the prostatic and bladder neck tissues. However, REC 15/2053 displayed greater activity in the detrusor than in the other tissues. The relaxant effect on the prostatic tissues suggests a potential use for these compounds in benign prostatic obstruction.

Comparison of single administration with an ovule of 600 mg fenticonazole versus a 500 mg clotrimazole vaginal pessary in the treatment of vaginal candidiasis.

Fenticonazole is an imidazole derivative with a broad spectrum of antimycotic activity. The therapeutic activity and tolerability of 600 mg fenticonazole versus 500 mg clotrimazole were evaluated in an investigator-blind trial in 80 patients with mycologically confirmed vaginal candidiasis. Fenticonazole was administered as an ovule and clotrimazole as a vaginal pessary, both in a single administration. Therapeutic efficacy was assessed by microbiological and clinical criteria 7 days after the start of treatment. Patients cured at the end of the trial were rechecked 4-5 weeks after the start of therapy in order to identify and evaluate possible relapse. Both treatments resulted in a statistically significant reduction in vaginal symptoms (erythema, itching, discharge and oedema) and in elimination of Candida albicans in about 90% of patients. The tolerance of both treatments was excellent since no local or systemic signs or symptoms of toxicity were reported. An equally high efficacy and safety for both drugs in the elimination of symptoms and objective evidence of vaginal candidiasis was indicated.

A review of flavoxate hydrochloride in the treatment of urge incontinence.

This article provides a review of the use of flavoxate hydrochloride in the treatment of urge incontinence. It outlines the pharmacology, mode of action, toxicology and pharmacokinetic studies which have been carried out, and then reviews the clinical studies, including those involving patients with benign prostatic hypertrophy. The effects of dosages of 600-1200 mg/day are compared, particularly regarding safety and tolerability factors. Finally, alternative therapies to flavoxate hydrochloride (alpha-adrenergic receptor blockers, oxybutinin chloride, terodiline hydrochloride, emepronium bromide and imipramine) are summarized. The article is written in the knowledge of recent evidence which indicates that flavoxate hydrochloride exhibits only weak anticholinergic activity on receptors involved in the control of the lower urinary tract.

Comparison of flavoxate hydrochloride in daily dosages of 600 versus 1200 mg for the treatment of urgency and urge incontinence.

Flavoxate hydrochloride at a daily dosage of 600 mg was compared to a daily dosage of 1200 mg for the treatment of unstable bladder. Twenty-seven patients were treated for 4 weeks in a double-blind, randomized, parallel-group trial. Clinically, both schedules were equally successful. In urodynamic terms, however, particularly with respect to uninhibited detrusor contractions, 1200 mg/day was significantly superior to 600 mg/day. Tolerability was excellent for both regimens. The side-effect free treatment of urgency and urge incontinence is of paramount importance for a patient's quality of life.

Fenticonazole cream once daily in dermatomycosis, a double-blind controlled trial versus bifonazole.

A randomized, double-blind clinical trial was undertaken in 41 patients with dermatomycosis to compare topical 2% fenticonazole cream (group A: 21 patients) with topical 1% bifonazole cream (group B: 20 patients). Treatment was performed as a once daily application. Mycological and clinical parameters were assessed before treatment and after 7, 14, 21 and 28 days. At the control visits the clinical investigator also expressed an overall judgement on the patient's state of disease. This parameter was based on a combined clinical and mycological assessment by the physician; laboratory screening investigations were undertaken before and at the end of treatments. All patients were checked for their state of disease 3-4 weeks after the end of treatment. All assessment criteria showed fenticonazole to be at least as efficacious as bifonazole. Several trends in favor of fenticonazole were also found: fenticonazole achieved superior results in the overall clinical evaluation, and after 3 weeks of treatment 15 patients out of 21 on fenticonazole were cured in mycological and clinical terms, whereas treatment with bifonazole resulted in complete healing of only 7 patients out of 20. This difference is statistically significant (p = 0.021) and indicates a more rapid therapeutic activity of fenticonazole. At the posttreatment rechecks no recurrent disease was registered, irrespective of whether patients had received fenticonazole or bifonazole. Laboratory screening investigations revealed no evidence of significant treatment-related changes or abnormalities in both treatments. No adverse events were noted for either treatment.

Flavoxate hydrochloride for urinary urgency after pelvic radiotherapy: comparison of 600 mg versus 1200 mg daily dosages.

This preliminary communication reports on a non-randomized pilot type trial of 34 females with urgency after pelvic radiotherapy who were treated with flavoxate hydrochloride for 4 weeks. A dosage of 600 mg/day was given to 21 patients and 1200 mg/day to 13 patients. Clinically, both regimens achieved comparable results. Urodynamically (first desire volume, bladder capacity and pressure at capacity) treatment with 1200 mg/day was significantly superior to 600 mg/day. Both schedules were equally well tolerated by patients and no treatment interruption occurred. A randomized double-blind trial comparing 600 and 1200 mg/day flavoxate hydrochloride is currently underway the results of which will be reported in due course.

Short-term treatment of vaginal candidiasis with fenticonazole ovules: a three-dose schedule comparative trial.

In an unblinded, randomized parallel group trial three different therapeutic dose schedules of fenticonazole (vaginal ovules) were compared in the treatment of vaginal candidiasis. A total of 60 patients, aged 17-71 years, affected by mycologically confirmed symptomatic vaginal candidiasis were included and randomly allocated to three treatment groups: 200 mg daily, for 3 days; 600 mg in a single administration; and 1000 mg in a single administration. Therapeutic efficacy was assessed by microbiological and clinical criteria 7 days after the end of the treatment. All mycologically cured patients were re-checked, microbiologically and clinically, 2 weeks after the end of treatment to identify and evaluate possible relapses. The results obtained indicate that vaginal application of fenticonazole ovules is highly effective in producing both symptomatic relief and mycological sterilization of vaginal swabs in 75-85% of treated patients. No relapses were noted at the time of re-check. The three administration schedules tested appear to be equally effective and well tolerated. In one case only of the group given 200 mg and two cases of those given 1000 mg, a local burning sensation was noted. These results show that short-term treatment of vaginal candidiasis with fenticonazole ovules is effective and well tolerated.

Protein deficiency reduces natural antitumor immunity.

Clinical data have shown that neoplastic diseases and/or related therapies frequently result in protein depletion of tumor-bearing patients. Depressions of acquired and specific immunity caused by protein depletion are well known. In an experimental model protein depletion was induced by lack of nutritional protein in otherwise isocaloric conditions in BALB/c and C57BL/6 mice over various time periods (max. 35 days). The results show that natural immune effector cells, natural killer cells, and monocyte/macrophages also during treatment with biological response modifiers (BRM) are depressed in their cytotoxic potentials in vitro and in vivo. Substantial and critical reductions of bone marrow cellularity (bone marrow nucleated cells) were also observed. In contrast, preliminary results show that if, following protein depletion, mice were treated parenterally with amino acids (Neo-aminomel, Boehringer-Ma. Co., FRG) complete restoration of immune parameters takes place. Adequate protein status is shown to be a crucial factor for natural immunity and therapy with BRM.

Antiproliferative activity of picolinic acid due to macrophage activation.

Activation and subsequent enhancement of cytotoxicity of mouse peritoneal macrophages (M phi) by picolinic acid (PLA) in vivo have been reported previously by the authors' group. The optimum dose was found to be 100 mg/kg. PLA-stimulated M phi lysed different tumor targets in vitro, MBL-2 lymphoma cells and Madison 109 lung carcinoma cells, with equal efficiency. Treatment with PLA was performed daily for 5 consecutive days with a dose of 100 mg/kg intraperitoneally in C57/BL mice, which previously had been inoculated with MBL-2 tumor cells. Treatment was initiated on the first day after tumor inoculation. Oral treatment with PLA (200 mg/kg) dissolved in the drinking water was also performed for 7 days. In addition, some groups received PLA treatment 1 or 2 days before tumor implantation but not afterwards, to elucidate the in vivo efficacy of M phi activation. Intraperitoneal therapy with PLA after tumor inoculation resulted in a highly significant increase in lifespan (46%); intraperitoneal pretreatment caused a significant increase (15%); orally administered PLA was without effect. Thus intraperitoneal treatment with PLA was found to have protective and therapeutic effects against the MBL-2 ascites tumor in vivo. These effects are most likely caused by macrophage activation.

Flavoxate, a drug with smooth muscle relaxing activity.

Flavoxate hydrochloride is a flavone derivative with smooth muscle relaxing activity. The product has a broad range of indications and has found one major application in the treatment of urge incontinence. Information on different forms of incontinence and epidemiologic data are summarized. Differences between the myolytic agent flavoxate and anticholinergics are highlighted. The vast amount of information deriving from some 20 years of clinical experience is analysed and major conclusions are drawn. The compound has valid therapeutic efficacy and excellent tolerability. By this token flavoxate is the agent of choice for therapy of disorders caused by smooth muscle spasms.

Adjuvant chemoimmunotherapy of cancer: influence of tumor burden and role of functional immune effector cells in mice.

Starting from the observation that success of combined treatment of MBL-2 tumor-bearing mice with the alkylating agent cyclophosphamide (CY; 150 mg/kg) and the immunomodulator maleic anhydride divinyl either copolymer (MVE-2; 25 mg/kg) was dependent upon a 1-3-day interval between treatment with CY and MVE-2, we have further analyzed in vitro and in vivo the relationship between tumor burden and the activity of immune effector cells in an adjuvant chemoimmunotherapy setting with CY and MVE-2. Treatment of MBL-2 tumor-bearing mice with CY (50-200 mg/kg) caused a dose- and time-dependent decrease in the i.p. tumor burden, which correlated with a significant increase in their median survival time. CY increased also the sensitivity of the residual MBL-2 tumor cells to Mø-mediated immunotherapy. The therapeutic efficacy of Mø-mediated immunotherapy with MVE-2, however, was restricted due to adverse effects of CY on the host's immune and hematopoietic functions. The time sequence with which these CY related positive effects on tumor burden and s(Tu)I, as well as the adverse effects on macrophages and hematopoietic functions occurred, gives sufficient explanation for the narrow window in time for successful immunotherapy with MVE-2 after preceding chemotherapy with CY. We therefore propose to modify the conventional chemoimmunotherapy of MBL-2 tumor-bearing mice by combining it with an intermittent in vivo transfer of in vitro cultivated Mø (therapy sequence: CY----Mø transfer----MVE-2), which would result in an increased Mø:MBL-2 tumor cell ratio at the site of the tumor while reducing the adverse effects of CY on macrophage functions.

[Protein deficiency, host defense and natural anti-tumor immunity]. / Proteinmangel, Körperabwehr und natürliche Anti-Tumor-Immunität.

Natural immuneffector cells, namely natural killer cells and monocyte/macrophages, have become in recent years an important part of theory and practice of immunotherapy. This is especially the case for therapy of malignant tumors with biological response modifiers (BRMs). Many BRMs increase cytotoxicity against tumor cells and cell numbers of natural immuneffector cells. Protein depletion on the other hand, which often is part of malignant diseases, results in well known negative effects on acquired and specific immunity. The data which are presented here show that depressions of natural immuneffector cells in terms of cytotoxicity and cell numbers also occur after protein depletion. The same is true for their pool, the bone marrow. The potentials of BRM therapy are considerably decreased. Host defense mechanisms in normal and protein depleted nutritional status, immunological tumor defense and BRM therapy are presented in the survey.

Effect of fenticonazole in vaginal candidiasis: a double-blind clinical trial versus clotrimazole.

Fenticonazole is an imidazole derivative which possesses a broad spectrum antimycotic activity, including activity against Candida albicans. Its therapeutic activity and tolerability have been evaluated, in a double-blind clinical trial versus clotrimazole, in 54 patients affected by mycologically confirmed symptomatic vaginal candidiasis. Both drugs were administered intravaginally as a cream once a day for 7 days. Assessment was by laboratory mycological investigations and symptomatic evaluation. Patients 'cured' at the end of the trial were re-evaluated after 4-6 weeks for possible relapses. Both treatments resulted in a progressive, statistically significant reduction in vaginal symptoms (itching and discharge) and in elimination of Candida in more than 95% of patients. When 'cured' patients were reassessed 4-6 weeks after therapy, relapses occurred in four patients after fenticonazole treatment, but in none following clotrimazole treatment. This apparent difference between treatments is far from being statistically significant and, therefore, may have been a chance occurrence. It should also be noted that patients from the fenticonazole group had a previous history of significantly more frequent episodes of candidiasis suggesting that they may have been at greater risk of re-infection than patients from the control group. The tolerance of both treatments was excellent since no local or systemic signs or symptoms of toxicity were reported. An equally high efficacy and safety for both drugs in the elimination of symptoms and objective evidence of vaginal candidiasis is indicated.

Effects of poly(I,C)-LC on growth and differentiation of normal and malignant myelopoietic progenitor cells.

Polyriboinosinic-polycytidylic acid with poly-L-lysine stabilized with carboxymethylcellulose [poly(I,C)-LC] augmented, in a dose- and time-dependent manner, secretion of colony-stimulating factor (CSF) by peritoneal macrophages (M phi) and bone marrow cells (BMC). Optimal effects were found after 2 days of in vitro culture of the cells with 50 micrograms/ml of poly(I,C)-LC or 14 h to 3 days after a single intraperitoneal injection of 1-2 mg/kg of poly(I,C)-LC into normal mice. The increase in CSF secretion by M phi and BMC was paralleled in vivo by an increase in serum CSF levels, followed by a rise in committed granulocyte and M phi progenitor cells (GM-CFU-C), nucleated BMC, and blood leukocytes of myelomonocytic origin. Poly(I,C)-LC at doses greater than 4 mg/kg, however, were strongly myelosuppressive. In vitro treatment of undifferentiated myelomonocytic leukemia cells from the WEHI-3B cell line with 10-1,000 micrograms/ml of poly(I,C)-LC resulted in a significant increase in CSF secretion by the leukemic cells and a concomitant inhibition of their proliferation. Incubation of cells from the WEHI-3B D+ subline, which differentiate in response to GM-CSF or G-CSF, with 50-100 micrograms/ml poly(I,C)-LC in agar cultures induced in approximately 45% of the leukemic colonies a differentiation into granulocytes and/or M phi. Poly(I,C)-LC, however, had no effect on differentiation of cells from the CSF unresponsive WEHI-3B D- subline. The CSF-inducing biological response modifier poly(I,C)-LC thus has the potential to stimulate growth and differentiation of normal, as well as differentiation of malignant myelopoietic progenitor cells.

Pharmacokinetic and therapeutic activity of polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(I,C)-LC].

Polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(I,C)-LC] significantly augmented natural killer (NK) cell activity in several tissues. Macrophage (M phi) tumoricidal activity was also markedly increased. Both effector cells were active for 9 days. Poly(I,C)-LC also increased effector cell response in vitro. Injections of poly(I,C)-LC resulted in elevated effector cell responses in four of five routes tested. Treatment with poly(I,C)-LC led to an earlier reconstitution of bone marrow cells, NK cell activity, and M phi effector cell activity in mice pretreated with cyclophosphamide (Cytoxan). Combined treatment of MBL-2 tumor cells with cytoreductive chemotherapy and poly(I,C)-LC resulted in an enhanced therapeutic response.