Acridone acetic acid, sodium salt, as an agent to stop vitiligo progression: a pilot study.

Vitiligo progression is attributed to immune system malfunctioning, thus immunomodulating compounds might be beneficial in stopping vitiligo progression which is a prerequisite for successful repigmentation. The goal of this study was to assess efficacy of acridone acetic acid, sodium salt (Na-AAA), an immunomodulating compound with favorable safety profile, in stabilizing active vitiligo, and to reveal prognostic factors of treatment outcome. Sixty consecutive patients with progressing nonsegmental vitiligo were treated with 10 i.m. injections of Na-AAA every other day. Disease stability was assessed in 1, 3, 6, and 12 months post-treatment. Statistical analysis was applied to correlate treatment outcome and available clinical parameters. Of the 60 patients treated, vitiligo stopped progression in 44 patients (73.3%). Older age (p = 0.0219), age of 35 and older (p = 0.0189, odds ratio (OR) = 5.2, 95% confidence interval (CI) 1.30-20.84) or age of 40 and older (p = 0.0039, OR = 6.48, 95% CI 1.86-22.61), longer disease duration (p = 0.0234), pre-treatment interleukin-6 level over 2 pg/mL (p = 0.0005, OR = 13.7, 95% CI 2.97-63), and over the reference threshold value 5.9 pg/mL (p = 0.0009, OR = 25.8, 95% CI 2.8-239) as well as presence of other autoimmune diseases (p = 0.038, OR = 7.0, 95% CI 1.14-42.97) were negative prognostic factors of treatment success. In conclusion, acridone acetic acid, sodium salt, emerges as an efficient option for stopping vitiligo progression.

[Efficiency of cycloferon application in often ill children in the period of raised seasonal morbidity of acute respiratory infections].

RESEARCH OBJECTIVE: to evaluate the efficiency of the cycloferon (in tablets) in treatment of frequently ill children (FIC) during seasonal acute respiratory infections and estimate its safety for children and adults. Research had open character. Under supervision there were 411 children of different age groups and 74 adults. 250 persons (100 frequently ill children from 4 to 7 years old , 76 - from 7 to 18 and 74 adults) were treated with cycloferon under the standard regimen. Control group included 235 FIC. It was found that the preventive courses of cycloferon administered during seasonal acute respiratory infections significantly reduced number of day offs taken by parents for sick 5 year old and younger FIC. The cycloferon administration in 94,8 % of cases was not accompanied by pathological symptoms.

[Evaluation of safety and pharmacotherapeutic efficacy of cycloferon in treatment of Astrakhan rickettsial fever].

Clinicopathogenetic impact of cycloferon, an endogenous interferon inductor, on the process of Astrakhan rikettsial fever, its complications and outcomes was analysed. The treatment scheme with addition of cycloferon to the complex therapy was optimized. The specificity of the disease clinical process and the level of the interferon status in the patients treated with cycloferon alone or with combination of the standard therapy and cycloferon was shown. It was observed that in the patients with moderate severity of the disease the combined use of the standard therapy and cycloferon was in favour of arresting the disease clinical signs (fever, headache, weakness, eruption, hepatomegaly, arthralgia and myalgia, lymphatic gland inflammation, primary affect) and lowered the hospitalization term vs. the standard therapy alone. In the patients with moderate severity of the disease the levels of the serous interferon-alpha before the treatment were found lower, while those of interferon-gamma were higher. The use of cycloferon in the treatment scheme resulted in increase of the interferon-alpha levels and decrease of the higher levels of interferon-gamma. The standard therapy in combination with cycloferon in the patients with moderate severity of the disease provided changes in the immune status: increase of the relative content of T- and B-lymphocytes and normalization of their absolute number. Normalization of the phagocytic activity and the coefficient of the active phagocytes, as well as increase of the phagocytic index, the levels of immunoglobulins G, A and M and the number of the circulating immune cells were stated. The standard therapy with addition of cycloferon resulted in normalization of the levels not only of succinic denydrogenase, lactate dehydrogenase and glucose-6-dehydrogenase but also of alpha-naphthylacetate esterase and alpha-naphthylbutirate esterase in the neutrophils, as well as of the whole spectrum of the monocyte enzymes, except NAD-diaphorase. The adverse reactions were observed in 2.5% of the cases (9 subjects). All of them were mild and did not require discontinuation of the drugs use.

[Monitoring of side effects and estimation of cycloferon efficacy in treatment of children with frequent and prolonged diseases].

Two hundred fifty patients, including 100 children with frequent and prolonged diseases at the age of 4 to 7 years, 76 children at the age of 7 to 18 years and 74 subjects at the age of 22 to 57 years were observed. The patients were treated with cycloferon in two courses with a 2-week interval according to the standard scheme. The tonsil surface microflora and its susceptibility to antibiotics were determined. Cycloferon lowered the Staphylococcus aureus titre and increased the culture susceptibility to benzylpenicillin, oxacillin, rifampicin, and erythromycin, reducing the variety of the fauces nonpathogenic microflora. The use of cycloferon induced no adverse (pathologic) reactions in 94.8% of the cases. In 4.4% of the children under school age the adverse reactions were transitory and did not require discontinuation of the drug use. Unforeseen reactions were recorded in 0.8% of the children and the use of the drug in them was discontinued. The use of cycloferon in two courses with a 2-week interval according to the standard scheme is recommended for prophylaxis of acute respiratory diseases in the group of children with frequent and prolonged diseases during epidemiologically unfavourable periods and for complex therapy of rhinopharinx infections as an agent increasing efficacy of other antibacterials.

[Efficacy of antiviral agents in the treatment of Crimean hemorrhagic fever].

The study aimed at estimating the pharmacotherapeutic efficacy of medications possessed of antiviral activity, such as ribavirin, cycloferon solution and tablets, in 410 patients with Crimean hemorrhagic fever: The early beginning of therapy (days 1-4 after the onset of the disease) with these drugs reduced the number of severe cases and manifestations of hemorrhagic syndrome. The duration of the disease decreased, the occurrence of intoxication syndrome reduced to a minimum, hemorrhagic rash rapidly disappeared, and the frequency of complications decreased. Adverse events were documented in 5.2% of the patients (n = 15); most of them developed on day 2 after using the drugs, their duration did not exceed 2.2 days. There were no cases of drug withdrawal.

[Herpetic infection in patients with psoriasis: the improvement of therapy].

The aim of the study was to estimate the efficacy of liniment cycloferon included in combined therapy of herpetic infection in 30 patients with psoriasis divided into 2 groups. Combined treatment of patients with recurrent herpetic infection promoted elimination of general infection syndrome, shortened duration of eruption and local inflammation, accelerated epithelization of herpetic erosion, and decreased the frequency of relapses during the follow-up.

Phase II trial of pyrazoloacridine (NSC#366140) in patients with metastatic breast cancer.

PURPOSE: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases 1 and 2. We conducted a phase II clinical study to determine the efficacy and toxicities of PZA in patients with metastatic breast cancer (MBC). EXPERIMENTAL DESIGN: In this phase II multicenter study, patients who were treated with no more than one prior chemotherapy for MBC were treated with 750 mg/m² of PZA given as a 3-hour intravenous infusion every 3 weeks. Treatment cycles were continued until disease progression or unacceptable toxicities. The study was designed to distinguish between a response rate of < 15% vs > 30% (alpha = 0.10, beta = 0.10) using Simons optimal 2-stage design. At least 2 responses were required in the first 12 patients in the 1st stage and 6 of 35 in the 2nd stage to recommend the agent for further study. RESULTS: Two patients in the first stage had a response allowing accrual to second stage. A total of 15 patients (out of 35 planned) were treated on the study prior to premature closure. Three patients had a partial response (20%) lasting 4.5-6 months. Two patients had stable disease for 3 and 5 months. The dose limiting toxicity was granulocytopenia with ten patients requiring dose reduction or dose delay for grade 4 neutropenia. Other grade 3 and 4 toxicities include vomiting (n = 2), nausea (n = 2), neurotoxicity (n = 1), fatigue (n = 1), anemia (n = 1), dyspnea 9n = 1) and renal (n = 1). CONCLUSIONS: Pyrazoloacridine demonstrated modest activity in patients with metastatic breast cancer.

[Combined therapy of patients with recurring anogenital herpes infection].

Up-to-date conceptions of etiology and epidemiology of anogenital herpetic infection are described. The main mechanisms of immunological shifts in subjects with anogenital Herpes infection are discussed. The efficacy and safety of cycloferon in the combined treatment of patients with recurring anogenital herptic infection were estimated. The clinical efficacy of the combined therapy (acyclovir in a dose of 200 mg 5 times a day for 5 days + cycloferon liniment applied topically on the eruptions twice a day for 5 days) was 85% or 25% higher vs. the control.

[Peculiarities of immunomodulating therapy in an immunocompromised patient with allergies].

The authors summarize recent data on the predisposition to, indications for, and efficacy of immunomodulating therapy of immunocompromised patients presenting with allergia. Clinical and immunological characteristic of pathology is presented including cytokine status before and after therapy. High efficacy of immunomodulators like interferons is exemplified by the most efficacious of them, cycloferon (meglumin acridonacetate). Disturbed immune reactivity promotes the development of pathological process. Results of the studies of various aspects of immunogenesis suggest desirability of inclusion of cycloferon therapy in the combined treatment of the disease under consideration. New aspects of clinical use of the immunomodulator cycloferon in combination with allergen-specific immunotherapy are discussed.

Quinpramine--a promising compound for treating immune-mediated demyelination of the nervous system.

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Different therapeutic options are available, but all require parenteral application and some expose patients to potentially lethal adverse effects. The response to treatment remains variable and often incomplete. Thus, the search for novel therapeutic agents is ongoing and relevant. The chimeric compound quinpramine-generated from its precursor substances imipramine and quinacrine-has recently demonstrated clinical efficacy in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mechanistic considerations and recent experimental data suggest that intracellular redistribution of antigen-presenting molecules and cholesterol-rich membrane domains may account for the clinical efficacy of this drug. This article summarizes available treatment options in MS and explains why the candidate compound quinpramine may transfer from bench to bedside in the near future.

Alpha-2c-adrenergic receptors contribute to basal nasal patency in the anesthetized cat.

BACKGROUND: Nasal congestion is the most troublesome symptom associated with a variety of upper airway diseases, including allergic rhinitis and the common cold. A better understanding of the mechanisms that regulate nasal cavity caliber may engender the development of novel treatment strategies. It is well accepted that alpha-adrenergic (both alpha(1) and alpha(2)) mechanisms play a fundamental role in the control and maintenance of basal nasal patency. JP-1302 is a selective alpha(2c)-subtype antagonist that has been recently described in the scientific literature. Thus, we sought to examine the potential effects of this new pharmacological tool on basal nasal patency. METHODS: Using acoustic rhinometry, we studied the activity of the selective alpha(2c)-antagonist JP-1302 on nasal cavity volumes in an anesthetized cat. Cumulative concentrations of JP-1302 were applied directly into the right nasal cavity. Changes in the nasal cavity geometry of the drug-treated naris relative to the untreated left nasal cavity were determined. In separate studies, the nonselective alpha(2)-antagonist yohimbine and the nonselective alpha(1)-antagonist prazosin were run as comparators. Systolic blood pressure was measured at the hind leg, using an ultrasonic Doppler flow detector. RESULTS: JP-1302 (0.03, 0.1, 0.3 and 1.0%) administered by the intranasal route decreased nasal cavity volumes from baseline values by 17, 25, 40 and 40%, respectively. Yohimbine (0.03, 0.1, 0.3 and 1.0%) decreased volumes by 19, 36, 46 and 53%, and topical administration of the nonselective alpha(1)-antagonist prazosin (0.001, 0.003, 0.01, 0.03 and 0.1%) decreased volumes by 6, 47, 56, 64 and 71%, respectively. JP-1302, yohimbine and prazosin, at the dose level tested, did not alter the blood pressure. CONCLUSIONS: The present set of experiments indicates that both alpha(1)- and alpha(2)-adrenergic receptors are involved in the maintenance of basal nasal patency in the cat. Moreover, alpha(2c)-receptors may play a significant role in the sympathetic control of upper airway function.

[Chemotherapy of chronic viral hepatitis B: randomized multicenter investigation results].

During treatment of patients with chronic hepatitis B the best therapeutic effect was obtained with the inclusion in the scheme of antiviral therapy cycloferon. Complete stable remission was achieved in 54.1% of patients in combination cycloferon with lamivudin, but the appointment of alpha-interferon with cycloferon provided remission 44.1% of patients resistant to treatment with lamivudin. Therapy of chronic hepatitis B with cycloferon can reduce the frequency and severity of side effects, prevents the development of resistance to lamivudin and the emergence of mutant viruses.

[Pathogenetically substantiated therapy of patients with virus hepatitis C, quality of life, and the disease outcome risk (clinical survey)].

The aspects of virus hepatitis C immunopathogenesis are discussed. The main attention is paid to higher production of Th1 cytokines providing active protection of the host from HCV. The up-to-date approaches to the therapy of chronic hepatitis C, described in the literature and the original ones, including the triple therapy with immunomodulators of various mechanisms of action, i.e. cycloferon (injections and tablets), galavit and derinat are presented. The comparative efficacy of the therapy is estimated. Cycloferon is shown to be the drug of choice in the treatment of patients with virus hepatitis addicted to narcotics. The clinical and laboratory efficacy of the metabolic hepatoprotector remaxol with antioxidant activity is described. Its high effictivity and satisfactory tolerability (side effects requiring discontinuation of the drug use were recorded only in 0.3% of the cases), as well as the minimal risk of no biochemical remission after its use allow to conseder remaxol as a highly efficient metabolic hepatoprotector for pathogenetic therapy of chronic hepatitis.

[Type 1 and type 2 interferon inductor (cycloferon) in therapy of children with pyelonephritis associated with herpes viruses].

The clinical and laboratory efficacy of the treatment of children with pyelonephritis with addition of cycloferon, an inductor of early interferon of types 1 and 2, to the main therapy was studied. The mechanism of the cycloferon action was described. The clinical and laboratory remission within a year was observed in 64.3% of the patients treated with addition of cycloferon vs. 47.1% of the patients under the main therapy without the cycloferon addition. The number of the relapses lowered to 7.1% vs. 20.6% of the episodes in the control group. The minimal risk of the disease exacerbation (0.37) in the patients treated with cycloferon and the relative risk of the unfavourable outcomes among the patients under the therapy with addition of cycloferon (0.5967< or =1) were determined.

[Effect of intranasal aerosol-therapy with cycloferon on the function of respiration in patients with some forms of rhinitis].

Total of 62 patients have been examined, out of which 34 patients had chronic catarrhal rhinitis, and 28 patients - perennial allergic rhinitis. It has been established that intranasal aerosol-therapy with cyclopheron induced expressed improvement of bronchial permeability in these patients, as well as increase of reserve possibilities of lungs and decrease, up to complete elimination, of arterial and venous hypoxemia. Above positive shifts were significant in chronic catarrhal rhinitis.

Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar.

Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000 mg in 12 healthy volunteers. A target Cmax was set at ≥ 200 ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9 ± 3.7 times higher compared to that from a crystalline powder mixture. Cmax and AUC0-∞ increased linearly with dose over the explored range. The target Cmax of ≥ 200 ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmax and AUC0-∞ were 326 ± 67 ng/mL and 13.4 ± 8.6 · 103 ng · h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.

Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.

PURPOSE: XR5000 (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) is a topoisomerase I and II inhibitor. Because the cytotoxicity of XR5000 increases markedly with prolonged exposure, we performed a phase I study of weekly XR5000 by 120-hour continuous infusion over 3 weeks. PATIENTS AND METHODS: Twenty-four patients with advanced solid cancer were treated at seven dose levels (700 to 4,060 mg/m2/120 hrs) for a total of 67 cycles. Three patients underwent positron emission tomography (PET) studies at the maximum-tolerated dose (MTD) to evaluate normal tissue and tumor carbon-11 radiolabeled XR5000 ([11C]XR5000) pharmacokinetics. RESULTS: The dose-limiting toxicity was National Cancer Institute Common Toxicity Criteria (version 1) grade 4 chest and abdominal pain affecting the single patient receiving 4,060 mg/m2/120 hours, and the MTD was 3,010 mg/m2/120 hours. Other grade 3-4 toxicities, affecting single patients at the MTD, were myelosuppression (grade 4), raised bilirubin, vomiting, and somnolence (all grade 3). There was one partial response (adenocarcinoma of unknown primary); the remainder had progressive disease. [11C]XR5000 distributed well into the three tumors studied by PET. Tumor uptake (maximum concentration or area under the concentration versus time curve [AUC]) was less than in normal tissue in which the tumors were located. Tumor exposure (AUC; mean +/- SD in m2/mL/sec) increased when [(11)C]XR5000 was administered during an infusion of XR5000 (0.242 +/- 0.4), compared with [11C]XR5000 given alone (0.209 +/- 0.04; P <.05), indicating that tumor drug exposure was not saturated [corrected]. CONCLUSION: The recommended dose for XR5000 in phase II studies is 3,010 mg/m2/120 hours. PET studies with 11C-labeled drug were feasible and demonstrated in vivo distribution into tumors. Saturation of tumor exposure was not reached at the MTD.

Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers.

PURPOSE: To define the maximum-tolerated dose (MTD), quantitative and qualitative toxicities, recommended phase II dose, and pharmacokinetics of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion in children and young adults with refractory cancers. PATIENTS AND METHODS: Twenty-two patients received PZA as a 1-hour infusion at doses of 380 mg/m2 (n = 3), 495 mg/m2 (n = 6), 640 mg/m2 (n = 6), and 835 mg/m2 (n = 7). An additional four patients received PZA as a 24-hour infusion at the MTD (640 mg/m2) for the 1-hour infusion schedule. Plasma samples were obtained for pharmacokinetic analysis in 17 patients. PZA concentration in plasma was measured by reverse-phase high-performance liquid chromatography (HPLC). A two-compartment pharmacokinetic model was fit to the PZA plasma concentration data. RESULTS: On the 1-hour infusion schedule, dose-limiting myelosuppression (neutropenia more than thrombocytopenia) was observed in two of seven patients at the 835-mg/m2 dose level. Myelosuppression did not appear to be ameliorated by prolonging the infusion to 24 hours. Nonhematologic toxicities were minor. Significant neurotoxicity, which was dose-limiting in adults treated with a 1-hour infusion of PZA, was observed in one patient treated at 640 mg/m2, but was not dose-limiting. There was marked interpatient variability in plasma PZA concentrations at all dose levels. The pharmacokinetic profile of PZA was characterized by an initial rapid decline (alpha half-life [t(1/2)alpha], 0.5 hours) followed by a prolonged elimination phase (t(1/2)beta, 30 hours). The volume of distribution at steady-state (Vd(ss)) was 700 L/m2 and the clearance was 300 mL/min/m2. There was no evidence of dose-dependent clearance. The area under the PZA concentration-time curve (AUC) correlated poorly with dose and was more predictive of the degree of myelosuppression than was PZA dose. CONCLUSION: PZA administered as 1- or 24-hour infusion is well tolerated by children and young adults. The dose-limiting toxicity (DLT) is myelosuppression. Neurotoxicity is not prominent in this age group. There was marked interpatient variation in plasma concentrations of PZA. The recommended dose for phase II studies is 640 mg/m2.

Phase I and pharmacologic studies of pyrazoloacridine, a novel DNA intercalating agent, on single-dosing and multiple-dosing schedules.

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacologic behavior of pyrazoloacridine (PZA), a novel DNA intercalator with a unique mechanism of action, on single- and multiple-dosing schedules. PATIENTS AND METHODS: PZA was administered on a single-dosing schedule as a 1- to 3-hour infusion and on a multiple-dosing schedule as a 1-hour infusion daily for 5 days to cancer patients at doses ranging from 400 to 935 mg/m2 and 40 to 180 mg/m2/d every 3 weeks, respectively. RESULTS: On the single-dosing 1-hour schedule, CNS toxicity, characterized by neuropsychiatric and neuromotor effects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures resulted in lower incidence of CNS toxicity. Neutropenia was the principal toxicity and precluded dose escalation to levels greater than 750 mg/m2 on the single-dosing (3-hour) schedule and 150 mg/m2/d x 5 (total dose, 750 mg/m2) on the multiple-dosing schedule. Thrombocytopenia, anemia, and nonhematologic effects occurred less frequently. Responses were observed in several patients with platinum- and taxane-refractory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and troughs was observed in the pharmacologic studies. The maximal PZA concentrations achieved in both studies exceeded drug concentrations associated with significant cytotoxicity in preclinical studies and correlated with the occurrence of CNS toxicity. CONCLUSION: Neutropenia is the dose-limiting toxicity on both schedules and 750 mg/m2 and 150 mg/m2/d are the recommended starting doses of PZA on single- and multiple-dosing schedules, respectively, for minimally pretreated patients in phase II studies; slightly lower doses are recommended for more heavily pretreated subjects. The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase II evaluations of this agent.

A phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients.

PURPOSE: Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks. EXPERIMENTAL DESIGN: Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m(2)). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose. RESULTS: Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m(2), but lower doses were well tolerated. No responses were seen, but 28% had stable disease for > or =3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m(2) indicated the following averages: maximum plasma level, 1.6 microM; area under the plasma concentration-time curve, 56 microM.h; terminal half-life, 27 h; urinary recovery, 17% over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at > or =281 mg/m(2)). CONCLUSIONS: Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m(2), which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.