Synthesis, characterization, and in vitro evaluation of gamma radiationinduced PEGylated isoniazid

Background: The search for innovative anti-tubercular agents has received increasing attention in tuberculosis chemotherapy because Mycobacterium tuberculosis infection has steadily increased over the years. This underlines the necessity for new methods of preparation for polymer-drug adducts to treat this important infectious disease. The use of poly(ethylene glycol)(PEG) is an alternative producing anti-tubercular derivatives. However, it is not yet known whether PEGylated isonicotinylhydrazide conjugates obtained by direct links with PEG are useful for therapeutic applications. Results: Here, we synthesized a PEGylated isoniazid (PEG-g-INH or PEG­INH) by gamma radiation-induced polymerization, for the first time. The new prodrugs were characterized using Raman and UV/Vis spectrometry. The mechanism of PEGylated INH synthesis was proposed. The in vitro evaluation of a PEGylated isonicotinylhydrazide macromolecular prodrug was also carried out. The results indicated that PEG­INH inhibited the bacterial growth above 95% as compared with INH, which showed a lower value (80%) at a concentration of 0.25 µM. Similar trends are observed for 0.1, 1, and 5 µM. Conclusions: In summary, the research suggests that it is possible to covalently attach the PEG onto INH by the proposed method and to obtain a slow-acting isoniazid derivative with little toxicity in vitro and higher antimycobacterial potency than the neat drug.

Review of the present situation and improvement of the level of reimbursement related to infec-tious diseases medical care:Take tuberculosis as an example / 中国卫生政策研究

Purpose:Taking tuberculosis as an example, this paper aims at to analyzing the level of reimburse-ment for infectious diseases care, and clarifying the government responsibility. Methods:In order to achieve the ob-jective of this research, UHC framework was used to analyze the security level. Result:The findings of this research reveal that TB in-patients' Compensation Ratio of the New Cooperative Medical Scheme ( NCMS) was lower than aver-age level of all the NCMS patients, the out-patients' was even lower. The categories of anti-tuberculotic for free was limited, the utilization was not as expected. Medical assistance covered few people in spite of its high level of reim-bursement. Conclusion:Based on the findings of this review, it has been revealed that the medical insurance didn't make a big difference in financial protection for patients with infectious diseases. As the treatment for of infectious diseases is a quasi-public good, the government has to shoulder the responsibility of improving the compensation ratio of the patients.

Bioavailability of TBI-166, a novel antituberculotic, in beagle dogs / 国际药学研究杂志

Objective To develop a LC-MS/MS method for the quantification of TBI-166, a novel antituberculotic, in beagle dog plasma, and apply it to the pharmacokinetic and bioavailability study. Methods The preparation of plasma sample was a simple deproteinization by the addition of acetonitrile followed by centrifugation. The separation was performed on a Symmetry C 8 column (2.1 mm × 50 mm,3.5μm) with mobile phase of acetonitrile/water containing 0.1%formic acid(V/V) using a gradient elution mode at a flow rate of 0.2 ml/min. The detection was performed in positive selected reaction monitoring (SRM) mode with an electrospray ionization source. The analytes were quantified at m/z 590→478 for TBI-166 and m/z 260→183 for propranolol (internal standard, IS). Results Linear detection responses were obtained for TBI-166 in dog plasma ranging from 2 to 1000 ng/ml. The intra- and inter-day precisions (RSD%) were no more than 10%. The average recovery was greater than 98.6%, and there was good stability and no obvious matrix effect for the quantification. The method was successfully applied in the pharmacokinetic study of TBI-166 in beagle dogs. The AUC(0-t), Cmax and Tmax of TBI-166 in male and female dogs were(897.2±318.6) and(2615.1±1524.4) h·μg/L,(65.4±2.3) and(122.0±34.6) ng/ml and(1.4±0.5) and(4.4±3.5) h after oral administration at 3 mg/kg. The t1/2z, AUC(0-t), and CL of TBI-166 in male and female dogs were (69.6±35.3) and (112.9±25.3) h, (1798.0±729.2) and (3222.4±1656.2) h·μg/L,(0.2±0.1) and (0.3 ±0.1) L/(h·kg) after intravenous administration at 0.5 mg/kg. Conclusion An accurate, simple and sensitive LC-MS/MS method for the determination of TBI-166 in beagle dog plasma was developed and validated. This method was applied to the pharmacokinetic study of TBI-166 in beagle dogs. There was a gender difference on the pharmacokinetic profiles of TBI-166 in dogs. TBI-166 was eliminated slowly and the bioavailability of TBI-166 was 8.3-13.5% in male and female dogs.

Clinical effect and safety of Feilaoling preparation combined with conventional therapy in treatment of pulmonary tuberculosis / 中草药

Objective: To observe the clinical effect and safety of Feilaoling preparation which is a traditional Chinese prescription that can improve immune function in 60 cases of untreated pulmonary tuberculosis patients. Methods: Patients with pulmonary tuberculosis (120 cases) were randomly divided into treatment (n = 60) and control (n = 60) groups. The patients in the treatment group were treated with both Feilaoling preparation and conventional chemotherapy, and the patients in the control group were only treated with conventional chemotherapy. The clinical effects, lesions absorption, and side effects of drugs were observed in two groups. Results: The clinical symptoms and signs in treatment group were better than those in control group. Sputum negative conversion rates of two months and six months and cavitates closure have no significant difference between two groups (P > 0.05). But the hemoptysis treatment, lesions absorption improved, incidence rates of liver damage, and white blood reduction in two groups were all effectively changed, the treatment group was better than the control group (P < 0.05). The treatment group has a significant change compared with the control group (P < 0.01) in the incidence rate of severe gastrointestinal discomfort. Conclusion: Feilaoling preparation has a reliable effect on promotion lesions absorption and reducing the side effects of Western anti-tuberculosis, with certain clinical value.

Antituberculotic Chemotherapy-General and Hepatic Toxicity Revisited.

Severe or pertinent hepatic toxicity interferes with antituberculotic chemotherapy resulting in dose reductions, treatment delays or cessation of therapy. Hepatic toxicity by antituberculotic agents is due to anaphylactic reactions (acetylaor phenotype polymorphism) and is relative to the cumulative dose intensity. Risk of hepatic toxicity is higher in the elderly and alcoholic patients. Patients with previous hepatic diseases such as hepatitis and comorbidities i.e. HIV infections, malnutrition and renal damages are prone to an added risk of hepatic toxicity. This review consolidates the pattern of hepatic adverse effects associated with each component of the antimyobacterial regimen e.g. isoniazid, rifampicin and pyrazinamaide. Higher propensities of hepatic adverse effects are associated with the first line agents, intensified by the incorporation of second line antibiotics, primarily metabolized in the liver. In conclusion the hepatic biomarkers should be monitored in the patient under a tuberculosis treatment plan as well as purposefully assessed during follow-up visits of the patients.

Investigation and Analysis of Antituberculotics Used in 138 Hospitals of Six Cities During the 1999～2001 Period and Trend Analysis / 中国药房

OBJECTIVE:To analyze the present situation and trend of the application of antituberculotics in hospitals of 6 cities METHODS:The antituberculotics used in 138 hospitals of 6 cities during the 1999～2001 period were analysed in respect to the cost,sales volume of pharmaceutical enterprises and situation of clinical application RESULTS:The costs of consumption of antituberculotics were 6 227 520,7 204 738 and 7 537 601 yuan in 1999,2000 and 2001 respectively with a rising trend year by year The average annual cost of antituberculotics was 282 yuan per sickbed CONCLUSION:The antituberculotics are fewer in kind and inexpensive in price but they occupy an important place in a hospital and their consumption is unceasingly increasing

Efficacy of Reduced Glutathione Against Hepatic Lesion Induced by Antituberculotic Agents / 中国药房

OBJECTIVE:To observe the efficacy of the reduced glutathione against hepatic lesion induced by antituberculotic agents.METHODS:A total of 226 patients with pulmonary tuberculosis undergoing short- course chemotherapy were randomly assigned to receive antituberculotic agents plus reduced glutathione throughout the course(treatment group,n = 114 cases) or to receive Inosine plus Glucurolactone(control group,n = 112).The patients were followed for 3～6 months with the incidence of hepatic lesion compared between the two groups.RESULTS:There were significant differences between the treatment group and the control group in the incidence of hepatic lesion,6 cases(5.3%) in treatment group vs.29 cases (25.9%) in the control group(P

Activity of Pyrazinamide Gel Against Mycobacterium Tuberculosis in Vitro and Eva luation of Its Security / 中国药房

OBJECTIVE:To observe the activity of Pyrazinamide gel against Mycob ac terium tuberculosis in vitro and its security in bronchial interventional therap y METHODS:The MIC and MBC of Pyrazinamide and Pyrazinamide gel were measured b y handwork method and instrument method and secuity of Pyrazinamide gel was asse ssed by bronchial interventional therapy in rabbits RESULTS:The MICs of pyrazi namide gel to M tuberculosis H37 RV,M bovis and M phlei were 1mg/L,1mg/L,1 0mg/L,the MBCs of Pyrazinamide gel to M tuberculosis H37RV,M bovis and M ph lei were 10mg/L,10mg/L,40mg/L respectively;the MIC and MBC of Pyrazinamide gel and those of Pyrazinamide had no significant differences;the animal security ex periment was negative CONCLUSION:These results suggest that Pyrazinamide gel a nd Pyrazinamide have the same efficacy against M tuberculosis,because carbomer dose not affect the activity of Pyrazinamide against M tuberculosis;Pyrazinami de gel which contains carbomer is safe in bronchial interventional therapy

The Present Status of Antituberculotic Drug Markets and Development of the New Varieties of Antituberculotic in China / 中国药房

In the whole world, about 10 millions people suffer from pulmonary tuberculosis each year, of them, three millions died of this disease. At present, there are 5～6 million patients suffering from pulmonary tuberculosis in China. The spread of AIDS results in increase of TB patients. This article emphatically describes the present status of antituberculotie drug markets and the development of the new varieties of antituberculotic in China.

Application of PASS System in Synchronized Monitoring of Medical Orders for Inpatients with Tuberculosis / 中国药房

OBJECTIVE:To evaluate the medical orders in terms of the medication for the inpatients with tuberculosis in our hospital.METHODS:The medical orders for the inpatients in Tuberculosis institute from Dec.7th,2007 to Jan.6th,2008 were synchronously monitored and analyzed.RESULTS:Of the total 5 592 medical orders monitored,1 461 were warned by PASS,of which,562 were warnings about drug interactions,884 about dosage and 15 were about incompatibility.CONCLUSION:Medical orders synchronously monitored by PASS could help correct and monitor the irrational medication.But the function of PASS remained to be strengthened and the data base remained to be enriched and renewed in time.