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The redback spider (Latrodectus hasseltii) is nonindigenous to Japan but has now spread throughout the country. Bites to humans are rare but can be fatal. We prepared freeze-dried redback spider antivenom for therapeutic use against bites in Japan by immunization of horse plasma. This study included two nonclinical tests of the antivenom: a local irritation study involving a single intramuscular administration to rabbits (with injections of physiological saline and an existing freeze-dried diphtheria antitoxin as control and comparison substances, respectively) and a 2-week repeated intermittent intravenous-dose toxicity study in rats. The irritation study showed the antivenom's irritancy to be comparable with that of the saline and the existing antitoxin preparations under the test conditions. In a repeated-dose toxicity study, no toxicity change was found in male or female rats, and the no-observed-adverse-effect level (NOAEL) was judged to be a dose volume of 20 mL/kg (1082 units/kg antivenom activity) in both male and female rats. In addition, there was no toxicological difference between proteinaceous diphtheria antitoxin and redback spider antivenom prepared to have the same protein content and the same additive composition. Based on these findings, we will further advance our research towards clinical application of the redback spider antivenom. This research was supported by the Research Program on Emerging and Re-emerging Infectious Disease of the Japan Agency for Medical Research and Development.

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The redback spider (Latrodectus hasseltii Thorell) reportedly invaded Japan in September 1995. To date, 84 redback spider bite cases have been reported; 7 of these cases employed the antivenom. Antivenom has been imported from Australia in the past, but because of restrictions on exportation it was evident that nearly all of the antivenom present in Japan would expire during 2014. In 2014, a plan was proposed to experimentally manufacture and stockpile a horse antiserum for ourselves, using redback spiders indigenous to Japan. A total of 11,403 female spiders were captured alive: 1,217 from the vicinity of Nishinomiya City, Hyogo prefecture, and 10,186 from Osaka prefecture. Of these, 10,007 females were dissected, and the venom was extracted from the venom glands of individuals and subjected to crude purification to yield 4 lots, of which the majority was α-latrotoxin. Among them, a large amount of single lots with an estimated protein content of 236 mg is subsequently scheduled to be used for immunizing horses. We also determined lethal toxicity of the venom (LD50: 9.17 µg per mouse), and established the assay for the determination of an anti-lethal titer of antivenom in mice.

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This is the first report on large-scale experimental production of an equine antivenom against the redback spider (Latrodectus hasseltii) lived in Japan. We captured 10,000 redback spiders in Japan and prepared the toxoids of crude venom extract, mixed the toxoids with a mineral oil adjuvant, and immunized healthy horses repeatedly over a period of several weeks. Thereafter, we separated the horse plasma, purified the γ-globulin fraction, and stocked it as a purified antivenom concentrate. Consequently, we manufactured approximately 6,500 vials of a single-dose freeze-dried test lot from a portion of the purified γ-globulin fraction, equivalent to the extract derived from 520 spiders. This test lot had an antitoxin titer comparable to that of a similar drug commercially available overseas (a liquid preparation), and the other quality met all quality reference specifications based on the Minimum Requirements for Biological Products and other guidelines relevant to existing antivenom drug products in Japan.

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In autumn 2014, with great effort by the Ministry of Health, Labour and Welfare, the research group will obtain several vials of redback spider (RBS) antivenom for emergency use. However, these small amounts of antivenom are insufficient to cover the demands from majority of hospitals in Japan. The research group carefully discussed the domestic RBS antivenom production by themselves for this emergency. We have now entered the second stage for large-scale antivenom production. Although the domestic production of RBS antivenom has started, great caution is required as we move forward with this plan.

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PURPOSE: Pyrazinamide is an antituberculous drug that is administered as a two-month course during treatment of pulmonary tuberculosis. Adverse reactions to pyrazinamide have been reported to include hyperuricemia. We performed a retrospective multicenter epidemiological survey to assess the relationship between various patient characteristics and the uric acid level, the changes of uric acid during pyrazinamide administration, and the use of medications for uric acid control as well as attacks of gout or arthralgia at the onset of hyperuricemia. A total of 226 patients who were admitted to four hospitals with pulmonary tuberculosis between January and December 2006 and received short-term intensive pyrazinamide therapy were studied. RESULTS: There were 172 men and 54 women with an average age of 59.5 years and an average body mass index of 19.8 kg/m2. The average serum uric acid concentration before pyrazinamide treatment was 4.73 +/- 1.78 mg/dl, while the average uric acid level after pyrazinamide treatment was 10.63 +/- 2.67 mg/dl, which was significantly higher than the pretreatment level (p<0.0001). During treatment, hyperuricemia (Serum uric acid > or = 8 mg/dl) was reported in 84.5% of patients and arthralgia developed in 4.42%. Although the therapy instituted in 51 patients (22.57%) had to be interrupted or discontinued due to liver dysfunction and skin rashes, which were probably caused by isoniazid and rifampicin, no patient ceased taking pyrazinamide due to an increase of uric acid. Drugs for uric acid control were administered to 21 patients (9.29%). Pyrazinamide is an important agent for intensive short-term antituberculous therapy. Hyperuricemia due to this drug can be managed by observation and does not require interruption of administration.

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PURPOSE: To study rifampicin (RFP) suppository formulations that were prepared by adding an absorption promoter and a holding agent to conventional rifampicin suppositories in order to achieve higher blood drug levels. SUBJECTS AND METHODS: The subjects were 3 healthy volunteers who gave consent to participate in this study. Suppository formulations were prepared by adding sodium caprinate (the absorption promoter) to 600 mg, 750 mg, or 900 mg of RFP at about 3% of the suppository weight and sodium alginate (the holding agent) at 25% of the RFP content. Serum samples collected at 2, 6, and 10 hours after insertion of a suppository were subjected to RFP concentration analysis. RESULTS: In subject no. 1, the maximum concentration was 0.807 Lg/ml, 1.093 microg/ml, and 1.291 microg/ml after administration of a suppository containing 600 mg, 750 mg, or 900 mg of RFP, respectively. DISCUSSION: Since an injectable RFP formulation has not been approved in Japan, formulation studies of RFP suppositories are important to achieve a better clinical response and to prevent the development of resistance. The present formulation that delivered a blood concentration of RFP considerably higher than 1 microg/ml was considered to have therapeutic potential. Its clinical utility will be examined in further formulation studies.

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PURPOSE: We reviewed the interaction between rifampicin (RFP) and clarithromycin (CAM) during treatment of pulmonary Mycobacterium avium complex infection. SUBJECTS AND METHODS: The subjects were patients with pulmonary non-tuberculous acid-fast bacillus infection during the period from September 2004 to January 2006 who consented to this study. Drug blood concentrations were compared with the minimum inhibitory concentrations for M. avium isolated from sputum and blood levels of CAM were assessed when the time of administration was changed for RFP. RESULTS: The blood concentration of CAM showed a marked decrease in all cases (n = 6) when administered together with RFP, but there was no significant difference in the blood concentration of 14-R-hydroxy-clarithromycin (M-5), the active metabolite of CAM. However, the total blood concentration of CAM and M-5 showed a significant fall, similar to the blood concentration of CAM alone. When the blood concentration and bacterial MIC were compared for RFP, the blood concentration exceeded five MIC(s) in six samples as did the CAM+M-5 level in four out of six samples. There was no significant difference in the blood concentration of CAM (n = 5) when the time of RFP administration was altered. CONCLUSION; Because the total blood concentration of CAM+M-5 fell markedly by co-administration of RFP, this might have an influence on the antibacterial effect of CAM. In addition, examination of the administration of RFP and CAM at different times showed that the blood concentration of CAM did not increase and the influence of induction of hepatic drug-metabolizing enzymes by RFP could not be avoided.

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Rifampicin (RFP) induces hepatic drug-metabolizing enzymes, making drug interactions a very important clinical problem. Clarithromycin (CAM) metabolism is reportedly enhanced by induction of hepatic drug-metabolizing enzymes (CYP3A4) by RFP, so that the blood lend of CAM decreases when RFP is administered concurrently. We connected an electrochemical detector to a high-performance liquid chromatograph (HPLC) for simple, rapid, easy measurement of blood concentrations of RFP and CAM. Using samples of patient serum, normal serum, and reference standards, we compared HPLC by an external laboratory and the results of LC/MS/MS analysis with those of this new assay. A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels (r=0.975, p<0.01). A strong correlation was also seen between results we obtained for CAM with the electrochemical detector in this assay and values measured by LC/MS/MS analysis (r=0.995, p<0.01). Our method enabled simple, rapid measurement of RFP and CAM by connecting the HPLC and electrochemical detector in tandem. This system was used to modulate dosage during combined therapy with RFP and CAM. The therapeutic effect for nontuberculous mycobacteriosis is expected to improve, and our HPLC is expected to be useful for simple, rapid, easy measurement of blood concentrations.

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