Filariasis: Current status, treatment and recent advances in drug development.

Lymphatic filariasis, onchocerciasis and loiasis caused by human filarial nematodes are diseases of tropical and subtropical countries causing considerable morbidity. The available control strategies have significant limitations such that current drugs are ineffective against macrofilariae (adult worms), require repeated and prolonged treatment over years and are threatened by emergence of drug resistance. Due to this concern, these diseases are the focus of renewed scientific interest and much has been done in filariasis research in the past decade. This review summarizes the current status of filariasis, different control strategies, recent advances in antifilarial chemotherapy including currently used drugs, their pros and cons, their mechanism of action, and recently discovered targets and prototypes.

Uterine choriocarcinoma in a postmenopausal woman.

Uterine choriocarcinoma developing in patients beyond reproductive age is a rare occurrence. We report a case of choriocarcinoma of uterine corpus in a 54-yr-old woman after 7 yr of menopause and 25 yr after last child birth. She presented with pain in the abdomen, and on radiological investigation a left uterine adnexal mass of 3.4 x 2.8 cm size was detected. Her serum CA125 level was 40 mIU/mL (normal up to 35 mIU/mL). Hysterectomy revealed an intramural growth in left uterine cornu measuring 3.5 x 3.0 x 2.5 cm. Histological features of the tumor were consistent with choriocarcinoma, and immunohistochemistry detected strong reactivity for beta-hCG in the tumor cells. Serum beta-hCG level 4 wk after surgery was 1345 mIU/mL. The patient was put on combination chemotherapy (EMACO). She achieved serological remission but showed a rise in serum beta-hCG level 4 wk after completion of chemotherapy. We conclude that a high level of suspicion may help in preoperative diagnosis of uterine choriocarcinoma in the postmenopausal age group. However, the response to chemotherapy in these cases may not be as encouraging as in choriocarcinoma of reproductive age.

Synthesis and antitubercular activities of bis-glycosylated diamino alcohols.

Conjugate addition of diamines to glycosyl olefinic esters 1a and 1b followed by reduction of resulting bis-glycosyl beta-amino esters (2-7 and 14-19) with lithium aluminium hydride led to the respective glycosyl amino alcohols (8-13 and 20-25) in moderate to good yields. All the compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H(37)Ra and H(37)Rv. Few of the compounds exhibited antitubercular activity with MIC as low as 6.25-3.12microg/mL in virulent and avirulent strains. Compound 13 was found to be active against MDR strain and showed mild protection in mice.

Synthesis and antimycobacterial activities of glycosylated amino alcohols and amines.

Reduction of glycosyl beta-amino esters (6-14 and 25-30) with lithium aluminum hydride resulted in glycosyl amino alcohols (15-23 and 31-36) in good yields. However, reductive amination of glycosyl aldehydes (1-3) with different amines in presence of sodium borohydride resulted in good to moderate yields of glycosyl amines (37-41). All the compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Ra and H37Rv. Compounds 18, 21, 35 and 36 exhibited antitubercular activities with MIC ranging from 6.25 to 3.12 microg ml(-1).

Synthesis and antimycobacterial activity of 3,5-disubstituted thiadiazine thiones.

A series of 3,5-disubstituted thiadiazine thiones (4-24) have been synthesized by reaction of primary amines with carbon disulphide followed by cyclocondensation of the resulting intermediate with formaldehyde and primary amines or amino acids. The compounds were screened for antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv. Three compounds 4, 12 and 18 showed antimycobacterial activity with MIC 12.5 microg/mL. Compound 4, was tested in vitro against five multidrug resistant (MDR) strains of M. tuberculosis and was found to be active. Compound 4 also exhibited activity in vivo. While all the mice died in the untreated group, the mean survival time (MST) of the compound treated mice was enhanced, 33% mice were surviving in treated group and the load of bacilli in the lung was considerably less in the compound treated group than in the untreated control group.

Synthesis and antifilarial evaluation of N1,Nn- xylofuranosylated diaminoalkanes.

A series of N(1),N(n)-xylofuranosylated diaminoalkanes (3-9 and 11-18) has been synthesized either by reductive amination of deoxy xylouloses (2a, 2b) with amines followed by one pot reduction with NaBH(4) or NaCNBH(3); or by 1,4-conjugate addition of amines to glycosyl olefinic esters (10a, 10b). The compounds were screened for their interference with filarial worms' glutathione metabolism, a potential target for chemotherapeutic attack. Interestingly, these compounds affected intracellular glutathione, gamma-glutamyl cysteine synthetase, glutathione reductase and glutathione-S-transferase(s) of bovine filarial worms to varying degrees. Some of the compounds though effected the motility and MTT reduction potential of filarial worms Brugia malayi, however, little microfilaricidal and macrofilaricidal were noted with compounds at 50mg/kg oral dose. Compounds 6, 16 and 17 were evaluated also for in vivo activity.