Improvement in the dissolution profile of diacerein using a surfactant-based solid dispersion technique.

In an attempt to improve the dissolution rate of poorly aqueous soluble diacerein (DCN), solid dispersions (SDs) were prepared with a surfactant Pluronic® F 127 (PXMR) at drug to polymer ratios of 1:0.5, 1:1.5, and 1:2.5 (w/w) by an ordinary melting technique. The interaction of DCN with PXMR in all solid binary systems was evaluated by thin layer chromatography (TLC), Fourier transform infrared spectrometry (FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) studies. TLC indicated an absence of chemical interaction of DCN with PXMR whereas FTIR studies demonstrated an existence of strong hydrogen bonding between them. A uniform molecular dispersion of DCN was observed in DSC thermograms, and this finding was further supported by loss of the crystalline and irregular shape of DCN detected in SEM photomicrographs. Dissolution studies were promptly conducted to examine the release rate performance of DCN from all binary systems. The drug dissolution properties of binary systems improved significantly in comparison to crystalline DCN. The rate and extent of DCN release were observed to be strongly dependent on the proportion of PXMR present within the formulations.

Synthesis and pharmacological studies of some 2-t-amino and 2,3-di-t-amino substituted 1,4-naphthoquinones and related compounds.

Series of 2-t-amino and 2,3-di-t-amino substituted-1,4-naphthoquinones have been synthesised from corresponding 1,4-naphthoquinones by reaction with secondary amines. The compounds have been evaluated for their broad spectrum antimicrobial, antiviral and anticancer activity. In the preliminary screening results 8a and 9a have shown profile of an antimicrobial agent.

Variation in random amplified polymorphic DNA (RAPD) profiles specific to fluconazole-resistant and -sensitive strains of Candida albicans.

Random amplified polymorphic DNA analysis was used to detect genotype relatedness among clinical fluconazole-resistant and -sensitive strains of Candida albicans recovered from twenty HIV-infected patients having oropharyngeal candidiasis. Sensitive strains were obtained from a local hospital and were from patients that had not been treated with azole drugs while resistant strains were recovered from patients in different parts of Europe and their resistance was a consequence of drug-treatment given to the patients. On amplification with different arbitrary sequence decamer primers, the results demonstrated a homogeneous banding pattern for all sensitive strains that was distinct from that obtained in case of the resistant strains. The DNA profiles of strains were thus broadly clustered into two major groups of resistant and sensitive strains. The RAPD technique may be useful in differentiating fluconazole-resistant strains from the -sensitive ones for early identification of resistant isolates from AIDS patients.

Antifeedant and antifungal activity of chromene compounds isolated from Blepharispermum subsessile.

Desmethyl isoencecalin and 5-hydroxy-6-acetyl-2-hydroxymethyl-2-methyl chromene isolated from Blepharispermum subsessile rhizomes were shown to have antifeedant activity against larvae of Spilarctia obliqua and also antifungal activity against Candida albicans and Cryptococcus neoformans (MIC 25-250 microg/ml).

Antifungal agents and immunomodulators in systemic mycoses.

The rising incidence of fungal infections and the emergence of several fungi as opportunistic pathogens have reawakened interest in chemotherapeutic and prophylactic agents for mycoses. During the past decades significant advances have been made in the development of novel antifungal agents for treatment of systemic mycoses. This brief review presents an update of the available information on polyenes, imidazoles, triazoles, flucytosine, allylamines, echinocandins, nikkomycins, sordarins and immunomodulators. A reference has also been made to the work in antifungals done or in progress at the Central Drug Research Institute (CDRI), Lucknow. Currently, antifungals represent more than 6% of the total world market for anti-infective agents and with 20% annual expansion they are expected to cross the 15 billion US Dollars in value within a decade.

Potent antifungal activity of garlic (allium sativum) against experimental murine dissemenated cryptococcosis.

The adequate management of cryptococcosis is difficult with the available armamentarium of synthetic antifungals. We made an effort to evaluate fresh extracts of garlic ( Allium sativum L.) to assess potential therapeutic use of this herb as an anticryptococcal agent. The in vitro antifungal activity in broth showed greatest activity in the aqueous extract (MIC 125-250 µg/ml; MFC 250 to = 500 µg/ml) compared to the alcoholic, crude or commercial extracts. Treatment of Balb/c mice with garlic extracts in mice (orally) showed that alcoholic extracts (5 mg/kg, q.i.d.) provided 100% protection of mice against disseminated cryptococcosis. A concomitant increase in MST (> 35 days) was observed, along with a significant reduction in cfu (log 10 ) burden of cryptococci in visceral (liver, spleen, kidney, lung and heart) tissues, especially brain (> 4.5 log 10 ). The efficacy of extracts was also evident in the sera of mice. Thus, alcoholic extracts of fresh garlic elicit potential anticryptococcal activity against murine disseminated cryptococcosis.

Aspergillus fumigatus strains recovered from immunocompromised patients (ICP): subtyping of strains by RAPD analysis.

Invasive pulmonary aspergillosis in immunocompromised patients (ICP) is the second most frequent opportunistic fungal infection. The causative organism includes 16 species of Aspergillus, of which A. fumigatus dominates the ubiquitous incidence of invasive or allergic broncho-pulmonary aspergillosis (ABPA). The definitive diagnosis of invasive aspergillosis is difficult. We have analyzed 24 strains of A. fumigatus recovered from ICP using the RAPD technique. The profiles generated with the 20 primers tested were mostly unique. These results may have a profound impact on the management of aspergillosis, especially in the ICP.

Pattern of malignant tumors observed in a university hospital: a retrospective analysis.

A retrospective analysis of all malignant tumors observed in adults over a four-years period is presented. From January 1, 1989 to December 31, 1992, 2623 patients were coded by the Indexing and Coding Unit of Medical Records, The Aga Khan University Hospital to have cancer. Data presented reflect the relative frequency of different cancers seen at a single institution. Lung cancer was the commonest tumor observed in males. It was closely followed by head and neck cancer and lymphoma. In females, breast was the commonest cancer followed by ovarian and gallbladder. In comparison to the Western figures, an increased frequency of lymphomas and head and neck cancers was observed in males. Prostatic and colorectal cancers were less frequently observed. In females, gallbladder cancer is strikingly more frequent. Cervical cancer was less commonly observed as compared to the other developing countries and uterine cancer was infrequent in comparison to the Western countries. These data carry important implications for future health planning.

Immuno-histochemical analysis of estrogen receptors on the malignant gallbladder tissue.

Sex steroids play an important part in the functioning of normal gallbladder, formation of gallstones and possibly in the pathogenesis of gallbladder cancer. Steroids receptors have been previously demonstrated on normal and malignant gall bladder tissues. To study this phenomenon further, we correlated clinicopathological features and survival with estrogen receptor (ER) status of the tumour in 30 patients with histologically-proven adenocarcinoma of the gallbladder. Estrogen receptor assay was performed immuno-histochemically utilizing Universal Immunoperoxidase Staining Kit. Tumor tissue was obtained either surgically or with fine needle aspiration of the gallbladder mass. There were 27 females and 3 males. Eighteen patients had estrogen receptors expressed on the malignant tissue, 12 were negative. Comparison of clinicopathological characteristics and survival between the two groups demonstrated no significant difference in gender, mean age, marital status and parity. Similarly, presence of gallstones, histologic grade or survival did not correlate with the estrogen receptor status. There is, however, a trend in favour of poorly differentiated tumors being more often receptor negative. Further studies are necessary to elucidate the biologic significance of these receptors.

The effect of subcutaneous recombinant human erythropoietin (r-HuEPO) on anemia in cancer patients receiving platinum-based chemotherapy.

Advanced cancer is commonly associated with significant anemia which worsens with the administration of cytotoxic drugs. Erythropoietin (EPO) levels in these patients are usually inappropriately low for the degree of anemia. We evaluated the effect of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) on hematologic parameters and transfusion requirements in anemic cancer patients who were receiving platinum-based chemotherapy. Baseline studies included complete hemogram, reticulocyte count, serum iron, TIBC, ferritin and determination of performance status and quality of life (QOL). Twenty-three patients, 13 females, 10 males with mean age 52 years received 150 units/kg of r-HuEPO three times weekly for a minimum of 10 weeks. They also received supplemental iron. Ovarian cancer was the commonest underlying malignancy. Most of the patients received platinum-based combination chemotherapy. Mean duration of r-HuEPO therapy was 12.6 weeks. Average baseline reticulocyte count was 1.8% which increased to 7.0% after one week therapy. Eight patients had normalization of hemoglobin values. Another eight patients improved their hemoglobin by at least 2 g/dl, however, hemoglobin values remained below the normal range. Two patients had only slight increase in hemoglobin but never required blood transfusion. Three patients who were transfusion dependent had decrease in the transfusion requirements. Two patients had no significant benefit. In most patients response was evident within 2 weeks. All responders had improvement in QOL. No significant toxicity was observed. We conclude that r-HuEPO, given subcutaneously, is highly effective in amelioration of anemia and prevention of or reduction in transfusion requirements in cancer patients receiving platinum-based chemotherapy.

RAPD analysis of Candida albicans strains recovered from different immunocompromised patients (ICP) reveals an apparently non-random infectivity of the strains.

The opportunistic imperfect fungus Candida albicans causing life-threatening infections in immunocompromised patients (ICP), especially in HIV-positive cases, is recognized to be one of the most important nosocomial pathogens in the recent decades. The extent of strain-to-strain variation within a species and its relationship to the ability of the organism to colonize or invade a specific group of patients or even a body site is, however, not well known. We have analysed 19 strains of C. albicans recovered from ICP at different locales and times, employing the RAPD technique. No two strains generated identical RAPD profiles with any of the 21 primers tested. Further, the UPGMA clustering of the strains seemingly reflected a certain relationship or nonrandomness in the infection of the patients with the strain of C. albicans vis-a-vis the immunocompromised status due to underlying disease such as diabetes, cancer, asthma and meningitis. These results may have a profound impact on the management of candidiasis, especially in the ICP.

Comparative in vitro and in vivo evaluation of himachalol in murine invasive aspergillosis.

Aspergilli are increasingly important infections in immunocompromised patients (ICP). The available antifungals often cause discrepancies in laboratory determination of MICs and a correlation in therapy. An effort was made to compare in vitro techniques for testing of antifungals, viz. polyenes, imidazoles, 5-fluorocytosine, amorolfine; and screened a phytoproduct- himachalol (a sesquiterpene alcohol) from Cedrus deodara (Roxb.) Loud against A. fumigatus clinical isolates (24) by macrobroth two-fold seal dilution (TFSD), microbroth microtitre (MT) and disc diffusion (DD) techniques using various broth/agar media at varying periods of incubation. The best activity in terms of geometric mean (GM) (GM.MIC < 0.39 microgrmas ml-1) was obtained with SCZ in the broth by both MT or TFSD technique followed by ECZ (GM.MIC 0.39 micrograms ml-1) and ITZ (GM.MIC 0.39-0.8 micrograms ml-1) in RPMI-1640. Overall RPMI-1640 was found to be the most suitable growth medium for testing of azoles or amorolfine, and YNB for polyene and 5-FC. MT technique was the most sensitive quantitative, reproducible, rapid and economical compared to other techniques. The treatment of Swiss mice with himachalol (200 mg kg-1, po) once a day, for 7 days, provided 60% protection concomitantly with increased MST (15 days) against invasive aspergillosis. A combination of himachalol (200 mgkg-1) plus SCZ (5 mgkg-1) showed better regimen in the therapy evidenced by enhanced survival (80%) of mice significantly (p < 0.001) with prolonged MST (> 15 days) compared to control. The treatments also reduced cfu (mean log10) burden of A. fumigatus from kidney.

Evaluation of himachalol in murine invasive aspergillosis.

Himachalol (a sesquiterpene alcohol) showed low in vitro minimum inhibitory concentrations against Aspergillus fumigatus by the macro- and microbroth dilution techniques (genometric mean 250 micrograms ml-1 and 46.4 micrograms ml-1 respectively) compared with saperconazole. Swiss mice treated with the phytoproduct (200 mg kg-1, p.o.) once daily for 7 days exhibited a significant (P < 0.001) protection (60%) together with an increase in the mean survival time (15 days) and a reduced CFU (mean log10) burden of A. fumigatus in the kidneys.

Cryptococcosis associated with HIV negative Indian patients and HIV positive Indian blood donors.

Cryptococcosis, particularly cryptococcal meningitis (CM), has become an increasing problem globally in the AIDS era. In the present investigation we have made an effort for the first time to study Indian cases (100) both HIV-positive (23 cases, male, mostly Indian professional blood donors, PBDs') confirmed by an ELISA test and Western Blot but asymptomatic for CM and HIV-negative (77:49 male and 28 female) asymptomatic or symptomatic. These subjects were patients from the Lucknow hospitals admitted during the period between February, 1991 to February, 1994, for suspected cryptococcosis or CM. Of those cases, 10% were positive for cryptococcosis or CM. Meningoencephalitis was the dominant clinical manifestation in four (HIV-negative) cases of CM. CT scanning of the head of those cases revealed a noncommunicating hydrocephalus due to aqueductal stenosis (in 2 cases) and a communicating hydrocephalus with granuloma (by MRI) in another case. The latex agglutination test (LAT) of the sera was positive for Cryptococcus antigen in 6 (26%) of the (HIV-positive) patients and 4 (5%), of the HIV-negative cases. In the cases of CM, there was a lower antigen titre in CSF than in the pronase-treated sera. The LAT was found to be useful in diagnosis of cryptococcosis, especially in asymptomatic cases. The CSF of CM-positive cases revealed low levels of glucose, reduced cell count and high proteins. Among the HIV-negative cases, the onset of meningitis in 4 cases was preceded by the presence of encapsulated budding yeast cells in CSF India ink smear, or cryptococci in a direct urine smear in one case. The CSF culture of 3 cases was positive for mucoid Cryptococcus neoformans, showing brown colour effect (BCE) on Staib agar (syn. Guizotia abyssinica creatinine agar, bird seed agar). The isolated yeast strains were identified as C. neoformans var. neoformans by physiological tests. The pathogenicity test of strains revealed virulence to BALB/c mice evidenced by a high mortality of mice and significantly (p < 0.05) high CN burden (> 4-5 mean log(10) cfu), in the brain followed by other visceral organs (lung, liver, spleen, kidney and heart). The in-vitro susceptibility (MIC mu gmL(-1)) of strains.