Practice patterns and outcomes with the use of regorafenib in metastatic colorectal cancer: Results from the Regorafenib in Metastatic colorectal cancer - An Indian exploratory analysis study.

BACKGROUND: Regorafenib is considered a standard of care as third-line therapy in metastatic colorectal cancers (mCRCs). MATERIALS AND METHODS: The study was based on a computerized clinical data form sent to oncologists across the country for entry of anonymized patient data. The data entry form was conceived and generated by the coordinating center's (Tata Memorial Hospital) gastrointestinal medical oncologists and disseminated through personal contacts at academic conferences as well as through E-mail to various oncologists across India. RESULTS: A total of 19 physicians contributed data resulting in 80 patients receiving regorafenib who were available for the evaluation of practice patterns. The median age was 55 years (range: 24-75). Majority had received oxaliplatin-based (97.5%), irinotecan-based (87.5%), and targeted therapy (65%), previously. Patients were primarily started on reduced doses of regorafenib upfront (160 mg - 28.8%, 120 mg - 58.8%, and 80 mg - 12.5%). The median duration of treatment (treatment duration) with regorafenib was 3.1 months (range: 0.5-18), while the median progression free survival was 3.48 months (range: 2.6-4.3). Forty-five percent of patients required dose modifications due to toxicities, and the most common were (all grades) hand-foot syndrome (68.8%), fatigue (46.3%), mucositis (37.6%), and diarrhea (31.3%). CONCLUSIONS: Majority of physicians in this collaborative study from India used a lower dose of regorafenib at the outset in patients with mCRC. Despite a lower dose, there was a significant requirement for dose reduction. Duration of treatment with regorafenib as an efficacy end point in this study is similar to available data from other regions as it is the side effect profile.

Baseline body mass index among children and adults undergoing allogeneic hematopoietic cell transplantation: clinical characteristics and outcomes.

Obesity is an important public health problem that may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic hematopoietic SCTs between 2004 and 2012. Pretransplant body mass index (BMI) was classified as underweight, normal weight, overweight or obese using the WHO classification or age-adjusted BMI percentiles for children. The study population was predominantly Caucasian, and the median age was 51 years (5 months-73 years). The cumulative 3-year incidence of nonrelapse mortality (NRM) in underweight, normal weight, overweight and obese patients was 20%, 19%, 20% and 33%, respectively. Major causes of NRM were acute and chronic GVHD. The corresponding incidence of relapse was 30%, 41%, 37% and 30%, respectively. Three-year OS was 59%, 48%, 47% and 43%, respectively. Multivariate analysis showed that obesity was associated with higher NRM (hazard ratio (HR) 1.43, P=0.04) and lower relapse (HR 0.65, P=0.002). Pretransplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese compared with normal weight patients (P=0.04 and P=0.05, respectively). The increase in NRM observed in obese patients was partially offset by a lower incidence of relapse with no difference in OS.

Bacterial LPS-mediated acute inflammation-induced spermatogenic failure in rats: role of stress response proteins and mitochondrial dysfunction.

Bacterial Lipopolysaccharide (LPS) induced inflammation is implicated in the infection associated testicular tissue damage. Earlier, using a LPS induced acute endotoxemic rat model, we have shown the involvement of inflammation-induced oxidative stress in the impaired steroidogenesis and spermatogenesis. In the present study, we report a significant induction (more than 2-fold) of stress response proteins HSP-60, HMGB-1 and 2 in the testes, as early as 6 h after LPS injection with a later decrease. This induction of acute stress is closely followed by a significant reduction (74%) in Bcl2/Bax ratio along with leakage of cytochrome c (3 fold increase, p < 0.05) from mitochondria and increased caspase-3 activity levels (2.9 fold, p < 0.05) at 12 h and 24 h post LPS injection respectively. Further studies on PARP cleavage revealed a pattern similar to necrotic death during early periods (3 h to 24 h) and apoptosis at later periods (24 h to 72 h) after LPS treatment. In conclusion, the present study shows the involvement of stress response proteins and mitochondrial dysfunction in LPS-induced germ cell death in male rats.

Secondary pseudomonas infection of fungal keratitis following use of contaminated natamycin eye drops: a case series.

AIM: To report a five case of secondary pseudomonas infection of fungal keratitis following use of contaminated natamycin eye drops. METHODS: A retrospective analysis of the course and clinical outcomes of five eyes of five patients with clinical and laboratory-confirmed fungal keratitis species was performed. Clinical worsening despite hourly topical 5% natamycin drops prompted a repeat corneal scraping and microbiological evaluation. RESULTS: The causative fungi for the initial keratitis were Fusarium and Aspergillus species. All the five specimens obtained from repeat scrapings revealed Pseudomonas aeruginosa. The cultures obtained from the natamycin eye drops being used by the patients also grew pseudomonas. On further evaluation, the source of contamination of the natamycin containers was obscure but speculated to be nosocomial, being within the hospital or the pharmacy. All patients had a poor visual outcome with one requiring evisceration because of panophthalmitis, whereas three underwent therapeutic keratoplasty. CONCLUSIONS: A high index of suspicion is recommended in all cases of worsening fungal keratitis to identify secondary contamination of antifungal agents with nosocomial infections.

Novel functional association of rat testicular membrane-associated cytosolic glutathione S transferases and cyclooxygenase in vitro.

AIM: To analyze the role of cytosolic glutathione S-transferases cGSTs and membrane-associated cytosolic GSTs macGSTs in prostaglandin biosynthesis and to evaluate the possible interaction between glutathione S-transferases GSTs and cyclooxygenase (COX) in vitro. METHODS: SDS-PAGE analysis was undertaken for characterization of GSTs, thin layer chromatography (TLC) to monitor the effect of GSTs on prostaglandin biosynthesis from arachidonic acid (AA) and spectrophotometric assays were done for measuring activity levels of COX and GSTs. RESULTS: SDS-PAGE analysis indicates that macGSTs have molecular weights in the range of 25-28 kDa. In a coupled assay involving GSTs, arachidonic acid and cyclooxygenase-1, rat testicular macGSTs produced prostaglandin E2 and F2alfa, while the cGSTs caused the generation of prostaglandin D2, E2 and F2alfa. In vitro interaction studies on GSTs and COX at the protein level have shown dose-dependent inhibition of COX activity by macGSTs and vice versa. This effect, however, is not seen with cGSTs. The inhibitory effect of COX on macGST activity was relieved with increasing concentrations of reduced glutathione (GSH) but not with 1-chloro 2,4-dinitrobenzene (CDNB). The inhibition of COX by macGSTs, on the other hand, was potentiated by glutathione. CONCLUSION: We isolated and purified macGSTs and cGSTs from rat testis and analyzed their involvement in prostaglandin biosynthesis. These studies reveal a reversible functional interaction between macGSTs and COX in vitro, with possible interactions between them at the GSH binding site of macGSTs.

Expression of cyclooxygenase-2 in rat testis.

Cyclooxygenase, the rate-limiting enzyme in the production of prostaglandins, exists in two isoforms, the constitutive cyclooxygenase 1 (Cox-1) and the inducible cyclooxygenase 2 (Cox-2). Cox-1 is involved in homeostatic functions while Cox-2 is implicated in various pathological processes such as inflammation and cancer. The present study describes the constitutive expression of Cox-2 in immature and mature rat testis, primarily localized in the spermatogonial cells. An interesting observation is the presence of Cox-2 on the chromatin and also in cytosol, apart from nuclear and endoplasmic reticular membranes. The significance of this observation is not yet clear, though its presence in the nucleus raises the possibility of Cox-2 having a more direct role in gene regulation than was thought earlier. In addition, the Cox-2 mRNA in testis is the smaller (2.8 kb) of the two isoform transcripts reported for Cox-2. Further hormone treatment regimes (testosterone/follicle stimulating hormone) increased the levels of Cox-2 protein within 6 h after treatment, suggesting that the sustained levels of Cox-2 protein in testis can be further influenced by gonadotrophins and androgens.

Studies on the development of oral colon targeted drug delivery systems for metronidazole in the treatment of amoebiasis.

The aim of the present study is to develop colon targeted drug delivery systems for metronidazole using guar gum as a carrier. Matrix, multilayer and compression coated tablets of metronidazole containing various proportions of guar gum were prepared. All the formulations were evaluated for the hardness, drug content uniformity, and were subjected to in vitro drug release studies. The amount of metronidazole released from tablets at different time intervals was estimated by high performance liquid chromatography method. Matrix tablets and multilayer tablets of metronidazole released 43-52% and 25-44% of the metronidazole, respectively, in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. Both the formulations failed to control the drug release within 5 h of the dissolution study in the physiological environment of stomach and small intestine. The compression coated formulations released less than 1% of metronidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 275 mg of guar gum coat released another 61% of metronidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 350 and 435 mg of guar gum coat released about 45 and 20% of metronidazole, respectively, in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression coated metronidazole tablets with either 275 or 350 mg of guar gum coat is most likely to provide targeting of metronidazole for local action in the colon owing to its minimal release of the drug in the first 5 h. The metronidazole compression coated tablets showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months.

Guar gum as a carrier for colon specific delivery; influence of metronidazole and tinidazole on in vitro release of albendazole from guar gum matrix tablets.

PURPOSE: The present investigation is to study the influence of metronidazole and tinidazole on the usefulness of guar gum, a colon-specific drug carrier based on the metabolic activity of colonic bacteria, using matrix tablets of albendazole (containing 20% of guar gum) as a model formulation. METHODS: The matrix tablets of albendazole were subjected to in vitro drug release studies in simulated colonic fluids (4%w/v of rat caecal contents) obtained after oral treatment of rats for 7 days either with varying doses of metronidazole/ tinidazole and 1 mL of 2%w/v of guar gum or with 1 mL of 2%w/v of guar gum alone (control study) after completing the dissolution study in 0.1 M HCl (2 h) and pH 7.4 Sorensen's phosphate buffer (3 h). RESULTS: The guar gum matrix tablets of albendazole were found degraded by colonic bacteria of rat caecal contents and released about 44% of albendazole in simulated colonic fluids (control study) at the end of 24 h indicating the susceptibility of the guar gum formulations to the rat caecal contents. However, the release of albendazole decreased when the drug release studies were carried out in caecal contents of rats treated for 7 days with either metronidazole (10-50 mg/ kg once daily) or tinidazole (10-30 mg/ kg once daily), and the release of albendazole from the matrix tablets was found to be dose dependent. The release of the drug from guar gum formulations was found to increase with a decrease in the dose of metronidazole/tinidazole administered. The antimicrobial activity of metronidazole/ tinidazole against the anaerobic bacteria of the rat"s GI flora might have been inhibited to a varying degree depending on the dose of metronidazole/tinidazole administered. CONCLUSIONS: The results of the study showed that concomitant administration of either metronidazole or tinidazole with guar gum based colon-specific drug delivery systems may interfere with the targeting of drugs to colon.

Effect of 2',4'-dichlorobenzamil hydrochloride, a Na(+)-Ca(2+) exchange inhibitor, on human spermatozoa.

The present study is aimed to investigate the contact spermicidal efficacy of 2',4'-dichlorobenzamil hydrochloride (DBZ), a Na(+)-Ca(2+) exchange inhibitor, on ejaculated human spermatozoa. The drug produced a dose- and time-dependent spermicidal action on human spermatozoa. A concentration of 4 mM produced total loss of sperm viability within 1 min of addition to total semen. On the other hand, a similar action on spermatozoa separated from semen was noted at 0.5 mM concentration. The loss of spermatozoal viability was accompanied with an increase in intracellular Ca(2+). Sperm revival testing with glucose suggested a spermicidal rather than a spermiostatic action.

Effect of various flours on the production of thermostable beta-amylase and pullulanase by Clostridium thermosulfurogenes SV2.

The effects of various flours on production of thermostable beta-amylase and pullulanase using Clostridium thermosulfurogenes SV2 was studied in submerged fermentation. Among the flours added to PYE basal medium, potato flour was the best substrate for enzyme production, and under optimal conditions C. thermosulfurogenes SV2 produced 0.87 and 0.98 U of thermostable beta-amylase and pullulanase, respectively, per ml culture broth.

Hormonal contraception for human males: prospects.

Development of an ideal hormonal contraceptive for man has been the goal of several research workers during the past few decades. Suppression of pituitary gonadotropic hormones, which in turn would inhibit spermatogenesis while maintaining normal libido and potential has been the approach for a contraceptive agent. Intramuscularly administered and orally active testosterone or testosterone in combination with progesterone have been shown to cause inhibition of spermatogenesis resulting in azoospermia in normal men. Similarly testosterone has been used in combination with gonadotropin releasing hormone antagonists and agonists to inhibit pituitary gonadotropic hormone release. Immunological approach to neutralize the circulating levels of follicle stimulating hormone has also been shown to cause inhibition of spermatogenesis. The available literature shows that testosterone causes reversible azoospermia without any significant side effects in Asian population effectively and appears to be a promising chemical for control of fertility in man.

Purification and characterization of rat testicular glutathione S-transferases: role in the synthesis of eicosanoids.

AIM: Purification of glutathione S-transferases (GSTs) from rat testis; separation and identification of various subunits and their role in eicosanoid biosynthesis. METHODS: Purification of rat testicular GSTs by affinity chromatography, employing S-hexylglutathione-linked epoxy-activated Sepharose 6B column and separation of individual subunits by reverse phase-high pressure liquid chromatography (RP-HPLC). Characterization of affinity purified GSTs by Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis. The role of testicular GSTs in eicosanoid biosynthesis was determine by incubating GSTs with 5, 6-Leukotriene A4Me (LTA4Me) and prostaglandin H2(PGH2) and analyzing the products formed on HPLC/TLC. RESULTS: The present study reveals that majority of rat testicular GSTs are of Yb size (60%) with molecular weight of 27 kDa. The most predominant subunits, however, are GST Yn2(27%), followed by GST Yc(24%) and GST Yn1(20%). These testicular GSTs showed very high Leukotriene C4 (LTC4) synthase activity with 5, 6-Leukotriene A4Me (LTA4Me) as the substrate and prostaglandin D (PGD) synthase activity with prostaglandin H2(PGH2) as the substrate. CONCLUSION: Majority of rat testicular GSTs are Yb sized and are involved in the synthesis of eicosanoids like LTC4 and PGD2.

Novel antidiabetic and hypolipidemic agents. 3. Benzofuran-containing thiazolidinediones.

Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2- ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.

Effect of glucose on stress induced antinociception in normal mice.

Stress induced analgesia has been shown to utilise both non-opioidergic and opioidergic mechanisms. Earlier studies indicate that opiodergic analgesics exhibit corollary changes in blood glucose level. In this study, the changes in blood glucose level by swim induced stress and the influence of exogenous glucose administration on the stress induced antinociception were studied. Stress per se (both 30 sec and 3 min) did not modify the blood glucose level. However, exogenous administration of glucose reversed the stress induced antinociception in both non-opioid and opioid segments. Our results favour a role for glucose in stress induced analgesic activity.

Pneumatosis coli: an uncommon but treatable cause of faecal incontinence.

Pneumatosis intestinalis is defined as the presence of gas within the bowel wall. Small bowel pneumatosis is less commonly reported and more severe than colonic disease in adults. Pneumatosis coli is characterised by multiple collections of encysted gas occurring within the sub-mucosa and subserosa of the colon and rectum. It is an uncommon condition which typically presents in late middle age and has been associated with a number of gastrointestinal (e.g. pyloric stenosis, sigmoid volvulus and ischaemic bowel) and non-gastrointestinal (e.g. chronic obstructive pulmonary disease, depression and multiple sclerosis) diseases. Some cases, however, are idiopathic or primary. Symptoms can include diarrhoea, constipation, mucus per rectum, bleeding, flatus, abdominal pain and, rarely, faecal incontinence. We report on two patients, one of whom presented with faecal incontinence, the other who had troublesome lower gastrointestinal symptoms including faecal incontinence. Both responded well to continuous oxygen therapy.

Elemental concentrations in medicinally important leafy materials.

Concentrations of elements, especially of trace elements toxic as well as non-toxic in biological materials show a high degree of biological, seasonal and spatial variability. These factors should be taken care of while sampling. Samples, even though collected at a great distance of time and space, should be representative and quantitatively comparable which is important for biomonitoring. Reference Materials (RM's) from biological materials such as leaves acquire importance in Analytical Quality Assurance work. A knowledge of element concentrations in highly consumed leafy samples is of interest. A large number of medicinally important leafy samples (50) have been analysed for elemental concentrations such as Zn, Cu, Ni, Co, Pb, As, Se, K, Cr, Na, P, S, Fe, Ca Mg, Mn and Fe. The concentrations of macro nutrients such as Ca, P, Mg, K, Fe and S range from 9.62 to 4174, 1.00-8.630, 3.53-35.50, 12.04-56.28, 0.111-3.845 g/kg and 1.124-5.843 mg/kg, of micro nutrients such as Cr, Co, Cu, Mn, Na and Zn range from 0.360-8.630, 0.050-3.470, 17.60-57.30, 10.5-81.6, 1.47-27.10 and 10.06-145.6 mg/kg whereas those of trace metals such as Pb, Cd, Ni, As and Se range from 1.19-16.30, 0.0036-0.453, 1.23-19.60, 0.12-7.360 and 0.654-3.50 mg/kg respectively. Influence of sampling parameters such as season and spatial variations has been assessed and the results are interpreted. Spatial variation and seasonal variation are observed to be statistically significant for Cu, Zn and Mn. Preparation of Secondary Reference Materials (SRM's) from the samples analysed is explored. Nutritive values of the leaves and intercorrelation between the metals are also discussed.

A comparative clinico-pathological study of oral submucous fibrosis in habitual chewers of pan masala and betelquid.

BACKGROUND: Oral submucous fibrosis associated with chewing of betel nut products has an estimated prevalence of 0.2-1.2% in India. The increasing use of pan masala/gutkha, a mix of tobacco and a less moist form of betelquid lacking the betel leaf, seems associated with an earlier age of onset of oral submucous fibrosis. METHOD: A prospective study examined the in vivo effects of pan masala/gutkha and betelquid chewing on buccal mucosal cytology in 50 patients with oral submucous fibrosis and 40 controls. RESULTS: The percentage of nucleolated intermediate cells or proliferative fraction of buccal mucosa cells was significantly higher in all habitual chewers than controls. Pan masala/gutkha chewers presented with oral submucous fibrosis after 2.7 +/- 0.6 y of use whereas the betelquid users presented with oral submucous fibrosis reported 8.6 +/- 2.3 y of use (p < 0.05). CONCLUSIONS: Habitual chewing of pan masala/gutkha is associated with earlier presentation of oral submucous fibrosis than betelquid use. Factors which may be responsible for these differences are the tobacco content, the absence of the betel leaf and its carotenes and the much higher dry weight of pan masala/gutkha.

Effect of thyroxine on DNA methyltransferase activity in cerebellum of rat.

DNA methyltransferase activity increased significantly in cerebellum from day 4 to day 8 and decreased in 30 day old rats. It was maintained at lower levels in the adult rats. Thyroxine administration markedly stimulated DNA methyl- transferase activity in the newly born pups. However, it did not cause any effect on this enzyme activity in 8 day old rat cerebellum. These results show that thyroxine has a role in the regulation of DNA methyltransferase activity in cerebellum of rat during early stages of development.

Recent advances in IOL surgery.

Tremendous progress is made in recent time in the field of Ophthalmology especially after advent of IOL implantation surgery. Recent advance in anaesthesia/IOL, designs/IOL, quotings/cantering, techniques/advances in operating microscope and advances in suture materials/needles etc. will be discussed.