Evolving Novel Chemical Entities for Management of Benign Prostatic Hyperplasia.

BACKGROUND: Proliferation of the smooth muscle and epithelial cells within the prostatic transition zone in older men leads to benign prostatic hyperplasia (BPH), which is hallmarked by the troublesome lower urinary tract symptoms. The affair responsible for the initiation and promotion of disease is still unresolved, though alpha-blockers and 5α-reductase inhibitors are used as management options for relief from the dynamic and static components respectively. METHOD: Combination therapy including both the alpha blocker and 5α-reductase inhibitor is emerging as inclusive parcel for treatment. However, selective androgen receptor modulators (SARM) and selective estrogen receptor modulators (SERM) are the other management resources, which are in the limelight. RESULT: This review gives a glimpse of BPH and the various chemical entities which have been reported in literature till date for the condition since 2005.

Evaluation of Quality and Readability of Health Information Websites Identified through India's Major Search Engines.

Background. The available health information on websites should be reliable and accurate in order to make informed decisions by community. This study was done to assess the quality and readability of health information websites on World Wide Web in India. Methods. This cross-sectional study was carried out in June 2014. The key words "Health" and "Information" were used on search engines "Google" and "Yahoo." Out of 50 websites (25 from each search engines), after exclusion, 32 websites were evaluated. LIDA tool was used to assess the quality whereas the readability was assessed using Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Level (FKGL), and SMOG. Results. Forty percent of websites (n = 13) were sponsored by government. Health On the Net Code of Conduct (HONcode) certification was present on 50% (n = 16) of websites. The mean LIDA score (74.31) was average. Only 3 websites scored high on LIDA score. Only five had readability scores at recommended sixth-grade level. Conclusion. Most health information websites had average quality especially in terms of usability and reliability and were written at high readability levels. Efforts are needed to develop the health information websites which can help general population in informed decision making.

Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor ß.

Estrogen Receptor-ß (ER-ß), a tumor-suppressor in prostate cancer, is epigenetically repressed by hypermethylation of its promoter. DNA-methyltransferases (DNMTs), which catalyze the transfer of methyl-groups to CpG islands of gene promoters, are overactive in cancers and can be inhibited by DNMT-inhibitors to re-express the tumor suppressors. The FDA-approved nucleoside DNMT-inhibitors like 5-Azacytidine and 5-Aza-deoxycytidine carry notable concerns due to their off-target toxicity, therefore non-nucleoside DNMT inhibitors are desirable for prolonged epigenetic therapy. Disulfiram (DSF), an antabuse drug, inhibits DNMT and prevents proliferation of cells in prostate and other cancers, plausibly through the re-expression of tumor suppressors like ER-ß. To increase the DNMT-inhibitory activity of DSF, its chemical scaffold was optimized and compound-339 was discovered as a doubly potent DSF-derivative with similar off-target toxicity. It potently and selectively inhibited cell proliferation of prostate cancer (PC3/DU145) cells in comparison to normal (non-cancer) cells by promoting cell-cycle arrest and apoptosis, accompanied with inhibition of total DNMT activity, and re-expression of ER-ß (mRNA/protein). Bisulfite-sequencing of ER-ß promoter revealed that compound-339 demethylated CpG sites more efficaciously than DSF, restoring near-normal methylation status of ER-ß promoter. Compound-339 docked on to the MTase domain of DNMT1 with half the energy of DSF. In xenograft mice-model, the tumor volume regressed by 24% and 50% after treatment with DSF and compound-339, respectively, with increase in ER-ß expression. Apparently both compounds inhibit prostate cancer cell proliferation by re-expressing the epigenetically repressed tumor-suppressor ER-ß through inhibition of DNMT activity. Compound-339 presents a new lead for further study as an anti-prostate cancer agent. © 2015 Wiley Periodicals, Inc.

Modulation of CYP1A1, CYP1B1 and DNA adducts level by green and white tea in Balb/c mice.

In the current investigation the ameliorative effect of 2% extract of green tea (GT) and white tea (WT) against benzo(a)pyrene (BaP) induced toxicity and DNA damage has been studied in liver and lung of Balb/c mice (8 animals per group). The activities of phase I enzymes such as 7-ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-depentylase (PROD) were found to be increased (p<0.05) both in liver and lung of BaP treated (125 mg/kg b.w. orally) group. The enhanced activities of EROD and PROD were inhibited in group that received pretreatment with GT and WT for 35 days. Pretreatment with GT and WT also elevated (p<0.05) the level of detoxifying enzymes such as glutathione S-transferase (GST) and quinone reductase (QR) in both the tissues. The BaPDE-DNA adducts level reflected the decreasing pattern from BaP treated group to the groups that received pretreatment with GT and WT. BaP exposure induced drastic alterations in the morphology of erythrocytes, pretreatment of GT and WT to BaP administered groups showed reduced alteration in topography of erythrocytes. WT elucidate greater efficacy in ameliorating BaP toxicity, but further long term studies are required to validate white tea as a cancer chemopreventive agent.

Protective effects of green and white tea against benzo(a)pyrene induced oxidative stress and DNA damage in murine model.

In the current investigation, the ameliorative effect of green tea (GT) and white tea (WT) against benzo(a)pyrene (BaP) induced oxidative stress and DNA damage has been studied in the livers and lungs of Balb/c mice. A single dose of BaP (125 mg/kg, b.w. orally) increased the levels of lipid peroxidation (LPO) and decreased endogenous antioxidants such as superoxide dismutase (SOD), glutahione reductase (GR), catalase (CAT), and glutathione (GSH) significantly. Pretreatment with GT and WT for 35 days before a single dose of BaP elevated the decreased activity of GR, SOD, and CAT in liver tissue and also tended to normalize the levels of GSH and LPO in both hepatic and pulmonary tissues. The percentage of DNA in comet tail and 8-hydroxy-2'-deoxyguanosine levels reflected the decreasing pattern of DNA damage from the BaP-treated group to the groups that received pretreatment with GT and WT. Our study concludes that both GT and WT are effective in combating BaP induced oxidative insult and DNA damage. However, WT was found to be more protective than GT with respect to CAT (only in the liver), percentage of DNA in comet tail (only in the lungs), GST activity, and GSH content in both the tissues.

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms--action of two new agents.

The existing drugs for benign prostatic hyperplasia (BPH) are partially effective with undesirable side-effects; hence new agents acting by different mechanism(s) are required as supplements. Modulation of estrogen receptor signaling using selective estrogen receptor modulators (SERMs) offers an alternative approach for BPH management. Using human BPH-derived stromal cells and tissue explants in culture we evaluated two SERMs, DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2 H-1-benzopyran (BP) and Ormeloxifene (Orm) in comparison to Tamoxifen (Tam) and 4-hydroxytamoxifen (OHT). BP, OHT and Tam were more effective than Orm in reducing stromal cell proliferation of human BPH. BP was either equipotent or more effective than OHT and Tam in increasing estrogen receptor(ER)-ß, TGFß1, Fas and FasL, and in decreasing ER-α, AR, EGF-R and IGF-I expressions in BPH stromal cells. BP, Tam and Orm (1.0 mg/Kg) reduced rat prostate weights by almost same extent as Finasteride (Fin, 5.0 mg/Kg); however combination treatment (SERM+Fin) was more effective. BP was exceptionally efficient in reducing IGF-1 and cleaving PARP while combination treatments more effectively increased bax:bcl-2 ratio. Fin reduced acinar diameter and prostatic DHT level but increased testosterone, estradiol (E(2)) and E(2)/T+DHT ratio. SERMs, especially BP, reduced epithelial cell height drastically without significantly altering steroid hormone levels and E(2)/T+DHT ratio. Combination treatment reduced both acinar diameter and epithelial cell height with modest increase in E(2), T and E(2)/T+DHT. The study reveals the potential of SERMs per se for BPH management, and more effectively in combination with a 5α-reductase inhibitor. BP appears promising for further evaluation as a drug candidate for BPH and prostate cancer.

The -137G/C polymorphism of interleukin 18 promoter and risk of HIV-1 infection and its progression to AIDS.

A growing body of evidence suggests that host genetic factors play an important role both in susceptibility to human immunodeficiency virus 1 (HIV-1) infection and in progression to AIDS. Interleukin 18 (IL-18) is a pleiotropic proinflammatory cytokine that serves as an important regulator of immune responses. It plays a key role in induction of both Th1 and Th2 cytokines and, thereby, modulates their immune responses. Single nucleotide polymorphisms in the IL-18 gene promoter region may lead to an altered transcriptional activity and IL-18 production, and so this may account for individuals' variation to the risk of HIV-1 infection. With this perspective, the -137G/C polymorphism in the promoter region of the IL-18 gene was studied in 500 patients with HIV-1/AIDS and an equal number of sex and age matched healthy controls using sequence specific polymerase chain reaction analysis. We did not observe any significant association of the heterozygous G/C genotype with the risk of HIV-1-infection/AIDS. However, statistically significant associations of the G allele and homozygous G/G genotype of -137 G/C polymorphism of IL-18 promoter with increased risk of HIV-1/AIDS were identified. The data of the present study suggest that IL-18 -137 G allele and G/G genotype seem to be involved in the pathogenesis of HIV-1 infection among North Indians.

Novel trichomonacidal spermicides.

Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of Trichomonas vaginalis to 5-nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing Trichomonas vaginalis (both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli) in vitro. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and Trichomonas in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and Trichomonas. We report here the in vitro activities, structure-activity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing Trichomonas vaginalis (including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of Trichomonas on HeLa cells. Experimentally in vitro, the new compounds appeared to be safer than N-9 for vaginal use.

Primary B-cell lymphoma presenting as bilateral ear lobule swelling.

We report a rare case of primary B-cell lymphoma presenting as bilateral ear lobule swelling. A 56-year-old white man presented with a one-year history of painless swelling of both ear lobules. An excision biopsy confirmed B-cell lymphoma. Detailed systemic investigation confirmed the primary nature of the tumour. This tumour is rare in the ear lobule. A review of the English literature revealed no previously reported case of bilateral primary ear lobule involvement. Clinicians should be aware that this tumour can present as a primary in the ear lobules.

Novel disulphide esters of carbothioic acid as potent, non-detergent spermicides with low toxicity to Lactobacillus and HeLa cells in vitro.

BACKGROUND: The design, synthesis, characterization and evaluation of a novel series of non-detergent spermicides has led to the discovery of two unique molecules (DSE-36 and DSE-37) that were approximately 25 times more potent spermicides than nonoxynol-9 (N-9). METHODS: Normal human spermatozoa were used to assess the spermicidal activity (Sander-Cramer Assay), the effect on sperm-membrane integrity [hypo-osmotic swelling test (HOST)], supravital staining and scanning electron microscopy (SEM) and the induction of apoptosis [fluorescein isothiocyanate (FITC) Annexin-V and JC-1 labelling using flow cytometry] by the new class of compounds. HeLa and Lactobacillus cultures were used to assess the cytotoxicity of compounds and their compatibility to normal vaginal flora, respectively. RESULTS: Compounds DSE-36 and DSE-37 exhibited a strong spermicidal activity [minimum effective concentration (MEC) = 0.002%], which was approximately 25 times more potent than that of N-9 and Sapindus saponins (MEC = 0.05%). As compared with surfactants, DSE-36 and DSE-37 were found to be safer at MEC towards the growth and survival of Lactobacilli and HeLa cells in vitro and to have a milder effect on sperm plasma membrane. At EC(50) both induced apoptosis in sperm cells as characterized by increased labelling with Annexin-V and decreased polarization of sperm mitochondria. CONCLUSION: Preliminary studies have revealed that in sharp contrast to the non-specific surfactant action of N-9, DSE-36 and DSE-37 have a highly potent, mechanism-based, detrimental action on human sperm. The unique ability of these non-detergent molecules to selectively kill sperm and spare Lactobacilli and HeLa cells at MEC values much lower than that required for N-9 indicates their potential as superior ingredients for formulation into microbicidal contraceptives.

The use of the CO2 laser in rhinophyma surgery: personal technique and experience, complications, and long-term results.

Rhinophyma is a slowly progressive disfiguring disorder of the nose that represents the end stage of acne rosacea. The cosmetic deformity is often the reason patients seek medical attention. Over the years, many treatment modalities, including dermabrasion, electrocautery, excision and grafting, decortication, and cryosurgery, among others, have been described to treat this condition, but none of them has proved very satisfactory. Special concern about the droplet dispersion of blood in dermabrasion has made this method less acceptable, as it poses a potential risk to health workers. We describe a technique in which this proliferative disorder can be treated, using CO2 laser excision and vaporization. This method provides a very dry surgical field, which allows the sculpting of the hypertrophic areas to be very effective, giving a very satisfactory immediate and long-term cosmetic results.

Treatment of rhinophyma with carbon dioxide laser.

Rhinophyma is a slowly progressive, disfiguring disorder of the nose which represents the end stage of acne rosacea. The cosmetic deformity is often the reason for patients to seek medical attention. Over the years many treatment modalities, including dermabrasion, electrocautery, excision and grafting, decortication and cryosurgery amongst others, have been described to treat this condition, but none of them are very satisfactory. Special concern about the droplet dispersion of blood in dermabrasion have made this method less acceptable as it poses a potential risk to health workers. We describe a technique in which this proliferative disorder can be treated, using carbon dioxide laser excision and vaporization. This method provides a very dry surgical field which allows the sculpting of the hypertrophic areas to be very effective, giving a very satisfactory cosmetic result.

Peptidergic mechanisms in feeding behaviour.

Hyperphagia was induced in mice by p.o. administration of different types of CNS depressant drugs, like chlordiazepoxide 25 mg/kg diazepam 2.5 mg/kg, cyproheptadine 2 mg/kg and phenobarbitone 25 mg/kg. Such hyperphagia was abolished by pretreatment with naloxone 0.1 mg/kg sc. Naloxone per se at this dose produced no significant effect on the food intake. This is suggestive of the role of peptidergic mechanisms in the feeding behaviour in mice.

Studies in enteric anthelmintics: activity profile of prodrug of a bisbenzimidazole [1].

The comparative anthelmintic activity of a possible prodrug, 2,2'-dicarbomethoxyamino-5,5'-dibenzimidazolyl methanol (2) with its parent compound 2,2'-dicarbomethoxyamino-5,5'-dibenzimidazolyl ketone (1) and the reference drug mebendazole (3a) is reported. At a dose of 25 mg/kg, compound 2 was 100% effective against Ancylostoma ceylanicum in hamsters. Compound 2 also exhibited a similar order of activity against Syphacia obvelata, Hymenolepis nana and H. diminuta at a dose of 100 mg/kg. The drug exhibited lethal effects against metamorphic forms of A. ceylanicum at a dose of 100 mg/kg. However the trichostrongylids, Nippostrongylus brasiliensis remained unaffected up to a dose of 250 mg/kg of 2. Both 1 and 3a exhibited inferior activity than 2 except against adult A. ceylanicum. The activity of 1 and 2 has been explained on the basis of their ability to resist systemic hydrolysis resulting in higher concentration of the active drug in biophase.

Syntheses and bioevaluation of substituted dihydropyridines for pregnancy-interceptive activity in hamsters.

A number of 2,6-dimethyl-3,5-bis(methoxycarbonyl)-4-substituted-1,4- dihydropyridines were synthesized and evaluated for pregnancy-interceptive activity in mated hamsters. Out of 24 compounds, 12, 15, 21, 22, 28, and 34 caused a marked reduction in the number of implantations when administered on days 3-8 postcoitum. In an in vitro competition assay, none of the compounds exhibited noticeable binding affinity for uterine progesterone receptors. The results reported here have helped to identify new leads for developing pregnancy-interceptive agents and the active compounds do not seem to elicit their interceptive effect through receptor-mediated inhibition of progesterone action in hamster uterus.

Possible antifertility agents, part III. Synthesis of 4-(substituted aminomethyl)-5, 6, 7-trimethoxy phthalid methiodides and 1-N-aminoacetyl-benz [1, 6] diazocin-5-ones.

PIP: 12 new heterocyclic compounds containing methoxy groups and/or amine side chain residues have been synthesized and 1 had some activity in an antiimplantation assay. The compounds included 7 4-(substituted aminomethyl)5,6,7-trimethoxy phthalid methiodides and 5 1-N-aminoacetylbenz[1,6]diazocin-5-ones. 50% anti-implantational activity was observed on a morpholino compound, 4-(4-morpholinomethyl)-5,6,7-trimethoxy phthalid methiodide.^ieng

Acoustic impedance measurements and their importance in cleft palate patients.

There is a high incidence of middle ear pathology in cleft palate patients, secretory otitis media being the most common lesion. Impedence audiometry gives more valid information about conditions in the middle ear, as confirmed by exploratory paracenteses. Impedance audiometry, therefore, should be done as a routine, wherever facilities exist, in conjunction with the clinical examination.