EVO100 prevents chlamydia and gonorrhea in women at high risk of infection.

BACKGROUND: According to the Centers for Disease Control and Prevention, rates of infection for Chlamydia trachomatis and Neisseria gonorrhoeae are increasing in the United States. EVO100 is an investigational antimicrobial, pH-modulating, vaginal gel with active ingredients L-lactic acid, citric acid, and potassium bitartrate that is being evaluated for the prevention of sexually transmitted infections. OBJECTIVE: The objective of this phase 2B/3 study was to assess the efficacy and safety of EVO100 for the prevention of chlamydia and gonorrhea. STUDY DESIGN: AMPREVENCE was a double-blinded, placebo-controlled, multicenter study based in the United States conducted over approximately 16 weeks in women at the age of 18 to 45 years who were at risk of urogenital chlamydia and gonorrhea infection. Enrolled women had been diagnosed as having and treated for chlamydia or gonorrhea ≤16 weeks before enrollment. Women received either EVO100 or placebo vaginal gel and were instructed to apply the study drug immediately before or up to 1 hour before each act of vaginal sexual intercourse. The primary and secondary endpoints were the prevention of urogenital chlamydia and gonorrhea, respectively. Exploratory outcomes include women's overall satisfaction with EVO100. RESULTS: In total, 860 women were randomized 1:1 to receive EVO100 (n=426) or placebo (n=434), and 764 women (EVO100, n=376; placebo, n=388) were documented as using the study drug at least once. Baseline characteristics were similar between treatment arms. Overall, women had a mean age of 27.7 years (standard deviation, 6.9) and body mass index of 28.9 kg/m2 (standard deviation, 8.0). Most women were of White (54.3% [467 of 860]) or African American (41.6% [358 of 860]) race and of non-Hispanic/Latina ethnicity (67.1% [577 of 860]). The chlamydia infection rate in EVO100 users was 4.8% (14 of 289) compared with 9.7% (28 of 290) among placebo users (P=.0256), representing a relative risk reduction of 50%. For gonorrhea, the infection rate was 0.7% (2 of 280) in the EVO100 arm compared with 3.2% (9 of 277) in the placebo arm (P=.0316), representing a relative risk reduction of 78%. Increased efficacy was observed with increased adherence, and chlamydia infection rates were significantly reduced with increased adherence in the EVO100 group compared with placebo. Across both arms, there were similar rates of all-cause adverse events (EVO100, 21.3% [80 of 376]; placebo, 20.4% [79 of 388]) and treatment-related adverse events (EVO100, 7.2% [27 of 376]; placebo, 7.5% [29 of 388]). The most common adverse events in the EVO100 arm were vulvovaginal candidiasis (5.1% [19 of 376]), vaginal discharge (3.2% [12 of 376]), and urinary tract infection (3.2% [12 of 376]) and, in the placebo arm, bacterial vaginosis (4.6% [18 of 388]), urinary tract infection (2.6% [10 of 388]), and vaginal discharge (2.6% [10 of 388]). Few women discontinued owing to adverse events in either arm (EVO100, 1.1% [4 of 376]; placebo, 1.5% [6 of 388]). No treatment-related serious adverse events were reported. Most EVO100 users (88%) were satisfied or very satisfied with EVO100 after 16 weeks of use. CONCLUSION: EVO100 significantly reduced the risk of chlamydia and gonorrhea infections in women at high risk of Chlamydia trachomatis and Neisseria gonorrhoeae infection and was well tolerated, with observed adverse events consistent with its known safety profile.

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis.

Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

Effectiveness of various interventions on maintenance of gingival health during 1 year - a randomized clinical trial.

BACKGROUND: Rinsing with the combined use of an oxygenating-agent (OA) and chlorhexidine (CHX) in addition to mechanical oral hygiene could improve and/or maintain good gingival health over a long period. METHODS: This study had an examiner-blinded, randomized, six-group parallel design consisting of two-phases: a 3-week treatment phase and a subsequent 12-month experimental phase. A total of 267 subjects in good general health (≥18 years), without periodontitis, with at least five teeth per quadrant, and with moderate to advanced gingivitis were enrolled. A 3-week treatment phase was initiated to improve gingival health. Subjects were assigned to one of the six groups: two basic oral hygiene groups (Control I & II), one professional oral hygiene instruction group (OHI), one professional prophylaxis group (PP), an OA&CHX rinse group and a group receiving a combination of all regimens (COMBI group), being OHI + PP + OA&CHX. Dental plaque, gingival bleeding and staining assessments were performed at the start of the treatment phase, at baseline and at 4, 7, 10, and 12 months. RESULTS: There was a significant reduction in dental plaque-scores for the OA&CHX and COMBI-group (0.51 [SD = 0.37], 0.38 [SD = 0.33] respectively) and a significant reduction in gingivitis scores for the OA&CHX and COMBI group (6.9% [SD = 14.0], 13.4% [SD = 13.4] respectively) from the start of the treatment phase to baseline. No clinically relevant changes were observed for the other four groups. After baseline, bleeding and plaque-scores increased back to a non-significant level between groups, and this level remained throughout the study. CONCLUSION: OA&CHX and COMBI-group showed a clinically relevant improvement after the treatment phase in terms of dental plaque and gingival bleeding levels. At the 4-month clinical assessment, there was no longer a significant difference between groups.

Immunomodulating tellurium compounds as anti-cancer agents.

Tellurium is a rare element, which has been regarded as a toxic, non-essential trace element; its biological role, if any, has not been clearly established to date. The investigation of therapeutic activities of tellurium compounds is rather limited in the literature, despite the relative abundance of tellurium in the human body. Nevertheless, the varied activities of tellurium agents in both malignant and normal cells are extremely exciting, though very complex. Not surprisingly, an increased interest in tellurium among biological chemists and pharmacists has fuelled the search for more and more diverse tellurium compounds. The present review will focus on two small inorganic tellurium complexes, ammonium trichloro(dioxoethylene-O,O')tellurate (AS101) and Octa-O-bis-(R,R)-tartarate ditellurane (SAS), thoroughly investigated by us, converging at their anti-cancer properties, and elucidating their mechanism of action. AS101 is probably the most extensively studied synthetic tellurium compound from the standpoint of its biological activity. It is a potent immunomodulator (both in vitro and in vivo) with a variety of potential therapeutic applications. It is probably the only tellurium compound to be tested in phase I/II clinical studies in cancer patients. The effects of AS101 and SAS are primarily caused by their specific Te(IV) redox-modulating activities enabling the inactivation of cysteine proteases such as cathepsin B, inhibition of specific tumor survival proteins like survivin, or obstruction of tumor IL-10 production. All of these have profound consequences regarding anti-tumor activity or sensitization of tumors to chemotherapy. These properties, coupled with the excellent safety profile of the compounds, suggest promising anti-cancer therapeutic potential for tellurium compounds such as AS101 or SAS.

Chemical composition and antidiabetic activity of Opuntia Milpa Alta extracts.

Three new compounds, 1-3, and 20 known compounds were isolated from the AcOEt and BuOH extract of edible Opuntia Milpa Alta. The petroleum ether extract was examined by GC and MS. A total of 26 compounds were identified, representing 95.6% of the total extract, phytosterol (36.03%) being the most abundant component, and polyunsaturated fatty acids (18.57%) represented the second largest group, followed by phytol (12.28%), palmitic acid, palmitate (13.54%), vitamin E (4.51%), and other compounds (7.47%). The effects of various extracts from edible Opuntia Milpa Alta (petroleum ether extract, AcOEt extract, BuOH extract, aqueous extract, H2O parts) and the positive control (received dimethylbiguanide) were tested on streptozotocin (STZ)-induced diabetic mice. The results indicated that all the treatment groups could significantly decrease blood glucose levels in STZ-induced diabetic mice compared to the model control group (P<0.01), except the aqueous extract group (P<0.05). Especially, the petroleum ether extract group and the positive control group showed remarkable decrease of blood glucose levels. Taken together, the results indicate that the petroleum ether extract is the major hypoglycemic part in edible Opuntia Milpa Alta, which may be developed to a potential natural hypoglycemic functional ingredient.

Upadacitinib tartrate in rheumatoid arthritis.

In rheumatoid arthritis (RA) there is an unmet therapeutic need, as a substantial proportion of patients does not achieve low disease activity or remission despite the use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or biological DMARDs (bDMARDs). The Janus kinase (JAK) inhibitors are the most recently added drug category in the therapeutic armamentarium in RA. Upadacitinib tartrate (Rinvoq), a selective and reversible JAK1 inhibitor, inhibited interleukin (IL)-6 and IL-7 and ameliorated adjuvant-induced arthritis in preclinical studies. In phase III randomized controlled trials (RCTs), upadacitinib, as monotherapy or in combination with csDMARDs, showed efficacy in RA patients with inadequate response to csDMARDs or bDMARDs. In a head-to-head RCT, upadacitinib 15 mg once daily was superior to adalimumab in achieving remission and in patient-reported outcomes. Upadacitinib has a good safety profile but it may increase the risk for herpes zoster, and as a substrate of cytochrome P450 (CYP) enzyme CYP3A4 it should not be coadministered with strong CYP3A4 inducers. Upadacitinib is contraindicated in patients with active tuberculosis, serious infections, active malignancy and in patients with severe liver impairment. Upadacitinib has been approved for the treatment of moderate to severe RA.

Preparation, characterization, and in vivo evaluation of a polymorphic form of valnemulin hydrogen tartrate.

We prepared a polymorphic form of valnemulin hydrogen tartrate (Form I) to overcome the instability and irritating odor of valnemulin hydrochloride that affect its use in the production and application of veterinary drugs. The physicochemical properties of Form I were characterized by scanning electron microscopy, X-ray powder diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The results showed the crystal structure and thermal properties of Form I were very different from those of a commercially available form of valnemulin hydrogen tartrate (Form II). Form I and Form II were more stable than valnemulin hydrochloride after storage under irradiation and high humidity conditions, respectively. The solubility of Form I was 2.6 times that of Form II, and Form I was selected for use in pharmaceutical kinetics experiments in vivo. Compared to valnemulin hydrochloride, after oral administration at a dose of 10 mg/kg in pigs, Form I had similar pharmaceutical kinetic behavior but a slightly higher area under the concentration-time curve from time zero to the last measurable concentration. Consequently, Form I should be suitable for the development of simple formulations and be effective in the clinical application of veterinary drugs.

Cyclopamine tartrate, a modulator of hedgehog signaling and mitochondrial respiration, effectively arrests lung tumor growth and progression.

Lung cancer remains the leading cause of cancer-related death, despite the advent of targeted therapies and immunotherapies. Therefore, it is crucial to identify novel molecular features unique to lung tumors. Here, we show that cyclopamine tartrate (CycT) strongly suppresses the growth of subcutaneously implanted non-small cell lung cancer (NSCLC) xenografts and nearly eradicated orthotopically implanted NSCLC xenografts. CycT reduces heme synthesis and degradation in NSCLC cells and suppresses oxygen consumption in purified mitochondria. In orthotopic tumors, CycT decreases the levels of proteins and enzymes crucial for heme synthesis, uptake, and oxidative phosphorylation (OXPHOS). CycT also decreases the levels of two regulators promoting OXPHOS, MYC and MCL1, and effectively alleviates tumor hypoxia. Evidently, CycT acts via multiple modes to suppress OXPHOS. One mode is to directly inhibit mitochondrial respiration/OXPHOS. Another mode is to inhibit heme synthesis and degradation. Both modes appear to be independent of hedgehog signaling. Addition of heme to NSCLC cells partially reverses the effect of CycT on oxygen consumption, proliferation, and tumorigenic functions. Together, our results strongly suggest that CycT suppress tumor growth in the lung by inhibiting heme metabolism and OXPHOS. Targeting heme metabolism and OXPHOS may be an effective strategy to combat lung cancer.

[Summary of the practice guideline 'Otitis externa' (first revision) from the Dutch College of General Practitioners]. / Samenvatting van de standaard 'Otitis externa' (eerste herziening) van het Nederlands Huisartsen Genootschap.

* The practice guideline 'Otitis externa', first developed by the Dutch College of General Practitioners in 1995, has been revised and updated. * It is no longer recommended to perform a KOH test on material collected from the auditory canal in patients with otitis externa. * Eardrops that contain both acid and corticosteroids are preferred over eardrops that contain acid only. * Suitable options include acidic eardrops with hydrocortisone 1% FNA and acidic eardrops with triamcinolone acetonide 0.1% FNA at a dose of 3 drops thrice daily. * The guideline contains a detailed discussion of the ototoxicity of eardrops in patients with tympanic membrane perforation. * Management of these patients, however, remains unchanged: the preferred approach is aluminium acetotartrate eardrops 1.2% FNA.

Comparative effectiveness of beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with heart failure.

Placebo-controlled randomized trials have demonstrated the efficacy of selected beta blockers on outcomes in chronic heart failure (HF), but the relative effectiveness of different beta blockers in usual clinical care is poorly understood. We compared 12-month risk of rehospitalization for HF associated with receipt of different beta blockers in 7,883 adults hospitalized for HF within 2 large health plans between January 1, 2001 and December 31, 2002. Beta-blocker use was ascertained from electronic pharmacy databases and readmissions within 12 months were identified from hospital discharge databases. Extended Cox regression was used to examine the association between receipt of different beta blockers and risk of readmission for HF after adjustment for potential confounders. During follow-up, there were 3,234 person-years of exposure to beta blockers (39.3% atenolol, 42.0% metoprolol tartrate, 12.3% carvedilol, and 6.4% other). Crude 12-month rates of readmissions for HF were high overall (42.6 per 100 person-years). After adjustment for potential confounders, cumulative exposure to each beta blocker, and propensity to receive carvedilol compared with atenolol, adjusted risks of readmission were not significantly different for metoprolol tartrate (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.05) or for carvedilol (adjusted hazard ratio 0.92, 95% confidence interval 0.74 to 1.14). In conclusion, in a contemporary cohort of high-risk patients hospitalized with HF, we found that adjusted risks of rehospitalization for HF within 12 months were not significantly different in patients receiving atenolol, shorter-acting metoprolol tartrate, or carvedilol.

The plaque removal effects of single rinsings and brushings.

Chemical plaque removal is one mechanism whereby an agent could improve oral hygiene and gingival health. As with toothpastes most agents, when delivered as rinses, would be considered adjunctive to mechanical tooth cleaning procedures. The aim of this study was to determine whether selected commercial rinses exhibited clinically significant plaque removal properties alone or when combined with toothbrushing with water or a toothpaste. A group of 12 volunteers took part in this single blind, randomized placebo-controlled, 12 cell cross-over study, employing 6 rinses. During each regimen subjects accumulated plaque from a zero baseline over 72 hours. Plaque removal was then measured by index and area after first a single rinse of product and second a subsequent brushing with water or toothpaste. Prebrushing rinsing removed less than 5% of the plaque with little difference between agents. No rinse was more adjunctive than water to postrinse brushings. Most statistically significant differences arose with the chlorhexidine rinse being apparently less effective. However, the possibility of a disclosing dye interaction cannot be discounted as explaining this anomalous result. This study could not support any claim of a direct prebrushing rinse benefit greater than that provided by water to mechanical plaque removal by any of the products tested.

Asymptomatic hyperuricaemia and its early treatment.

Sixteen patients with asymptomatic hyperuricaemia were treated with "Citro-Soda', an urinary alkanlinizing agent, in a dose of 4 g four times daily for one month. Ten of the sixteen patients exhibited a meaningful reduction in serum uric acid (greater than 15%). No adverse effects were noted and various haematological and urinary tests were all normal. 'Citro-Soda' could, therefore, be considered a useful and well-tolerated adjunct in the treatment of hyperuricaemia.

The use of QLF to quantify in vitro whitening in a product testing model.

BACKGROUND: Professional and consumer interest in whitening products continues to increase against a background of both increased oral health awareness and demand for cosmetic procedures. In the current legal climate, few dentists are providing 'in-office' whitening treatments, and thus many patients turn to home-use products. The most common of these are the whitening toothpastes. Researchers are keen to quantify the effectiveness of such products through clinically relevant trials. AIM: Previous studies examining whitening products have employed a variety of stained substrates to monitor stain removal. This study aimed to quantify the removal of stain from human enamel using a new device, quantitative light-induced fluorescence (QLF). The experimental design follows that of a product-testing model. MATERIALS AND METHODS: A total of 11 previously extracted molar teeth were coated with transparent nail varnish leaving an exposed window of enamel. The sound, exposed enamel was subject to a staining regime of human saliva, chlorhexidine and tea. Each of the eleven teeth was subjected to serial exposures of a positive control (Bocasan), a negative control (water) and a test product (Yotuel toothpaste). Following each two-minute exposure QLF images of the teeth were taken (a total of 5 applications). Following completion of one test solution, the teeth were cleaned, re-stained and the procedure repeated with the next solution. QLF images were stored on a PC and analysed by a blinded single examiner. The deltaQ value at 5% threshold was reported. ANOVA and paired t-tests were used to analyse the data. RESULTS: The study confirmed the ability of QLF to longitudinally quantify stain reduction from human enamel. The reliability of the technique in relation to positive and negative test controls was proven. The positive control had a significantly (alpha = 0.05) higher stain removal efficacy than water (p = 0.023) and Yotuel (p = 0.046). Yotuel was more effective than water (p = 0.023). CONCLUSION: The research community, the practicing clinician and the consumer all require sound product evaluation data. The use of human enamel specimens may offer more relevant clinical data. QLF has been designed as an in vivo device. Further development of the technique should permit in vivo clinical whitening trials.

Effect of an oral bulking agent and a rectal laxative administered alone or in combination for the treatment of constipation.

OBJECTIVES: The aim of the present study was to search for a synergetic action between psyllium and a defecation-inducing drug, Eductyl, for symptom relief in patients suffering from chronic constipation. METHODS: Twenty healthy volunteers and 20 patients complaining of chronic constipation were included in a randomized crossover study. The study was divided into four 2-weeks periods: pre-inclusion and three periods of treatment with psyllium, Eductyl, and Eductyl + psyllium respectively. Colonic transit time was determined at the end of each period of treatment. During each of the four periods, a self-administered questionnaire was used to assess symptoms of constipation. RESULTS: For constipated patients, treatment with Eductyl and Eductyl-psyllium improved clinical symptoms of constipation: increased stool frequency, resulted in fewer hard stools and less sensation of incomplete evacuation and less straining to defecate. The improvement was associated with a decrease in total and segmental colonic transit time. The Eductyl-psyllium combination did not exhibit any synergetic effect. CONCLUSION: Treatment with Eductyl alone is more efficient than with psyllium alone in providing symptom relief. Combination with psyllium is not synergetic.

Current chemotherapy of schistosomiasis japonica in the Philippines.

For the past several decades, the drug being used for the treatment of schistosomiasis in the Philippines has been Stibophen. It is administered intramuscularly at a dose of 1 ml per 10 kg body weight with a maximum of 5 ml every other day after 2 initial daily smaller sensitivity doses at a total dose of 45 to 70 ml fof adult patients. In recent years, a number of drugs for the treatment of schistosomiasis have been developed. These were evaluated clinically either in the hospital or in field trials in Leyte. Unfortunately, none of these were found to be suitable for mass treatment on account of toxicity to prolonged course of treatment. In view of the pressing need for a safe and effective schistosomicidal agent, the search for a better drug is imperative.

[Choice of ear drops in chronic otorrhea]. / De keuze van oordruppels voor chronische otorroe.

In chronic otitis, the use of ear drops has certain advantages over the use of systemic antibiotics. The choice of ear drop depends on the condition of the eardrum, microbial pathogens present and the efficacy of the components of the ear drop. Ototoxicity, contact allergy and the development of bacterial resistance have to be taken into account. Ototoxicity is a rare complication of the application of ear drops, most often described when aminoglycosides were applied. Contact allergy is also most often seen in aminoglycoside-containing eardrops. Evaluation of ear swabs demonstrated a 5% resistance of Pseudomonas aeruginosa to ciprofloxacin. The appearance of resistant strains may impede systemic use of fluoroquinolones. Therefore, this class of antibiotics should be considered as reserve medication only. The first choice in local application of antiseptics in case of an open eardrum is aluminium acetotartrate 1.2% and, of a combination preparation, bacitracin-colistin-hydrocortisone. In case of a closed eardrum (external otitis) aluminium acetotartrate 12%--combination preparations with corticosteroids are advised against in these cases.

The kappa opioid receptor agonist SA14867 has antinociceptive and weak sedative effects in models of acute and chronic pain.

We examined the analgesic effect of the selective kappa opioid receptor agonist SA14867 and the balance of its antinociceptive and sedative effects. The ED(50) values of SA14867 after oral administration for acetic acid-induced writhing, first and second phases of the formalin test, and rotarod test in mice were 6.1, 9.3, 2.7, and 19.5mg/kg, respectively. These values were smaller than those of the conventional kappa receptor agonists asimadoline and U-50488H. However, the balance of the antinociceptive and sedative effects of SA14867 was better than those of the other two drugs. Orally administered SA14867 (0.1-1mg/kg) significantly improved the decreased pain threshold in a specific alternation of rhythm in an environmental temperature (SART)-stressed model by prophylactic and therapeutic treatment. Improvement in the decreased pain threshold of SA14867-treated animals was attenuated by the opioid receptor antagonist naloxone. Furthermore, orally administered asimadoline (10-100mg/kg) improved the decreased pain threshold in a SART-stressed model, but the doses were close to those known to induce sedative effects. In addition, SA14867 (0.1-1mg/kg) significantly inhibited the arthritis-induced decrease in the pain threshold. Subcutaneously administered morphine (0.1-1mg/kg) improved the decreased pain threshold in a SART-stressed model; on the contrary, morphine did not inhibit the arthritis-induced decrease in the pain threshold. Moreover, orally administered SA14867 (0.1-1mg/kg) strongly attenuated mechanical allodynia and thermal hyperalgesia in a sciatic nerve ligation model. These results suggest that SA14867 has analgesic effects on chronic pain and may serve as a new therapeutic agent for pain treatment.