Star-Shaped Poly(furfuryl glycidyl ether)-Block-Poly(glyceryl glycerol ether) as an Efficient Agent for the Enhancement of Nifuratel Solubility and for the Formation of Injectable and Self-Healable Hydrogel Platforms for the Gynaecological Therapies.

In this paper, we present novel well-defined unimolecular micelles constructed a on poly(furfuryl glycidyl ether) core and highly hydrophilic poly(glyceryl glycerol ether) shell, PFGE-b-PGGE. The copolymer was synthesized via anionic ring-opening polymerization of furfuryl glycidyl ether and (1,2-isopropylidene glyceryl) glycidyl ether, respectively. MTT assay revealed that the copolymer is non-cytotoxic against human cervical cancer endothelial (HeLa) cells. The copolymer thanks to furan moieties in its core is capable of encapsulation of nifuratel, a hydrophobic nitrofuran derivative, which is a drug applied in the gynaecology therapies that shows a broad antimicroorganism spectrum. The study shows high loading capacity of the copolymer, i.e., 146 mg of nifuratel per 1 g of copolymer. The load unimolecular micelles were characterized using DLS and TEM microscopy and compared with the reference glyceryl glycerol ether homopolymer sample. The presence of numerous 1,2-diol moieties in the shell of PFGE-b-PGG macromolecules enabled the formation of reversible cross-links with 2-acrylamidephenylboronic acid-based polyacrylamide. The obtained hydrogels were both injectable and self-healable, which was confirmed with a rheological study.

Tinidazole: Another Therapeutic Option for Syphilis?

After the incidental observation of an almost complete resolution of maculopapular eruption in a patient having simultaneously secondary syphilis and trichomonas vaginalis infection, we extended the treatment with tinidazole (500 mg 4 times daily for 7 days) to 10 other early syphilis patients before the start of the conventional penicillin treatment. All patients showed marked improvement of their lesions in a few days. After the introduction of the conventional penicillin regimen, the lesions further improved and VDRL titers declined at least 4-fold within 6 months in all patients. Tinidazole is a 5-nitroimidazole derivative as well as metronidazole but with a longer plasma half-life. It is activated intracellularly by bacterial/parasitic enzymes to a redox cytotoxic intermediate that damages large protein molecules and inhibits repair and transcription of DNA affecting also the cell wall. With this action, tinidazole might also have a synergic action with penicillin and doxycycline, facilitating the entry of such drugs. It is possible that tinidazole has the same bactericidal action on spirochetes other than Borrelia, such as Treponema pallidum, explaining its rapid therapeutic action on the lesions of early syphilis. Whether this action could be confirmed by studies on larger series of patients, tinidazole might be considered in case of allergy to penicillin or other antibiotics usually prescribed in syphilis.

Controlled delivery of the antiprotozoal agent (tinidazole) from intravaginal polymer matrices for treatment of the sexually transmitted infection, trichomoniasis.

Microporous polymeric matrices prepared from poly(ɛ-caprolactone) [PCL] were evaluated for controlled vaginal delivery of the antiprotozoal agent (tinidazole) in the treatment of the sexually transmitted infection, trichomoniasis. The matrices were produced by rapidly cooling co-solutions of PCL and tinidazole in acetone to -80 °C to induce crystallisation and hardening of the polymer. Tinidazole incorporation in the matrices increased from 1.4 to 3.9% (w/w), when the drug concentration in the starting PCL solution was raised from 10 to 20% (w/w), giving rise to drug loading efficiencies up to 20%. Rapid 'burst release' of 30% of the tinidazole content was recorded over 24 h when the PCL matrices were immersed in simulated vaginal fluid. Gradual drug release occurred over the next 6 days resulting in delivery of around 50% of the tinidazole load by day 7 with the released drug retaining antiprotozoal activity at levels almost 50% that of the 'non-formulated' drug in solution form. Basic modelling predicted that the concentration of tinidazole released into vaginal fluid in vivo from a PCL matrix in the form of an intravaginal ring would exceed the minimum inhibitory concentration against Trichomonas vaginalis. These findings recommend further investigation of PCL matrices as intravaginal devices for controlled delivery of antiprotozoal agents in the treatment and prevention of sexually transmitted infections.

Intravenous metronidazole, liquid tinidazole, and intra-vaginal boric acid to cure trichomonas in a patient with gastric bypass surgery.

This study presents a case report of a female patient with symptomatic refractory Trichomonas vaginalis infection who was not able to clear her infection with high-dose oral metronidazole, oral tinidazole, intra-vaginal zinc sulfate, intra-vaginal metronidazole, intra-vaginal tinidazole, and intra-vaginal boric acid. She was unable to tolerate intra-vaginal paromomycin. A combination of intravenous metronidazole, oral tinidazole liquid suspension, and intra-vaginal boric acid for 14 days subsequently achieved a complete symptomatic and laboratory cure.

Chitosan-sodium alginate blended polyelectrolyte complexes as potential multiparticulate carrier system: colon-targeted delivery and gamma scintigraphic imaging.

OBJECTIVES: The objective of this study is to develop stable, biodegradable chitosan-sodium alginate-based dual, ionic cross-linked multiparticulate system (microbeads) of tinidazole for targeted colon delivery and sustained drug release for the treatment of amoebiasis and thereby evaluating its targeting approach through in vivo gamma scintigraphic imaging technique. METHODS: The chitosan-sodium alginate-based multiparticulate system developed was producing sustained effect by virtue of its mechanical strength using double ionotropic gelation method utilizing calcium chloride and sodium sulfate as first and second cross-linkers respectively. Prepared formulations were evaluated for percent yield, drug entrapment efficiency, particle size, degree of swelling, in vitro kinetics, and in vivo targeting potentials using gamma scintigraphic imaging technique. RESULTS: The obtained particulates were spherical, free flowing, and had a mean particle size ranging from 1.422 mm to 1.881 mm, whereas percent yield and percent drug entrapment efficiency was found to be in between 72.61 to 82.43% and 63.25 to 79.32% respectively. CONCLUSION: The prepared multiparticulate system showed better sustained release property and in vivo ability to target colon for drug delivery. Hence, the developed multiparticulate system could be a promising device to achieve greater site-specificity to colon.

Metronidazole immediate release formulations: a fasting randomized open-label crossover bioequivalence study in healthy volunteers.

Metronidazole is a BCS (Biopharmaceutics Classification System) class 1 drug, traditionally considered the choice drug in the infections treatment caused by protozoa and anaerobic microorganisms. This study aimed to evaluate bioequivalence between 2 different marketed 250 mg metronidazole immediate release tablets. A randomized, open-label, 2×2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a 7-day washout period. The formulations were administered as single oral dose and blood was sampled over 48 h. Metronidazole plasma concentrations were determined by a liquid chromatography mass spectrometry (LC-MS/MS) method. The plasma concentration vs. time profile was generated for each volunteer and the pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC0-∞, ke, and t1/2 were calculated using a noncompartmental model. Bioequivalence between pharmaceutical formulations was determined by calculating 90% CIs (Confidence Intervall) for the ratios of Cmax, AUC0-t, and AUC0-∞ values for test and reference using log-transformed data. 22 healthy volunteers (11 men, 11 women; mean (SD) age, 28 (6.5) years [range, 21-45 years]; mean (SD) weight, 66 (9.3) kg [range, 51-81 kg]; mean (SD) height, 169 (6.5) cm [range, 156-186 cm]) were enrolled in and completed the study. The 90% CIs for Cmax (0.92-1.06), AUC0-t (0.97-1.02), and AUC0-∞ (0.97-1.03) values for the test and reference products fitted in the interval of 0.80-1.25 proposed by most regulatory agencies, including the Brazilian agency ANVISA. No clinically significant adverse effects were reported. After pharmacokinetics analysis, it concluded that test 250 mg metronidazole formulation is bioequivalent to the reference product according to the Brazilian agency requirements.

[Preparation and in vitro and in vivo study on tinidazole in situ forming sustained-release injection].

This study is to prepare the in situ forming sustained-release injection which can perform sustained release behavior at the periodontal site for 7 days and to evaluate its in vitro and in vivo properties. After preparation of in situ forming sustained-release injection the in situ time was studied. And the surface of the solid injection was characterized by SEM. The rheological curve at 0 degrees C, 25 degrees C, 37 degrees C was determined and the impact of the temperature on the viscosity was examined. The in vitro release behavior was investigated. At last, rabbit periodontitis model was established to study its pharmacokinetics. The injection was stable, hard to stratify and decompose. The in situ forming time was about 6 seconds. It can easily adhere into periodontal pockets. There were lots of holes on the surface of the solid injection for the drug to diffuse. The drug releasing curves could be fit by Korsmeyer-Peppas equation. The drug smoothly released for 7 days at pH 7.4 PBS buffer with a very slight burst release and maintained a certain concentration. In vivo pharmacokinetics results indicated that after administration with the in situ forming injection, achievement of tinidazole (TNZ) concentration in gingival crevicular fluid (GCF) was more comparable and long-lasting than usual solution of TNZ management and relatively constant TNZ levels were attained until 168 h. All these results supported the prospect of tinidazole in situ forming sustained-release injection in clinical applications.

Resistant trichomoniasis: successful treatment with combination therapy.

Metronidazole-resistant vaginal trichomoniasis remains a major therapeutic challenge. Two women with symptomatic metronidazole-resistant trichomoniasis had multiple unsuccessful courses of therapy with a broad array of medications. Both patients finally responded to combination treatment with intravaginal paromomycin cream and high-dose oral tinidazole.

A randomized treatment trial: single versus 7-day dose of metronidazole for the treatment of Trichomonas vaginalis among HIV-infected women.

OBJECTIVE: To determine if the metronidazole (MTZ) 2-gm single dose (recommended) is as effective as the 7-day 500 mg twice a day dose (alternative) for treatment of Trichomonas vaginalis (TV) among HIV+ women. METHODS: Phase IV randomized clinical trial; HIV+ women with culture confirmed TV were randomized to treatment arm: MTZ 2-gm single dose or MTZ 500 mg twice a day 7-day dose. All women were given 2-gm MTZ doses to deliver to their sex partners. Women were recultured for TV at a test-of-cure (TOC) visit occurring 6-12 days after treatment completion. TV-negative women at TOC were again recultured at a 3-month visit. Repeat TV infection rates were compared between arms. RESULTS: Two hundred seventy HIV+/TV+ women were enrolled (mean age = 40 years, ±9.4; 92.2% African American). Treatment arms were similar with respect to age, race, CD4 count, viral load, antiretroviral therapy status, site, and loss-to-follow up. Women in the 7-day arm had lower repeat TV infection rates at TOC [8.5% (11 of 130) versus 16.8% (21 of 125) (relative risk: 0.50, 95% confidence interval = 0.25, 1.00; P < 0.05)] and at 3 months [11.0% (8 of 73) versus 24.1% (19 of 79) (relative risk: 0.46, 95% confidence interval = 0.21, 0.98; P = 0.03)] compared with the single-dose arm. CONCLUSIONS: The 7-day MTZ dose was more effective than the single dose for the treatment of TV among HIV+ women.

Treatment of metronidazole-resistant Trichomonas vaginalis.

A 58-year-old Caucasian woman presented with a 14-month history of persistent trichomoniasis not responsive to numerous courses of metronidazole and tinidazole. Vaginal secretion samples were obtained for sensitivity testing and treatment recommendations. In vitro susceptibility testing revealed the patient's Trichomonas vaginalis isolate was highly resistant to both metronidazole and tinidazole. She was treated with topical furazolidone and experienced a complete symptomatic cure and culture remained negative 35 days post furazolidone treatment.

Evaluation of selected tropical seaweeds for in vitro anti-trichomonal activity.

ETHNOPHARMACOLOGICAL RELEVANCE: Human parasitic infections are a serious problem in tropical and sub-tropical developing countries. Trichomoniasis, responsible for the annual infection of 180 million people, is a common sexually transmitted disease caused by the protozoan Trichomonas vaginalis. Traditionally seaweeds have been used in folk medicine by coastal people in Asia and the Caribbean to treat parasitic infections and are a valuable source of novel anti-trichomonals. AIM OF THE STUDY: In our search for therapeutical alternatives to anti-protozoal chemotherapy, we collected a selection of 25 tropical seaweeds (12 Rhodophyta, 5 Phaeophyta and 8 Chlorophyta) from the coast of Yucatan (Mexico) in order to undertake ethnopharmacological and chemotaxonomic investigations. MATERIALS AND METHODS: Organic algal extracts were tested for their anti-trichomonal properties on the growth inhibition of Trichomonas vaginalis. The cytotoxicity of seaweed extracts on mammal cell lines was also assessed. RESULTS: The results indicated that 44% of the seaweeds studied had high to moderate anti-trichomonal activity. Lobophora variegata and Udotea conglutinata showed the maximal anti-trichomonal activity with IC(50) values of 1.39 and 1.66microg/ml, respectively, with good selectivity. CONCLUSIONS: Lobophora variegata and Udotea conglutinata demonstrated promising anti-trichomonal potential and have been selected for further bio-guided fractionation and isolation of active anti-trichomonal compounds.

Bioequivalence evaluation of two different tablet formulations of tinidazole in healthy volunteers.

The bioequivalence of two different tablet formulations of tinidazole (CAS 19387-91-8) was determined in healthy volunteers after a single dose in a randomized crossover study, with a 1-week washout period between the doses. Reference and test products were administered to 24 volunteers with 240 mL water after overnight fasting. Plasma concentrations of tinidazole were monitored by a high-performance liquid chromatographic method (HPLC) over a period of 72 h after the administration. The pharmacokinetic parameters AUC(o-t), AUCo-infinity, C(max), T(max), T((1/2)el) and beta were determined from plasma concentration time profile of both formulations and found to be in good agreement with previously reported values. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals for the ratio of C(max) (93.9 -102.6%), AUC(o-t) (94.9-101.1%) and AUC(o-infinity) (94.6-100.8%) values for the test and reference products were within the 80-125% interval, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. These results Indicate that the test and the reference products of tinidazole are bioequivalent and, thus, may be prescribed interchangeably.

Effectiveness of two tinidazole regimens in treatment of bacterial vaginosis: a randomized controlled trial.

OBJECTIVE: To assess the effectiveness at 21-30 days after treatment of tinidazole administered orally at 1 g once daily for 5 days and 2 g once daily for 2 days, compared with placebo, in the treatment of bacterial vaginosis, using rigorous U.S. Food and Drug Administration (FDA)-recommended criteria to define cure. METHODS: A total of 235 women at 10 U.S. centers participated in this prospective, randomized, double-blinded, placebo-controlled trial. Presence or absence of all five following criteria was required to define diagnosis or cure of bacterial vaginosis: 1) clue cells were at least 20% of squamous cells in microscopic examination of vaginal fluid; 2) positive potassium hydroxide whiff test; 3) a homogeneous, thin, white-gray vaginal discharge; 4) vaginal pH greater than 4.5; and 5) Nugent score greater than or equal to 4 on Gram-stained vaginal fluid. Compliance, tolerability, and safety were assessed using patient diaries and interviews at 8-10 days and 21-30 days after treatment. Cochran-Mantel-Haenszel statistical analysis with Bonferroni adjustment was used to compare outcomes. RESULTS: Superior efficacy was demonstrated by tinidazole for the 1 g once daily for 5 days regimen (36.8% cured, P<.001, number needed to treat 3.2) and for the 2 g once daily for 2 days regimen (27.4% cured, P<.001, number needed to treat 4.5), when compared with placebo (5.1% cured) in the primary endpoint analysis. Using more traditional criteria for cure, efficacy was greater. Compliance with study therapy and tolerability were comparable in the three treatment groups. CONCLUSION: Both tinidazole regimens studied provided effective treatment for bacterial vaginosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00229216 LEVEL OF EVIDENCE: I.

Tinidazole for the treatment of vaginal infections.

Tinidazole has been used for vaginal infection worldwide but not in the US for > 40 years. Recently, tinidazole has been re-introduced and approved by the FDA for trichomoniasis and restudied as an alternative to metronidazole for bacterial vaginosis. In vitro antimicrobial activity and pharmacokinetics studies indicate that tinidazole has minor but possibly relevant antimicrobial as well as pharmacokinetic advantages when compared directly with metronidazole. Clinical comparison has been infrequent although the limited head-to-head studies indicate minimal therapeutic advantage with tinidazole. Perhaps the more relevant differences relate to the enhanced tolerance and reduced toxicity of tinidazole. Ongoing, as yet incomplete, studies directly comparing the clinical efficacy of metronidazole and tinidazole for bacterial vaginosis should clarify the status of tinidazole; however, cure rates are unlikely to be significantly different. Although uncommon, high-level trichomonal metronidazole resistance can be reliably cured by using tinidazole, which is an invaluable advantage.

Study on the compatibility of cefotaxime with tinidazole in glucose injection.

An efficient HPLC method for the compatibility study of cefotaxime with tinidazole in glucose injection is described, which has been developed for the simultaneous determination of cefotaxime and tinidazole in glucose injection. The appearance and pH value of the mixed solution were investigated and the concentrations of cefotaxime and tinidazole were determined by RP-HPLC with an Agilent ZORBAX Eclipse XDB-C8 column, gradient elution and dual wavelength detection on diode-array-detector (DAD) at room temperature (20 degrees C) within 24 h. It was found that the resulting appearance and pH value of the mixed solution showed slight changes, on the other hand, the quantity of cefotaxime decreased significantly. The results show that the mixed solution of cefotaxime with tinidazole in glucose injection must be used within 8 h in clinical due to the possible degradation of cefotaxime in tinidazole glucose injection. This study provides a convenient method for rational use of compatible drugs in clinical practice.

Study on poly(vinyl alcohol)/carboxymethyl-chitosan blend film as local drug delivery system.

The distinguishable films composed of poly(vinyl alcohol) (PVA) and carboxymethyl-chitosan (CMCS) were prepared by blending/casting method, and loaded with ornidazole (OD) as local drug delivery system. In vitro test, the blend films showed pH-responsive swelling behavior and moderate drug release action, and also exhibited a little antimicrobial activity against E. coli and S. aureus strains. Those characteristics of CMCS/PVA blend films were essentially governed by the weight ratio of CMCS and PVA. Increasing the content of PVA in blend film would decrease swelling and decelerated the drug release. However, increasing the content of CMCS would enhance the antimicrobial activity. The biocompatibility and bioactivity of the blend film were also evaluated using rabbit blood and Wister rats. This blend drug system was of no hemolysis, no toxicity to rat periodontia and no cytotoxicity to the rat muscle. After subcutaneously implanting the blend drug films in Wister rat, the systems kept a good retention at the application site and maintained high drug concentration in long time (5 days) which was longer than the period of drug released in vitro (160 min).