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Clinical Therapeutics Dec 2005Tinidazole, a structural analogue of metrondazole, is an antiprotozoal agent that has been widely used in Europe and developing countries for >2 decades with established... (Review)
Review
BACKGROUND
Tinidazole, a structural analogue of metrondazole, is an antiprotozoal agent that has been widely used in Europe and developing countries for >2 decades with established efficacy and acceptable tolerability. It was recently approved by the US Food and Drug Administration for the treatment of trichomoniasis, giardiasis, amebiasis, and amebic liver abscess.
OBJECTIVE
This article reviews the pharmacologic and pharmacokinetic properties and clinical usefulness of tinidazole.
METHODS
Relevant information was identified through a search of MEDLINE (1966-August 2005), Iowa Drug Information Service (1966-August 2005), and International Pharmaceutical Abstracts (1970-August 2005) using the terms tinidazole, Fasigyn, and nitroimidazole.
RESULTS
In vitro, tinidazole exhibits activity against pathogenic protozoa (eg, Tricbomonas vaginalis, Entamoeba bistolytica, Giardia duodenalis), a wide range of clinically significant anaerobic bacteria (eg, Bacteroides fragilis, Clostridium difficile), and the microaerophilic bacterium Helicobacter pylori. In susceptible protozoal and bacterial cells, tinidazole is reduced to cytotoxic intermediates that covalently bind to DNA, causing irreversible damage. In human adults, tinidazole had a bioavailability of 100% and a V(d) of 50.7 L, was minimally bound to plasma protein (12%), had a plasma elimination t((1/2)) of 12.3 hours, and was eliminated primarily by hepatic metabolism (approximately 63%). Dose adjustment does not appear to be necessary on the basis of race, sex, or renal function. No data were found on the disposition of tinidazole in patients with hepatic insufficiency; therefore, use of tinidazole in patients with severe hepatic impairment (Child-Pugh class C) is not recommended. Clinical cure rates in patients with trichomoniasis, giardiasis, amebiasis, and amebic liver abscess were generally >90%. In comparative trials, tinidazole was as effective as metronidazole in the treatment of trichomoniasis and was significantly more effective than metronidazole in the treatment of giardiasis (P < 0.05) and amebiasis (P < 0.05). The most commonly reported (>1%) adverse effects included bitter taste, nausea, abdominal discomfort, anorexia, vomiting, and fatigue. The recommended dosage of tinidazole is a single dose of 2 g for trichomoniasis and giardiasis, and 2 g/d for 3 to 5 days for amebiasis.
CONCLUSIONS
Tinidazole appears to be a promising agent for the treatment of trichomoniasis, giardiasis, amebiasis, and amebic liver abscess. Clinical studies are needed to evaluate the use of tinidazole against anaerobic bacteria and H pylori.
Topics: Antiprotozoal Agents; Clinical Trials as Topic; Drug Interactions; Humans; Molecular Structure; Tinidazole
PubMed: 16507373
DOI: 10.1016/j.clinthera.2005.12.012 -
Antimicrobial Agents and Chemotherapy May 2002
Review
Topics: Animals; Antifungal Agents; Antiprotozoal Agents; Atovaquone; Babesia; Humans; Naphthoquinones; Plasmodium; Pneumocystis; Pneumonia, Pneumocystis; Protozoan Infections; Randomized Controlled Trials as Topic; Toxoplasma
PubMed: 11959541
DOI: 10.1128/AAC.46.5.1163-1173.2002 -
Molecules (Basel, Switzerland) Jun 2016Adverse effects and drug resistance to the current onchopharmacologicals have increased the demand for alternative novel therapeutics. We herein introduce justicidin B,... (Review)
Review
Adverse effects and drug resistance to the current onchopharmacologicals have increased the demand for alternative novel therapeutics. We herein introduce justicidin B, an arylnaphthalen lignan isolated from different plant origins, especially Justicia, Phyllanthus, Haplophyllum and Linum species. This cyclolignan exhibits a wide array of biological properties ranges from piscicidal to antifungal, antiviral and antibacterial activities. Activity against Trypanosoma brucei makes justicidin B a potential antiprotozoal agent for the treatment of neglected tropical diseases. Pharmacological properties like antiplatelet, anti-inflammatory and bone resorption inhibition have been also attributed to justicidin B. This compound is a potent cytotoxic substance on several cell lines, especially chronic myeloid and chronic lymphoid leukemia. Pharmacological values, natural variation, as well as biotechnological production of justicidin B by plant cell, tissue and organ culture are also described in this review. Chemical characteristics and chromatographic methods to identify justicidin B and its biosynthetic pathway have been discussed. Different approaches to the total synthesis of justicidin B are compared. This review would shed light on the role of justicidin B as an intriguing natural compound and provides a chance to optimize conditions for industrial applications.
Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antiprotozoal Agents; Biological Products; Biosynthetic Pathways; Biotechnology; Chemistry; Dioxolanes; Humans; Lignans; Metabolomics; Plant Extracts; Platelet Aggregation Inhibitors; Toxicity Tests
PubMed: 27347906
DOI: 10.3390/molecules21070820 -
Pharmaceutical Development and... Mar 2019Microporous polymeric matrices prepared from poly(ɛ-caprolactone) [PCL] were evaluated for controlled vaginal delivery of the antiprotozoal agent (tinidazole) in the...
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.
Topics: Administration, Intravaginal; Antitrichomonal Agents; Chemistry, Pharmaceutical; Crystallization; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Female; Humans; Parasitic Sensitivity Tests; Polymers; Porosity; Sexually Transmitted Diseases; Tinidazole; Trichomonas Infections; Vagina
PubMed: 29799300
DOI: 10.1080/10837450.2018.1481430 -
Archiv Der Pharmazie Mar 2023Herein we report the synthesis of 21 novel small molecules inspired by metronidazole and Schiff base compounds. The compounds were evaluated against Trichomonas...
Herein we report the synthesis of 21 novel small molecules inspired by metronidazole and Schiff base compounds. The compounds were evaluated against Trichomonas vaginalis and cross-screened against other pathogenic protozoans of clinical relevance. Most of these compounds were potent against T. vaginalis, exhibiting IC values < 5 µM. Compound 20, the most active compound against T. vaginalis, exhibited an IC value of 3.4 µM. A few compounds also exhibited activity against Plasmodium falciparum and Trypanosomal brucei brucei, with compound 6 exhibiting an IC value of 0.7 µM against P. falciparum and compound 22 exhibiting an IC value of 1.4 µM against T.b. brucei. Compound 22 is a broad-spectrum antiprotozoal agent, showing activities against all three pathogenic protozoans under investigation.
Topics: Humans; Metronidazole; Schiff Bases; Structure-Activity Relationship; Antiprotozoal Agents; Trichomonas vaginalis; Malaria, Falciparum
PubMed: 36446720
DOI: 10.1002/ardp.202200409 -
International Journal of Pharmaceutical... 2015Metronidazole is an antiprotozoal agent used in the treatment of bacterial and protozoal anaerobic infections. The objectives of this study were to develop concentrated...
Metronidazole is an antiprotozoal agent used in the treatment of bacterial and protozoal anaerobic infections. The objectives of this study were to develop concentrated metronidazole suspensions that are inexpensive and easy to prepare and determine the stability of these suspensions after storage in amber polyvinyl chloride bottles at room temperature (23°C) and under refrigeration (5°C). Metronidazole suspensions (50 mg/mL) were prepared from powder using Ora-Blend or simple syrup as the vehicles. Samples were collected in triplicate from each container on days 0, 7, 14, 28, 56, and 93. Samples were assayed using a high-performance liquid chromatography method that had been validated as stability indicating. Color, change in physical appearance, and pH were also monitored at each time interval. There was no apparent change in color or physical appearance. The pH values changed by less than 0.20 units over the 93 days. The stability of metronidazole suspensions compounded from United States Pharmacopeia powder using Ora-Blend or simple syrup and packaged in amber polyvinyl chloride bottles was determined to be 93 days when stored at either room temperature or under refrigeration.
Topics: Antiprotozoal Agents; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Color; Drug Compounding; Drug Packaging; Drug Stability; Drug Storage; Excipients; Hydrogen-Ion Concentration; Metronidazole; Pharmaceutical Solutions; Polyvinyl Chloride; Technology, Pharmaceutical; Temperature; Time Factors
PubMed: 26714365
DOI: No ID Found -
Current Opinion in Infectious Diseases Dec 2006This review focuses on recent developments on evaluation of 8-aminoquinoline analogs with broader efficacy and reduced toxicity, which would provide better drugs for... (Review)
Review
PURPOSE OF REVIEW
This review focuses on recent developments on evaluation of 8-aminoquinoline analogs with broader efficacy and reduced toxicity, which would provide better drugs for treatment of protozoal infections.
RECENT FINDINGS
The earlier efforts towards development of 8-aminoquinoline analogs have been directed to extensive derivatization programs. This has led to discovery of tafenoquine for prophylaxis against malaria infections and sitamaquine with utility for treatment of visceral leishmaniasis. Bulaquine, a primaquine pro-drug, has shown reduced methemoglobin toxicity and better malaria-transmission-blocking activity than primaquine. Stereoselective pharmacologic and toxicologic characteristics of chiral 8-aminoquinolines provided the lead for enantiomeric separation of an 8-aminoquinoline analog NPC1161B, with greatly reduced toxicity and potent antimalarial action against blood as well as tissue stages of the parasite. NPC1161B has also shown promising use as an antileishmanial agent. Better understanding of the mechanisms of toxicity and efficacy may help in development of 8-aminoquinoline analogs with superior therapeutic actions, reduced toxicity and broader utility.
SUMMARY
Extensive derivatization approaches followed by better understanding of structure-activity relationships and biotransformation mechanisms of toxicity have provided 8-aminoquinoline analogs with better pharmacologic and reduced toxicologic profiles. The novel 8-aminoquinoline analogs may have broader utility in public health as future antiprotozoals.
Topics: Aminoquinolines; Animals; Antiprotozoal Agents; Humans; Leishmania; Protozoan Infections; Trypanosoma
PubMed: 17075340
DOI: 10.1097/QCO.0b013e328010b848 -
Proceedings of the National Academy of... Nov 1996A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum...
A novel fungal metabolite, apicidin [cyclo(N-O-methyl-L-tryptophanyl-L -isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)], that exhibits potent, broad spectrum antiprotozoal activity in vitro against Apicomplexan parasites has been identified. It is also orally and parenterally active in vivo against Plasmodium berghei malaria in mice. Many Apicomplexan parasites cause serious, life-threatening human and animal diseases, such as malaria, cryptosporidiosis, toxoplasmosis, and coccidiosis, and new therapeutic agents are urgently needed. Apicidin's antiparasitic activity appears to be due to low nanomolar inhibition of Apicomplexan histone deacetylase (HDA), which induces hyperacetylation of histones in treated parasites. The acetylation-deacetylation of histones is a thought to play a central role in transcriptional control in eukaryotic cells. Other known HDA inhibitors were also evaluated and found to possess antiparasitic activity, suggesting that HDA is an attractive target for the development of novel antiparasitic agents.
Topics: Animals; Antiprotozoal Agents; Eimeria tenella; Enzyme Inhibitors; Eukaryota; Female; Histone Deacetylase Inhibitors; Humans; Kinetics; Malaria; Mice; Mice, Inbred BALB C; Neospora; Peptides, Cyclic; Plasmodium berghei; Plasmodium falciparum; Protein Binding; Protozoan Infections; Structure-Activity Relationship; Toxoplasma
PubMed: 8917558
DOI: 10.1073/pnas.93.23.13143 -
Angewandte Chemie (International Ed. in... Jul 2021Leucinostatin A is one of the most potent antiprotozoal compounds ever described, but little was known on structure-activity relationships (SAR). We used Trypanosoma...
Leucinostatin A is one of the most potent antiprotozoal compounds ever described, but little was known on structure-activity relationships (SAR). We used Trypanosoma brucei as a protozoal model organism to test synthetically modified derivatives, resulting in simplified but equally active compounds 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in-depth SAR understanding. The antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity, leaking, and dynamics were studied. The mode of action is discussed based on a structure-activity analysis of derivatives in efficacy, ultrastructural studies in T. brucei, and artificial membrane models, mimicking membrane stability and membrane potential. The main site of antiprotozoal action of natural and synthetic leucinostatins lies in the destabilization of the inner mitochondrial membrane, as demonstrated by ultrastructural analysis, electron microscopy and mitochondrial staining. Long-time sublethal exposure of T. brucei (200 passages) and siRNA screening of 12'000 mutants showed no signs of resistance development to the synthetic derivatives.
Topics: Antimicrobial Cationic Peptides; Antiprotozoal Agents; Molecular Conformation; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanosoma brucei brucei
PubMed: 33730410
DOI: 10.1002/anie.202102153 -
Computational Biology and Chemistry Oct 20201-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole (1EMI) CHNOS also known as Tinidazole, selected for its antiprotozoal property is extensively used for spectroscopic...
Spectroscopic elucidation (FT-IR, FT-Raman and UV-visible) with NBO, NLO, ELF, LOL, drug likeness and molecular docking analysis on 1-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole: An antiprotozoal agent.
1-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole (1EMI) CHNOS also known as Tinidazole, selected for its antiprotozoal property is extensively used for spectroscopic elucidations and computational aspects using density functional methods. Along with spectral conclusions, further investigations on fundamental reactive properties such as electrical, optical, nonlinear combined with DFT simulations were performed. Molecular docking procedure supports the results of chosen appropriate antiprotozoal agent based on ligand-protein interactions. Experimental and simulated (B3LYP/6-311++G (d,p)) IR and Raman spectra showed concurrence. NLO analysis through first order hyperpolarizability parameter helps in finding the potential of 1EMI as a good NLO candidate. Charge delocalization and the stability of the compound were discussed using natural bond orbital (NBO) analysis. Furthermore, Electron localization function (ELF), local orbital locator (LOL), and Frontier molecular orbitals (FMO) were studied. Besides, Mulliken population analysis on atomic charges, Energy gap, chemical potential, global hardness, softness, ionization potential, electronegativity, electrophilicity index along thermodynamic parameters (enthalpy, entropy and heat capacity) have been calculated. Drug likeness parameters and molecular docking approach enabled to check pharmaceutical potential and biological activity of 1EMI. The biological activity of 1EMI through ligand and protein interactions have been confirmed theoretically for the treatment of Malaria, Invasive aspergillosis and Mycobacterium tuberculosis with respect to chosen proteins. Three different activity targets and protein interactions are quite successful revealing the bond distances, intermolecular energy, binding energy and inhibition constant. 2D interaction profile image of the two maximum interacted proteins and also Ramachandran plot used to show stereochemistry of selected protein. The activities of 1EMI were studied in accordance with literature survey and the results were presented.
Topics: Antiprotozoal Agents; Density Functional Theory; Imidazoles; Molecular Docking Simulation; Molecular Structure; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman
PubMed: 32711354
DOI: 10.1016/j.compbiolchem.2020.107330