Degradation kinetics of metronidazole in solution.
ABSTRACT The degradation kinetics of metronidazole in aqueous solutions of pH 3.1 to 9.9 under accelerated storage conditions were studied. The stability of metronidazole in solutions containing propylene glycol or polyethylene glycol 400 was also investigated. The reaction order for metronidazole in these aqueous and solvent systems followed pseudo-first-order degradation kinetics. The degradation rate of metronidazole was invariant under various total buffer concentrations at each specific pH within the investigated pH range. These results indicate that no general acid/base catalysis imposed by acetate, phosphate, and borate buffer species is responsible for the degradation of metronidazole. The catalytic rate constants for hydrogen ion, water, and hydroxyl ion for the degradation of metronidazole were 6.11 x 10(-5) M/s, 3.54 x 10(-8) L/s, and 4.10 x 10(-3) M/s, respectively. The pH-rate profile shows a pH-independent region of pH 3.9-6.6. Maximum stability of metronidazole was at pH 5.6 under zero total buffer species conditions. The ionic strength effect on metronidazole degradation in acetate and phosphate buffers followed the modified Debye-Huckel equation well. The Arrhenius plot showing the temperature dependence of metronidazole degradation indicates estimates of activation energy of 15.35 kcal/mol and a half-life of 963 h at room temperature in 0.1 M pH 3.1 acetate buffer solution (ionic strength = 0.5). Irradiation with UV light (254 nm) of the metronidazole solutions (pH 3.1 acetate buffer) accelerated degradation in comparison with light-protected samples. Incorporation of propylene glycol into the metronidazole solution at pH 3.1 increased stability; however, an adverse effect on the stability of metronidazole was seen when polyethylene glycol 400 solvent system was used.
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ABSTRACT: Giardia lamblia is a pathogenic protozoan presenting as the main characteristic, the trophozoite capacity to adhere in host intestinal epithelium, infecting mammals, including humans. The clinical treatment of this disease is based on metronidazole (Mz) that acts as an alternative electron acceptor, and its reduction promotes DNA impairment. In veterinary treatment, one of the best options is pyrantel pamoate (Pm), which the mode of action has not elucidated yet. Different strategies for Giardia treatment have been explored to avoid side effects to the host. In this context, the efficiency of treatment combining drugs raise as an interesting alternative for protozoan diseases. Here, we evaluated in vitro synergic effect of Mz and Pm on trophozoites and on its adherence to IEC-6 cells. The treatment with Mz or Pm was effective on trophozoites, with IC(50)/24h values of 5.3±0.9 μM and 13.8±1.4 μM, respectively. The treatment of trophozoites with different combinations of Mz and Pm were also evaluated, as showed by fractional inhibitory concentration index (FICI) under 0.5 in all conditions tested, corresponding to the synergic effect. This synergic activity was also observed when the combinations of 5.3 μM Mz+0.4 μM Pm and 13.8 μM Pm+0.1 μM Mz induced a remarkable reduction in % adhesion (85-90% and 52-59%, respectively) and in number of adhered parasites per 100 cells. The low cytotoxicity to the host cells of the combinations, associated to the strong synergic potential of the combination, encourage us to further investigate its effect in in vivo models.Parasitology International 10/2010; 60(1):54-8. · 2.30 Impact Factor
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ABSTRACT: Proton pump inhibitor-amoxicillin-metronidazole is recommended as second-line Helicobacter pylori therapy in Japan. The authors assessed the efficacy and safety of second-line eradication using the H2-receptor antagonist famotidine as a substitute for proton pump inhibitor. Sixty-one patients who failed in first-line H. pylori eradication using proton pump inhibitor-clarithromycin-amoxicillin were randomly assigned to either second-line therapy including metronidazole: a 7-day course of lansoprazole 30 mg, amoxicillin 750 mg, and metronidazole 250 mg, b.i.d. (lansoprazole group); or a 7-day course of famotidine 40 mg, amoxicillin 750 mg, and metronidazole 250 mg, b.i.d. (famotidine group). Eradication was assessed for each group at least 4 weeks after completing eradication therapy. Drug susceptibility test was performed using 57 strains in pretreatment to clarithromycin, metronidazole, and amoxicillin. Prior to second-line H. pylori eradication, the rate of resistance to clarithromycin was high at 84% (48/57). Similarly, resistance to metronidazole was low at 5.3% (3/57); however, no amoxicillin-resistant strains were found. The eradication rates for both lansoprazole and famotidine treatment groups were high at 97% (29/30) and 94% (29/31), respectively. Famotidine treatment including metronidazole-amoxicillin as second-line therapy provided a high eradication rate similar to lansoprazole therapy. Famotidine is therefore expected to serve as a useful H. pylori eradication regimen in patients with proton pump inhibitor allergy, an economic benefit in terms of reduced health-care costs is also anticipated.Helicobacter 11/2006; 11(5):436-40. · 3.51 Impact Factor
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ABSTRACT: Penethamate (PNT) is a diethylaminoethyl ester prodrug of benzylpenicillin used to treat bovine mastitis via the intramuscular route. Because of its instability, PNT products must be reconstituted before administration and the reconstituted injection has a short shelf life (7 days at 2-8°C). The purpose of this paper was to investigate whether the stability of PNT can be improved in order to achieve a chemically stable ready-to-use aqueous-based PNT formulation or at least to extend the shelf life of the reconstituted suspension. A chemical stability study of PNT in aqueous-based solutions as a function of pH, buffer strength, solvent mixtures and temperature, supported by studies of its solubility in mixed solvents, allowed predictions of the shelf life of PNT solution and suspension formulations. PNT degraded in aqueous solutions by several pathways over the pH range 2.0-9.3 with a V-shaped pH-rate profile and a minimum pH of around 4.5. The stability of PNT solutions in mixed solvents was greater than in aqueous solutions. For example, in propylene glycol:citrate buffer (60:40, v/v, pH 4.5), the half-life of PNT was 4.3 days compared with 1.8 days in aqueous buffer. However, solubility of PNT in the mixed solvent was higher than that in aqueous solution and this had an adverse effect on the stability of suspensions. By judicious choosing of pH and mixed solvent, it is possible to achieve a storage life of a PNT suspension of 5.5 months at 5°C, not sufficient for a ready-to-use product but a dramatic improvement in the storage life of the reconstituted product.Drug Development and Industrial Pharmacy 06/2011; 38(1):55-63. · 1.54 Impact Factor