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Propolis is an attractive natural ingredient to design health products due to its pharmacological effects. Our chemical investigation of a polar extract of Nigerian propolis (NP) led the isolation and identification of five isoflavonoids ( 1-4 , 6 ), one diarylpropane ( 5 ) and one prenylated flavanone ( 7 ) by the combination of chromatographic and spectroscopic techniques. Compounds 1 , 4 and 7 were found to be the main markers in NP (8.0, 5.0 and 4.0 mg/g of dry extract, respectively). Moreover, NP and its phenolic constituents exhibited in vitro free radical scavenging activity together with a promising antidiabetic effect against α-amylase and α-glucosidase enzymes. Finally, NP showed also a moderate inhibition of Helicobacter pylori growth. These results suggested that NP could be a good candidate in nutraceuticals and food products.

Ethnopharmacological Relevance: Coccinia barteri (Hook. F.) is traditional used in Southeast of Nigeria in management of fever. This study aimed to evaluate the antimalarial activities of hydro-methanol crude extract and solvent fractions of Coccinia barteri leaf., Materials and Methods: Two animal models employed for the study were, 4-day suppressive and curative assays against chloroquine sensitive Plasmodium berghei NK65. Level of parasitaemia, mean survival time (MST), anal temperature and weight loss were measured to assess antimalarial efficacy of the extract/fractions. Chloroquine (10 mg kg -1 ) was used as positive control. Chemo-profile of extract was evaluated using GC-MS, HPLC techniques and standard phytochemical analysis. Preliminary toxicity test was done using modified Lorke's method., Results: The crude extract (100-400 mg kg- 1 ) and solvent fractions (20-80 mg kg- 1 ) demonstrated antimalarial activity in both models compared to controls. Semi purified fractions of the extract produced stronger percentage chemosuppression and inhibition of parasite. The % inhibition of the fractions, hexane, chloroform, ethyl acetate and aqueous at 80 mg kg -1 were 96.0 0, 95.29, 89.86 and 96.00% respectively on day 8 (D 8 ). While on D 14 , 100% parasite clearance, indicating cure was obtained for hexane, chloroform and aqueous fraction treatment groups, no death occurred in these groups. Ethyl acetate fraction treated groups lived longer but were not fully protected. Some marker compounds were identified., Conclusions: These results support the use of C. barteri as malaria remedy and potential source of antimalarial templates. Long acting parasitaemia reduction effect indicates its possible combination potential in poly-herbal combination therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Malaria is a leading cause of death in Nigeria., Aim: Antimalarial activity of Stemonocoleus micranthus stem bark was evaluated in mice with an objective to finding scientific evidence for its use as antimalarial remedy in South-east Nigeria., Methods: Antiplasmodial activities of hydro-methanolic extract and solvent fractions (hexane, chloroform, ethyl acetate and aqueous) of S. micranthus stem bark against chloroquine-sensitive Plasmodium berghei infected mice were determined using suppressive and curative procedures. Chloroquine was used as positive control. In vitro models, DPPH (1, 1-diphenyl-2- picrylhydrazyl) radical scavenging, FRAP (ferric reducing antioxidant power) and TPC (total phenolic content) were used to assay antioxidant activity of the test samples. Phytoconstituents of the active fractions were analysed by GC-MS., Results: Chemosuppressive effect exerted by extract (50, 100, 200, 400 mg kg -1 ) and fractions (20, 40, 80 mg kg -1 ) ranged between 54.14 - 67.73% and 59.41-94.51% respectively. Curative effects was also dose dependent. In both models, ethyl acetate was the active fraction. At low doses the animals lived longer but not protected (D 0 - D 29 ). At high doses, extract (400 mg kg -1 ), active fractions (80 mg kg -1 ) and chloroquine (5 mg kg -1 ) the animals were fully protected.The extract and fractions exhibited antioxidant potentials which could have contributed individually or synergistically to antimalarial activities reported in this study. Oral LD 50 was estimated to be greater than 4000 mg kg -1 , in mice., Conclusion: The results of this study may have provided support on traditional therapeutic use of the plant in treatment of malaria., (© 2019 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Background: Petersianthus macrocarpus (Lecythidaceae) is widely used in the folk medicine in Nigeria to relieve pain and fever associated with malaria. This study evaluated the analgesic and antioxidant activities of the methanol extract and fractions of the stem bark of the plant., Materials and Methods: The analgesic activity was determined in mice using hotplate and acetic acid-induced writhing models. Morphine sulphate (5 mg/kg, i.p.) and aspirin (100 mg/ml, p.o.) were used as reference analgesic agents. The antioxidant potential was evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical; reducing power, iron chelating properties and determination of total phenolic content., Results: The extract at 200 and 500 mg/kg, produced an insignificant (P > 0.05) increase in pain threshold in hotplate but a significant (P < 0.05) increase at 1000 mg/kg. The extract significantly (P < 0.05) reduced the writhing induced by acetic acid in mice in a dose dependent manner. Fractionation increased the analgesic activities significantly (P < 0.05) in ethyl acetate and aqueous fractions (200 mg/kg). The extract demonstrated strong DPPH radical scavenging activity with IC50 0.05 mg/ml, good reducing power and weak iron chelating activities. The total phenol content was 142.32 mg/gin term of gallic acid. The antioxidant effects were more pronounced in ethyl acetate and aqueous fractions., Conclusion: The findings of the study suggested that the extract has strong analgesic and antioxidant activities which reside mainly in the polar fractions thus confirming the traditional use of the plant to alleviate pains., Summary: Analgesic and antioxidant activities of extract and solvent fractions of Petersianthus macrocarpus investigated indicated that extract has analgesic and antioxidant properties that reside mainly in the polar fractions. Abbreviations Used: DMSO: Dimethyl sulphoxide,, Anova: analysis of variance, EDTA: ethylene diamne tetraacetic acid, SDM: standard deviation of mean, PGE: prostaglandins E, PDF: prostaglandins F.

Four new prenylated anthranols, harunganols C-F (1-4), along with kenganthranol A (5), harunganin (6), and ferruginin A (7), were identified from the leaves of Harungana madagascariensis. The structures of compounds 2, 5, and 7 were confirmed by single-crystal X-ray diffraction analysis. Compound 1 is a unique symmetrical anthranol dimer connected via a CH2 group. Compound 4 possesses a unique C-10 hemiketal group. All anthranols were evaluated for their α-glucosidase inhibitory activities. They displayed a higher potency compared to acarbose except for 3 and 4. In particular, harunganol C (1) showed an IC50 value of 1.2 μM.

Background: The manufacture of paint involves a variety of processes that present with medical hazards. Safety initiatives are hence introduced to limit hazard exposures and promote workplace safety. This aim of this study is to assess the use of available control measures/initiatives in selected paint factories in Lagos West Senatorial District, Nigeria., Methods: A total of 400 randomly selected paint factory workers were involved in the study. A well-structured World Health Organization standard questionnaire was designed and distributed to the workers to elicit information on awareness to occupational hazards, use of personal protective devices, and commonly experienced adverse symptoms. Urine samples were obtained from 50 workers randomly selected from these 400 participants, and the concentrations of the heavy metals (lead, cadmium, arsenic, and chromium) were determined using atomic absorption spectroscopy., Results: The results show that 72.5% of the respondents are aware of the hazards associated with their jobs; 30% have had formal training on hazards and safety measures; 40% do not use personal protective devices, and 90% of the respondents reported symptoms relating to hazard exposure. There was a statistically significant (p < 0.05) increase in the mean heavy metal concentrations in the urine samples obtained from paint factory workers as compared with nonfactory workers., Conclusion: The need to develop effective frameworks that will initiate the integration and ensure implementation of safety regulations in paint factories is evident. Where these exist, there is a need to promote adherence to these practice guidelines.

From the ethanol extract of the stem of Lecaniodiscus cupanioides Planch, two known compounds 1 and 2 were isolated and identified as triterpenoid saponins 3-O-[α-L-arabinofuranosyl- (1→3)-α-L-rhamnopyranosyl- (1→2)-α-L-arabinopyranosyl-]-hederagenin and 3-O- [α-L-arabinopyranosyl- (1→3)-α-L-rhamnopyranosyl (1→2)-α-L-arabinopyranosyl-]-hederagenin. The structures were established by physicochemical and spectroscopic investigations (MS and NMR) as well as comparison of literature data. The compound 1 exhibited anticancer activity against human colon carcinoma H-116, human lung carcinoma A-549 and human lung carcinoma HT-29 cell lines with IC 50 5.0, 2.5 and 2.5μg/ml respectively and compound 2 exhibited similar activities with IC 50 5.0, 5.0 and 2.5μg/ml respectively. This suggests that the isolated triterpenoid saponins may be considered as potential anticancer leads for further studies.

During immunoglobulin (Ig) diversification, activation-induced deaminase (AID) initiates somatic hypermutation and class switch recombination by catalysing the conversion of cytosine to uracil. The synergy between AID and DNA repair pathways is fundamental for the introduction of mutations, however the molecular and biochemical mechanisms underlying this process are not fully elucidated. We describe a novel method to efficiently decipher the composition and activity of DNA repair pathways that are activated by AID-induced lesions. The in vitro resolution (IVR) assay combines AID based deamination and DNA repair activities from a cellular milieu in a single assay, thus avoiding synthetically created DNA-lesions or genetic-based readouts. Recombinant GAL4-AID fusion protein is targeted to a plasmid containing GAL4 binding sites, allowing for controlled cytosine deamination within a substrate plasmid. Subsequently, the Xenopus laevis egg extract provides a source of DNA repair proteins and functional repair pathways. Our results demonstrated that DNA repair pathways which are in vitro activated by AID-induced lesions are reminiscent of those found during AID-induced in vivo Ig diversification. The comparative ease of manipulation of this in vitro systems provides a new approach to dissect the complex DNA repair pathways acting on defined physiologically lesions, can be adapted to use with other DNA damaging proteins (e.g. APOBECs), and provide a means to develop and characterise pharmacological agents to inhibit these potentially oncogenic processes.

Ethno-Pharmacological Relevance: Soil pollution due to increasing industrialization is a reality that is taking its toll on mankind today. Considering the population of people that use herbal remedies especially in developing countries and the discharge of industrial waste on surrounding herbal vegetation, it is imperative to determine the heavy metals contamination in some commonly used medicinal plants., Materials and Methods: Representative samples of five medicinal plants Ageratum conyzoides, Aspilia africana, Alchornea cordifolia, Amaranthus brasiliensis and Chromolaena odorata were collected from Ikpoba-Okha L.G.A, Edo State Nigeria, around a paint company and another set of same plants were collected from a non-polluted source. Dried leaves and roots of collected plants were digested and analyzed using Atomic Absorption Spectrophotometer (AAS) for the presence of Lead (Pb), Cadmium (Cd), Chromium (Cr), Nickel (Ni) and Zinc (Zn). Soil samples from polluted and non-polluted areas were also analyzed to ascertain the levels of these heavy metals in the environment., Results: Results show that the concentrations of these heavy metals in the leaves and roots of plants collected from polluted soil were significantly higher than those obtained from unpolluted soil. Correspondingly heavy metal concentrations were significantly higher in polluted than in unpolluted soil samples., Conclusion: As part of continuing effort in the standardization of traditional remedies, environmental contamination control and abatement is evident. The source of medicinal plants/herbs should also be a cause for concern since the toxicity of medicinal plants is sometimes associated with environmental sources of the plants., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Adverse effects attributed to exposure to paints are currently a concern because of the continued widespread use of paint containing trace elements. Thus, occupational survey amongst painters in Lagos and determination of trace elements and oxidative stress parameters were carried out. Descriptive cross-sectional survey was done using a standardized questionnaire to obtain job safety-related information. Forty-eight percent of the painters were aware of hazards associated with painting and 52 % of these workers were aware of the necessary precautionary measures during painting. There were no significant differences (p ≥ 0.05) between the levels of trace elements in the blood of painters and the control subjects. However, there was a significance increase (p ≤ 0.0001) in the level of malondialdehyde and a decrease (p ≤ 0.001) in the levels of reduced glutathione, superoxide dismutase, and catalase of the painters compared to the control. An increase in oxidative stress parameters may not only be due to trace element concentrations, but also the painters' exposure to some petrochemical solvents during mixing of paints.

Background: Pesticides are used widely in agriculture to control destructive pests and hence increase food supply. Their use inadvertently leads to residues in food crops and the environment. Pesticides, by nature are poisonous and exposure of humans to their residues may cause health hazards which include neurotoxicity and carcinogenicity among others. Evaluation of pesticide residues in food is therefore of public health importance and would help to ensure that levels are kept within safety limits., Objective: The aim of this study was to determine the incidence and quantity of organochlorine pesticide residues in maize samples collected from various markets in Lagos State and compare values obtained with established safety values in order to highlight possible health hazards., Methods: In this study, samples of white maize (Zea mays L.) purchased from different markets in Lagos State were analyzed for residues of organochlorine pesticides using gas chromatograph with mass spectrometric detector (GC-MS) after careful extraction and cleanup., Results: The results showed that 96% of the maize samples contained residues of one or more organochlorine pesticides. Mean concentrations ranged from 7.9-52.0 microg/kg and maximum residue limits (MRLs) of some pesticides were exceeded in up to 7% of samples. The estimated total diet intakes (ETDIs) for aldrin and dieldrin exceeded their maximum permissible intakes., Conclusion: It is concluded that residues of organochlorine pesticides are present in maize in Lagos markets. Some exceed safety levels with possible adverse effects on human health. There is therefore a need for more stringent monitoring of the use of pesticides in agriculture and food storage in Nigeria.

Ficus congensis (Moraceae) is used traditionally in the treatment of various diseases including infectious diseases, infertility, and gastrointestinal disorders. Investigation of hexane extract of the stem bark using chromatographic techniques led to isolation of a xanthone, 1-hydroxy-3,7,8-trimethoxyxanthone (Decussatin). The compound was elucidated based on spectroscopic methods such as nuclear magnetic resonance (NMR), UV, IR, and mass spectrometry (MS). Decussatin and the hexane extract were screened in vitro for antibacterial and antifungal activities using broth microdilution (MHB) and disc Agar diffusion (DAD) techniques against Escheichia coli, Bacilus substilis, Klebsiela pneumonia, Staphylococcus aureus, Aspergillus fumigatus, Trichophyton mentagrophytes, Trichophyton rubrum and Candida albicans. Hexane extracts showed potent antibacterial activity against E. coli and B. subtilis with minimum inhibitory concentrations (MIC) of 8 mg/mL and 5 mg/mL, respectively, while Decussatin of the highest concentration (8 mg/mL) used in this study showed no appreciable antimicrobial activity. Only hexane extract was active against C. albicans with a MIC of 1 mg/mL.

Background: Quinolones have a broad spectrum of activity against bacteria and are a class of synthetic antimicrobial modeled after nalidixic acid., Objective: To determine the dissolution efficiencies of ciprofloxacin and sparfloxacin in 0.1NHCL, deionized water, 0.1 M acetic acid and pH 7.4 phosphate buffer., Methods: The in-vitro dissolution profiles of ciprofloxacin (250 mg and 500 mg) and sparfloxacin (200 mg) tablets were studied in the respective media using US Pharmacopoeia (USP) Apparatus II. In order to monitor the comparative rate of dissolution, samples were withdrawn from the medium for quantification over nine pre-determined time points during a total period of two hours. Samples were analyzed by an HPLC method capable of concurrent elution of ciprofloxacin/sparfloxacin., Results: The medium with most stable release pattern for the representative quinolones was 0.1M acetic acid, followed by 0.1NHCl, distilled water and pH 7.4 buffer respectively. The %Q30 of Ciprofloxacin(CP) and Sparfloxacin(SP) was found to conform entirely to both USP2004 and FDA specifications. Sparfloxacin was found to be unstable due to cloudiness observed in 0.1N HCl medium. The CP and SP showed highest %Q(max) in 0.1M acetic acid compared to other media. This result has implication in the choice of medium for dissolution testing of quinolones, particularly for comparative purposes in the absence of specific monograph recommendations. Furthermore, it supports the change from 0.1N to 0.01NHCI for ciprofloxacin in the USP as a monographic modification., Conclusion: We conclude that there is a need to have a general-purpose dissolution medium for comparing profiles of different quinolones, 0.1M acetic acid may be a suitable candidate. Furthermore, the study may serve as guidance to the drug regulatory authorities in formulation of monographs for the drugs.

This study evaluated the antioxidant activity as well as bioflavonoid content of the methanol and ethanol-water extracts of the fresh and dried leaves of Tetracarpidium conophorum. Antioxidant activity was determined by spectrophotometric methods using DPPH free radical, nitric oxide radical inhibition and ferric reducing antioxidant power assays. In addition, total phenolics, flavonoids and proanthocyanidin content were also determined. The ethanol: water extract of the dried leaves had the highest antioxidant activity with a 50% inhibition of DPPH at a concentration of 0.017 mg/mL compared to the standards, Vitamin C and Vitamin E with inhibition of 0.019 and 0.011 mg/mL, respectively. This extract also showed nitric oxide radical inhibition activity comparable to that of rutin, 54.45% and 55.03% for extract and rutin, respectively, at 0.1 mg/mL. Ferric reducing power was also comparable to that of ascorbic acid (281 and 287 μM Fe (11)/g, resp.) at a concentration of 1 mg/mL. The methanol extract of both the dried and the fresh leaves had higher phenolic, flavonoids and proanthocyanidin content than the ethanol:water extract. The study reveals that T. conophorum can be an interesting source of antioxidants with their potential use in different fields namely food, cosmetics and pharmaceuticals.

A methanol extract of dried leaves of Melanthera scandens was examined for antioxidant activities using a variety of assays, including 1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, reducing power, ferrous chelating, and ferric thiocyanate methods with ascorbic acid and EDTA as positive controls. The extract showed noticeable activities in most of these in vitro tests. The amount of phenolic compounds in the extract expressed in gallic acid equivalent was found to be 52.8 mg/g. The extract demonstrated inhibition of linoleic acid lipid peroxidation, active reducing power, and DPPH radical scavenging activities which were less than that of the positive controls. The extract also showed weaker iron chelating effect when compared with the EDTA positive control. The present results showed that M. scandens leaf extract possessed antioxidant properties and this plant is a potential useful source of natural antioxidants., (Copyright © 2010 Korean Pharmacopuncture Institute. Published by .. All rights reserved.)

The World Health Organization (WHO) has shown concern about the burden of tuberculosis in the developing countries. Even though rifampicin is an effective drug in the management of tuberculosis, it has been documented to have some toxic effects in humans. Therefore, this study intends to investigate the modulatory effect of vitamins C and E on the hepatotoxicity, sperm quality and brain toxicity of Rifampicin. Forty Wistar albino rats were used, 10 animals per group. Group 1 animals received 0.3 mL of distilled water, the Group 2 animals received the therapeutic dose of rifampicin, Group 3 animals received therapeutic doses of rifampicin plus vitamin E, while Group 4 received therapeutic doses of rifampicin and vitamin C. The administration was performed orally during three months; the animals were sacrificed by cervical dislocation at the end of that period. Blood samples were collected and liver function and lipid profile was analyzed using fully automated clinical chemistry device. The liver, brain and reproductive organs underwent histopathological examination. Sperm samples were collected from the epididymis to achieve count and motility and morphological analysis. Results showed rifampicin alone to raise (p < 0.05) liver function enzymes (Aspartate amino transferase [AST], Serum alanine amino transferase [ALT] and Total Bilirubin) when compared with controls. While the vitamin E treated group showed remarkable protection, the vitamin C treated group showed questionable protection against the rifampicin induced liver damage. Sperm count results showed an important (p < 0.05) increase in the sperm quality in vitamin E and C treated groups. However, the vitamin E plus Rifampicin treated group showed increased lipid peroxidation. The histopathological findings revealed structural damages by rifampicin in liver, brain and epididymis while some remarkable architectural integrity was observed in the antioxidant-treated groups. It can be concluded that vitamin E or C improved sperm quality and protected against the brain damage caused by rifampicin. Moreover, vitamin E demonstrated remarkable hepatoprotection against rifampicin induced damage while vitamin C shows a questionable hepatoprotection.

The uses of medicinal plants have always been part of human culture. The World Health Organization estimates that up to 80% of the world's population relies on traditional medicinal system for some aspect of primary health care. However, there are few reports on the toxicological properties of most medicinal plants especially, their mutagenicity and carcinogenicity. Therefore, this research is to determine the mutagenic potentials of Morinda lucida [Oruwo (Root)], Azadirachta indica [Dongoyaro (Leaf)], Terapluera tetraptera [Aridan (Fruit)], Plumbago zeylanica [Inabiri (Root)], Xylopia aethiopica [Erunje (Fruit)], Newbouldia laevis [Akoko (Leaf)], Alstonia boonei [Ahun (Bark)], Enantia chlorantha [Awopa (Bark)], and Rauvolfia vomitoria [Asofeyeje (Root)] using the Allium cepa Linn. model and the modified Ames assay. Allium cepa model was used to determine the mean root length, mitotic index and chromosomal aberrations effects of these plants on onion bulbs using 0.1, 1, 5 and 10mg/ml concentration of the plant extracts. The modified Ames test which is a modification of the standard Ames test as described by Ames et al. [Ames, B.N., McCann, J., Yamasaki, E., 1975. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian microsome mutagenicity test. Mutation Research 31, 347-364] was done using Escherichia coli (0157:H7) that has the phenotypic characteristics of glucose and lactose fermentation, motile, urease negative, indole positive and citrate negative. The results obtained from Allium cepa assay showed increasing root growth inhibition with increased concentration, decreasing mitotic index with increased concentration and chromosomal aberrations. The modified Ames test showed an alteration in the biochemical characteristics of Escherichia coli (0157:H7) for all plants except Rauvolfia vomitoria and Plumbago zeylanica. Three of the medicinal plants altered at least three of the normal biochemical characteristics thus demonstrating mutagenic potentials. The results of internationally accepted Allium cepa were comparable with the modified Ames test. However, a long term in vivo and dose dependent study should be carried out to validate these results and the findings should be communicated to drug and food regulatory body and also to the general public.

It is well established that hormones can cause cancer, much less known is how they induce this change in our somatic cells. This review highlights the recent finding that estrogen can exert its DNA-damaging potential by directly activating DNA deaminases. This recently discovered class of proteins deaminate cytosine to uracil in DNA, and are essential enzymes in the immune system. The enhanced production of a given DNA deaminase, induced by estrogen, can lead not only to a more active immune response, but also to an increase in mutations and oncogenic translocations. Identifying the direct molecular link between estrogen and a mutation event provides us with new targets for studying and possibly inhibiting the pathological side-effects of estrogen.

The antioxidant activities of crude extract of Phaulopsis fascisepala leaf were evaluated and compared with alpha-tocopherol and BHT as synthetic antioxidants and ascorbic acid as natural-based antioxidant. In vitro, we studied its antioxidative activities, radical-scavenging effects, Fe(2+)-chelating ability and reducing power. The total phenolic content was determined and expressed in gallic acid equivalent. The extract showed variable activities in all of these in vitro tests. The antioxidant effect of P. fascisepala was strongly dose dependent, increased with increasing leaf extract dose and then leveled off with further increase in extract dose. Compared to other antioxidants used in the study, alpha-Tocopherol, ascorbic acid and BHT, P. fascisepala leaf extract showed less scavenging effect on alpha,alpha,-diphenyl-beta-picrylhydrazyl (DPPH) radical and less reducing power on Fe(3+)/ferricyanide complex but better Fe(2+)-chelating ability. These results revealed the in vitro antioxidant activity of P. fascisepala. Further investigations are necessary to verify these activities in vivo.

Purpose: Co-administration of quinolone antibiotics with cation-containing medicaments such as, antacids has been reported to influence the overall bioavailability leading to subtherapeutic plasma concentrations of these antibiotics in humans., Objectives of the Study: The present work was designed to evaluate the binding constant, binding molar ratio, influence of temperature on the binding constant of ciprofloxacin-Mg2+ and to determine the antimicrobial activity of ciprofloxacin and ciprofloxacin-Mg2+., Methods: Job's method of continuous variation and Bonesi-Hildebrand equation were adopted to determine the molar ratio and stability constant respectively. The antibacterial activity was determined by the Agar diffusion method., Results: A complexation molar ratio of 1:1 was obtained for ciprofloxacin-Mg2+ complex. The stability constants were 3.59 and 3.50 at 25 degrees C and 60 degrees C respectively. There was a significant difference between the zones of inhibition of ciprofloxacin-Mg2+ complex and that of ciprofloxacin alone against E. coli, P. aeruginosa, and S. aureus (p < 0.05). This difference showed that the complex formed was not as active as ciprofloxacin., Conclusion: The present studies have shown that ciprofloxacin readily complex with Mg2+ and that the stability constant was temperature dependent. The antibacterial activity of ciprofloxacin was markedly reduced in the presence of Mg2+. Concomitant administration of ciprofloxacin with Mg2. containing medicaments should be avoided to prevent resistance.

Background: The use of substandard drugs is a great threat to the lives of people in the community. Identification of substandard drugs is important to exclude their use in clinical practice. These drugs may lead to reduced efficacy of pharmacotherapy. Antacid preparations are weakly basic and consist of metal salts, most commonly aluminium hydroxide or magnesium hydroxide. These salts dissociate to neutralise gastric acid and form neutral salts. The ultimate goal of antacid therapy is to reduce the concentration and the total load of acid in gastric juice with a pH of 1.3 to a pH between 3.5 and 5.0., Objective: The aim of this work is to carry out an in-vitro test on the acid neutralising capacity (ANC) of commonly available antacid brands in Lagos market., Method: The British pharmacopoeia (BP) method of analysis of antacids was adopted. Twenty different brands of antacid suspensions and tablets were analysed., Result: Brand SH suspension gave the highest neutralising capacity, 101.65 ml +/- 0.15, while brand SN gave the lowest, 99.75 ml +/- 0.75. All the fourteen antacid suspensions analysed complied with the official specification and therefore passed the analysis. Brand TB tablet gave the highest acid neutralising capacity (ANC), 54.10 ml +/- 0.2 while brand TD 49.50 ml +/- 0.1 gave the lowest. All the six antacid tablet brands analysed passed the assay. The ANC of an antacid is a parameter used to measure the effectiveness of an antacid in relieving ulcer pain., Conclusion: The acid-neutralising capacity of the antacid brands analysed were within the BP specification. The acid neutralising capacity of antacids should be determined before administration.

Objective: To study if the present widely used artemisin derived anti-malaria drugs have vascular effects., Methods: Aortic rings were obtained from adult male Sprague-Dawley rats. The rings were mounted in an organ bath and tension recorded using isometric force transducers. After pre-contraction with noradrenaline, cumulative doses of artesunate were added to the bath containing the rings. The effects of nitric oxide inhibition with L-NAME, on the responses to artesunate were also assessed. Lastly the effects on the contractile responses of the rings to noradrenaline (NA) were determined before and after incubation in artesunate., Results: Cumulative addition of artesunate from 6 x 10(-4) to 6 x 10(-1) mg/ml resulted in relaxation of pre-contracted aortic rings. L-NAME significantly reduced the relaxation response to artesunate (P < 0.05). Vascular contraction response to NA was significantly reduced (P < 0.01) following the addition of artesunate., Conclusion: Artesunate causes relaxation of precontracted rat aortic rings which is partly mediated by Nitric Oxide (EDRF). It also reduces the contractile responses of the rings to noradrenaline.

The stem bark extract of S. ellipticum (Hochst) Pax was investigated for its antioxidant properties in this study. The extract was evaluated for antioxidant activity in vitro in terms of its ability to inhibit lipid peroxidation and its free radical scavenging, reducing and metal chelation powers. The total amount of phenolic compounds in the extract was also determined in terms of gallic acid equivalent. The extract produced effective free radical scavenging and reducing activities in a dose dependent fashion. The extract exhibited noticeable inhibition of lipid peroxidation of linoleic acid emulsion. These activities were less than that of ascorbic acid and 2,6-Di-tert-butyl-4-methylphenol used as positive controls. The extract however demonstrated poor iron chelating ability compared to ethylene diamine tetraacetic acid. The total phenolic content of the extract was 50.61 +/- 0.08 mg g(-1) in terms of gallic acid. This study showed that the stem bark extract of S. ellipticum exhibits significant antioxidant activity and is a good source of natural antioxidants.

AID deaminates cytosine in the context of single stranded DNA to generate uracil, essential for effective class-switch recombination, somatic hypermutation and gene conversion at the B cell immunoglobulin locus. As a nuclear DNA mutator, AID activity must be tightly controlled and regulated, but the genetic analysis of AID and other DNA deaminases has left unstudied a number of important biochemical details. We have asked fundamental questions regarding AID's substrate recognition and processing, i.e. whether AID acts distributively or processively. We demonstrate that in vitro, human AID exhibits turnover, a prerequisite for our analysis, and show that it exhibits a distributive mode of action. Using a variety of different assays, we established that human AID is alone unable to act processively on any of a number of DNA substrates, i.e. one AID molecule is unable to carry out multiple, sequential deamination events on the same substrate. This is in contrast to the cytoplasmically expressed anti-viral DNA deaminase APOBEC3G, which acts in a processive manner, possibly suggesting that evolutionary pressure has altered the ability of DNA deaminases to act in a processive or distributive manner, depending on the physiological need.

Objective: To determine the effect of interaction of five Alive fruit juice on the dissolution and absorption profiles of ciprofloxacin tablets using urinary excretion., Methods: In-vitro dissolution of ciprofloxacin 500 mg tablets was studied using US Pharmacopoeia dissolution apparatus II. This was conducted using 0.1N HCl and equal volumes of the fruit juice and 0.1N HCL. Samples were collected at predetermined time intervals for two hours. For the in-vivo study, eleven (5 males and 6 females) healthy volunteers participated in an open, single dose, cross-over randomized trial. After an overnight fasting, each volunteer either ingested a 500 mg ciprofloxacin tablet with 250 ml table water or with the fruit juice. Total urine voided was collected for 72 hrs after each dose of ciprofloxacin. Dissolution and urine samples were assayed using a controlled and validated UV spectrophotometric analysis., Results: A lag time of 5 minutes was observed in dissolution profile of ciprofloxacin in the juice. The percent dissolved of ciprofloxacin in 0.1NHCl and fruit juice were found to be dissimilar (f2 =18.2) using similarity factor. There was statistical difference between the K(el) (elimination constant), K(e) (excretion rate) and X(u) (cumulative amount excreted unchanged) of subjects on water (0.1759 +/- 0.0144; 12.81 +/- 1.36; 375.5 +/- 41.2) and that of fruit juice (0.1250 +/- 0.0161; 7.6 +/- 1.07; 241.6 +/- 34.0). However, there was no difference between the t(1/2) of the subjects (4.2 +/- 0.3; 5.5 +/- 0.8). There was a decrease in relative availability of the drug by 35.75%., Conclusion: We conclude that the absorption of ciprofloxacin can be reduced by concomitant ingestion of the juice containing calcium carbonate and grape. Therefore to avoid drug therapeutic failures and subsequent bacterial resistance as a result of subtherapeutic level of the drug in the systemic circulation, ingestion of the juice with ciprofloxacin should be discouraged.

The DNA deaminase family encompasses enzymes that have been highly conserved throughout vertebrate evolution and which display wide-ranging positive effects upon innate and adaptive immune system and development. Activation-induced cytidine deaminase was identified as a DNA mutator after its necessity in the successful development of high-affinity B cells via somatic hypermutation, class switch recombination, and gene conversion was determined. APOBEC3 exhibits the ability to deaminate retroviral first strand cDNA in a variety of viral infections, including HIV and hepatitis. Recent work has highlighted the potential importance of activation-induced cytidine deaminase (AID) and APOBEC1 in epigenetic reprogramming, and also the role that AID and the APOBECs may have in the development of cancer. In addition to the known activities of these members of the protein family, there are still other deaminases, such as APOBEC2, whose targets and functions are as yet unknown. This chapter provides the details of two assays that have proved to be invaluable in elucidating the exact specificities of deaminases both in vitro and in Escherichia coli. The application of these assays to future studies of the deaminase family will provide an indispensible tool in determining the potentially diverse functions of the remainder of this family of enzymes.

The present study investigated the vasorelaxant action of the aqueous leaves extract of Persea americana on isolated rat aorta. The results showed that the extract produced significant vasorelaxation and that the effect is dependent on the synthesis or release of endothelium-derived relaxing factors (EDRFs) as well as the release of prostanoid. The extract also reduced vasoconstriction probably by inhibiting Ca2+ influx through calcium channels.

Background: IgE antibody-producing B cells are enriched in the nasal mucosa in patients with allergic rhinitis because of local class switching to IgE. The expressed IgE VH genes also undergo somatic hypermutation in situ to generate clonal families. The antigenic driving force behind these events is unknown., Objective: To examine the possible involvement of a superantigen in allergic rhinitis, we compared the variable (VH) gene use and patterns of somatic mutation in the expressed IgE heavy-chain genes in nasal biopsy specimens and blood from allergic patients and the IgA VH use in the same biopsy specimens and also those from nonallergic controls., Methods: We extracted mRNA from the nasal biopsy specimens of 13 patients and 4 nonallergic control subjects and PBMCs from 7 allergic patients. IgE and IgA VH regions were RT-PCR amplified, and the DNA sequences were compared with those of control subjects. We constructed a molecular model of VH5 to locate amino acids of interest., Results: We observed a significantly increased frequency of IgE and IgA VH5 transcripts in the nasal mucosa of the allergic patients compared with the normal PBMC repertoire. Within IgE and IgA VH5 sequences in the nasal mucosa, the distribution of replacement amino acids was skewed toward the immunoglobulin framework regions. Three of 4 nonintrinsic hotspots of mutation identified in the VH5 sequences were in framework region 1. The hotspots and a conserved VH5-specific framework residue form a tight cluster on the surface of VH5., Conclusion: Our results provide evidence for the activity of a superantigen in the nasal mucosa in patients with allergic rhinitis.

IgE-expressing B cells are over 1000 times more frequent in the nasal B cell than the peripheral blood B cell population. We have investigated the provenance of these B cells in the nasal mucosa in allergic rhinitis. It is generally accepted that expression of activation-induced cytidine deaminase and class switch recombination (CSR) occur in lymphoid tissue, implying that IgE-committed B cells must migrate through the circulation to the nasal mucosa. Our detection of mRNA for activation-induced cytidine, multiple germline gene transcripts, and epsilon circle transcripts in the nasal mucosa of allergic, in contrast to nonallergic control subjects, however, indicates that local CSR occurs in allergic rhinitis. The germline gene transcripts and epsilon circle transcripts in grass pollen-allergic subjects are up-regulated during the season and also when biopsies from allergic subjects are incubated with the allergen ex vivo. These results demonstrate that allergen stimulates local CSR to IgE, revealing a potential target for topical therapies in allergic rhinitis.

DNA deaminases of the Aid/Apobec family convert cytosine into uracil and play key roles in acquired and innate immunity. The epigenetic modification by methylation of cytosine in CpG dinucleotides is also mutagenic, but this is thought to occur by spontaneous deamination. Here we show that Aid and Apobec1 are 5-methylcytosine deaminases resulting in a thymine base opposite a guanine. Their action can thus lead to C --> T transition mutations in methylated DNA, or in conjunction with repair of the T:G mismatch, to demethylation. The Aid and Apobec1 genes are located in a cluster of pluripotency genes including Nanog and Stella and are co-expressed with these genes in oocytes, embryonic germ cells, and embryonic stem cells. These results suggest that Aid and perhaps some of its family members may have roles in epigenetic reprogramming and cell plasticity. Transition in CpG dinucleotides is the most frequent mutation in human genetic diseases, and sequence context analysis of CpG transitions in the APC tumor suppressor gene suggests that DNA deaminases may play a significant role in tumor etiology.

Immunoglobulin E is produced by nasal B cells in response to allergen. We have analyzed IgE V(H) region sequences expressed in the nasal mucosa of patients suffering from allergic rhinitis. V(H) region sequences were amplified by RT-PCR from IgE(+) B cells from nasal biopsies. In two of six patients, sequence analysis clearly demonstrated the presence of closely related IgE(+) B cell clones: cells displaying identical signature regions across CDR3/FWR4, indicating a common clonal ancestry, but a mixture of shared and diverse somatic mutations across the V(H) region. Furthermore, in one of the two patients exhibiting related IgE(+) B cell clones, five IgA(+) B cell clones, related to the IgE(+) B cell family, were also isolated from the patient's nasal mucosa. This evidence, combined with the local expression of mRNA transcripts encoding activation-induced cytidine deaminase, suggests that local somatic hypermutation, clonal expansion, and class switch recombination occur within the nasal mucosa of allergic rhinitics. The presence of related B cells in the nasal mucosa does not appear to result from the random migration of IgE(+) cells from the systemic pool, as analysis of a nonatopic subject with highly elevated serum IgE did not exhibit any detectable V(H)-Cepsilon transcripts in the nasal mucosa. We have provided evidence that suggests for the first time that the nasal mucosa of allergic rhinitics is an active site for local somatic hypermutation, clonal expansion, and class switch recombination, making it of major significance for the targeting of future therapies.

Allergic individuals exposed to minute quantities of allergen experience an immediate response. Immediate hypersensitivity reflects the permanent sensitization of mucosal mast cells by allergen-specific IgE antibodies bound to their high-affinity receptors (FcepsilonRI). A combination of factors contributes to such long-lasting sensitization of the mast cells. They include the homing of mast cells to mucosal tissues, the local synthesis of IgE, the induction of FcepsilonRI expression on mast cells by IgE, the consequent downregulation of FcgammaR (through an insufficiency of the common gamma-chains), and the exceptionally slow dissociation of IgE from FcepsilonRI. To understand the mechanism of the immediate hypersensitivity phenomenon, we need explanations of why IgE antibodies are synthesized in preference to IgG in mucosal tissues and why the IgE is so tenaciously retained on mast cell-surface receptors. There is now compelling evidence that the microenvironment of mucosal tissues of allergic disease favors class switching to IgE; and the exceptionally high affinity of IgE for FcepsilonRI can now be interpreted in terms of the recently determined crystal structures of IgE-FcepsilonRI and IgG-FcgammaR complexes. The rate of local IgE synthesis can easily compensate for the rate of the antibody dissociation from its receptors on mucosal mast cells. Effective mechanisms ensure that allergic reactions are confined to mucosal tissues, thereby minimizing the risk of systemic anaphylaxis.

The absolute bioavailability (BA) of ciprofloxacin and fleroxacin were evaluated in 19 adult Nigerian male volunteers. Subjects meeting the selection criteria were randomized to receive treatment either with fleroxacin (200 mg-i.v. and 200 mg oral dose) or ciprofloxacin (200 mg-i.v. and 250 mg oral dose). The i.v./oral or oral/i.v. switch was made after a one week washout period. Blood and urine samples were collected at pre-determined time intervals over a 72 h period for analysis of drug levels. Following intravenous administration the maximum serum concentration (Cmax) was 2.7+/-1.06mg/l for ciprofioxacin and 0.99+/-0.41 mg/l for fleroxacin; the area under the blood level curve (AUC) was 8.82+/-3.19 mg x h/l with ciprofloxacin and 8.52+/-3.83 mg x h/l with fleroxacin. Following oral administration the Cmax was 1.52+/-0.94 mg/l with ciprofloxacin and 0.57+/-0.08 mg/l with fleroxacin; the AUC was 9.87+/-4.10 and 7.55+/-1.42 mg x h/l, respectively. The absolute BA following oral administration was found to be 0.79+/-0.47 for ciprofloxacin and 1.01+/-0.78 for fleroxacin. When these BA results were corrected for renal clearance [Cl(r)] and elimination half-life (t1/2) the values were reduced to 0.37+/-0.17 and 0.31+/-0.18, respectively, for ciprofloxacin and 0.53+/-0.23 and 0.99+/-0.38, respectively, for fleroxacin. Only 38% with ciprofloxacin and 59% with fieroxacin, of the administered dose, was excreted unchanged following oral administration. More work, however, needs to be done on ciprofloxacin to support and/or confirm the above findings. Fleroxacin, on the one hand, exhibited a different trend from that observed in the literature with respect to Cmax and AUC where the values observed in this study were 3--4 fold lower than expected following identical doses, whilst on the other hand the observed BA profile in this study was consistent with literature trends.

Chlorpheniramine (CP), a histamine H1-receptor antagonist, enhances the efficacy of chloroquine (CQ) in acute uncomplicated falciparum malaria. The effects of this combination therapy on the pharmacokinetic disposition of CQ is, however, unpredictable. A standard treatment with 25 mg CQ base per kg bodyweight was orally administered over 3 days, alone or in combination with CP, to 17 semi-immune Nigerian children with Plasmodium falciparum parasitaemia attending hospital in Lagos, Nigeria, and observed for 28 days. Whole-blood CQ concentrations were monitored 14 times during the follow-up by high-performance liquid chromatography analysis of blood dried on filter paper. Parasitaemia was determined on thick blood films stained with Giemsa, and treatment failures were established following the WHO classification for CQ resistance. Our pharmacokinetic data showed that the peak whole-blood CQ concentration was significantly increased (P < 0.05) by CP administration, and the time to achieve the peak was reduced in the presence of CP. The area under the first-moment drug-concentration-time curve was also significantly increased (P < 0.05) by CP administration. Treatment with CQ-CP combination resulted in a shorter parasite clearance time (2.0 +/- 0.5 days) and a higher cure rate (87.5%) compared to treatment with CQ alone (3.5 +/- 0.5 days; 66.7%). Our data suggest that CP enhanced the efficacy of CQ against resistant P. falciparum in acute uncomplicated malaria by increasing the uptake/concentration of CQ in resistant parasites.

The kinetics of absorption, distribution and elimination of ciprofloxacin and fleroxacin (following an intravenous dose of 200 mg), were evaluated in 24 adult healthy male Nigerian volunteers. Appropriate mathematical models were applied with the aid of a microcomputer software program for the estimation of the basic pharmacokinetic parameters. Appropriate statistical tests and profiles formed the basis for accepting or rejecting a proposed model. For parametric comparisons between the profile of the two drugs, the null hypothesis of no difference in their pharmacokinetic profile was proposed. All statistical tests were performed at a significance level of 95% (alpha = 0.05) and the 95% confidence level was determined where appropriate. Additionally, the model-independent or stochastic method of analysis was also employed in the pharmacokinetic evaluation of the blood level data. The parametric estimates obtained from both methods were compared. The plasma elimination half-life (t1/2) was estimated as 13.8 +/- 5.5 h for fleroxacin and 7.5 +/- 4.0 h for ciprofloxacin; the maximal plasma concentration (Cmax) was 0.8 +/- 0.3 and 2.3 +/- 1.0 mg/l for fleroxacin and ciprofloxacin, respectively, whilst the volume of distribution (Vd) was 2.5 +/- 1.6 and 0.4 +/- 0.3 liters/kg for fleroxacin and ciprofloxacin, respectively. 71 and 70% of unchanged drug were excreted in urine for fleroxacin and ciprofloxacin, respectively. With respect to comparative values, the results confirmed trends already observed in the literature, particularly as regards the t1/2. However, for fleroxacin there was a significant deviation from the literature trends with respect to Vd, Cmax and AUC. The results also confirmed earlier findings, advocating a once-daily dosage schedule for fleroxacin also in the Negroid population.

Objective: The antibacterial efficacy of fleroxacin was compared with that of ciprofloxacin in 72 adult Nigerian patients with typhoid fever., Patients and Methods: On inclusion into the study, patients were randomised to treatment with either fleroxacin 400mg once daily for 7 days or ciprofloxacin 500mg twice daily for 14 days. Clinical evaluations were performed on days 0, 1, 2, 3, 5 and 7 or 14, and 2 weeks after treatment. Bacteriology was performed on days 0, 3, 7 or 14, and 21 or 28. Laboratory tolerability parameters were monitored for all patients as well as incidence of adverse events., Results: Bacteriological response on day 3 was 93.5 and 64.0% for fleroxacin and ciprofloxacin, respectively. At term and follow-up there was bacteriological cure in 97.0% of patients with fleroxacin and 100% with ciprofloxacin. The clinical cure was 100% for both groups at term. The incidence of adverse events was 5.4% with fleroxacin and 2.8% with ciprofloxacin., Conclusion: The results demonstrated that while the clinical response rate with both drugs was comparable, fleroxacin exhibited a faster bacteriological clearance rate. We therefore concluded that 7 days' therapy with fleroxacin 400mg once daily was as effective as 14 days' therapy with ciprofloxacin 500mg given twice daily in the management of typhoid fever in Nigerian patients. It was also observed that the quinolones possessed greater potential and benefits as first-line therapy for the management of typhoid fever in this environment. The tolerability profile was good for both treatment regimens.

The antihypertensive effect of aqueous extracts of the calyx of Hibiscus sabdariffa (HS) has been investigated in anaesthetized rats. Hibiscus sabdariffa caused a dose-dependent decrease in mean arterial pressure (MAP) of the rats. Sectioning of the right and left vagi nerves did not have a significant effect on the fall in MAP produced by HS. Cholinergic blockade with 0.2 mgkg-1 atropine and histaminergic blockade with 1 mgkg-1 cimetidine and 15 mgkg-1 promethazine significantly attenuated the hypotensive response to HS. Pretreatment of the rats with 20 mgkg-1 HS extract did not have a significant effect on increase in blood pressure induced by bilateral carotid occlusion (48.05 +/- 6.83 mmHg vs 46.53 +/- 7.49 mmHg). The cumulative addition of HS to noradrenaline precontracted aortic rings produced dose-dependent relaxation of the rings. The maximum relaxation response was 86.96 +/- 5.20% and this was observed at the dose of 1.70 mgml-1. These findings suggest that the antihypertensive effect of the extracts of calyx of HS is not mediated through inhibition of the sympathetic nervous system but it could be mediated through acetylcholine-like and histamine-like mechanisms as well as via direct vaso-relaxant effects.

We have studied the effects of mefloquine on isolated rat aorta. Mefloquine (10(-8) to 1.6 x 10(-4) mol.l-1) relaxed aortic rings precontracted with both noradrenaline (10(-7) mol.l-1) and potassium chloride (60 mmol.l-1). The mefloquine-induced relaxation was somewhat attenuated by removal of the endothelium. Contractile responses to noradrenaline, potassium chloride, and calcium chloride were reduced by incubating the aortic rings in physiological salt solution containing mefloquine, suggesting that mefloquine reduces calcium influx, which is required for excitation-contraction coupling. The results show that mefloquine relaxes vascular smooth muscle via mechanisms which are partly endothelium-dependent and which is also associated with inhibition of Ca2+ influx from the extracellular medium.

Treatment of tinidazole with a mixture of hydrogen peroxide and acetic acid, or liver homogenate preparations, yields the N-3 oxide. This was identified by thin-layer chromatographic analysis on silica gel G, Rf 0.6, using ethanol-chloroform-ammonia (50:49:1) as solvent, and by chemical reduction with sulphur dioxide. UV spectrophotometry and high performance liquid chromatography (HPLC) gave an RT of 0.55 min using Pye Unicam apparatus equipped with a UV detector at 330 nm, a reversed-phase RP 18 (10 microns) column which was 12.5 cm long, a mobile phase of methanol-0.005 M KH2PO4 (pH 4) (20:80, v/v) and a flow rate of 2 ml/min. In-vitro metabolic N-oxidation was achieved by incubating the parent drug, tinidazole, with rat liver homogenates fortified with cofactors at 37 degrees C. HPLC analysis of blood and urine samples from healthy volunteer subjects who took a single oral dose of tinidazole showed the presence of an in-vivo N-oxidation metabolite of the drug. The identical physico-chemical characteristics of the synthetic and biologically produced tinidazole N-oxide strongly suggest that tinidazole, a tertiary amine drug, undergoes metabolic N-oxidation.

Renal effects of nifedipine were assessed in 3 groups of healthy normotensive volunteers. In the first group (N = 10), a single 20-mg dose of the slow-release formulation caused an increase in 8-h sodium excretion (P less than 0.025) and urine volume (P less than 0.005). Natriuresis (P less than 0.05) and diuresis (P less than 0.05) were still evident after 1 wk of pretreatment, but were significantly attenuated (P less than 0.05), in each case, compared to levels after a single dose. Natriuresis and diuresis after 2 wk of intake were indistinguishable from control levels. In another group of 8, a single 10 mg dose of the conventional formulation (capsule) effected natriuresis (P less than 0.01) and diuresis (P less than 0.001) similar to those associated with intake of a single 20-mg dose of the slow-release formulation. Natriuresis and diuresis associated with a 20-mg single dose of the conventional formulation were not different from control but were less than those following intake of the 10-mg dose (P less than 0.025 in each case). In the third group of 6, nifedipine, though weaker than chlorothiazide, promoted natriuresis (P less than 0.025) and diuresis (P less than 0.025) of the thiazide without augmenting its kaliuresis. In all the groups, there were no changes in creatinine clearance, and nifedipine did not alter kaliuresis. It is suggested that natriuretic and diuretic effects of nifedipine in healthy normotensive individuals are dependent on the dose employed, the formulation used, and the duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Metronidazole when treated at the N-3 nitrogen with a mixture of hydrogen peroxide and acetic acid, or liver homogenate preparations, yields the N-3 oxide as identified by thin-layer chromatographic analysis on silica gel G, RF 0.62 in ethanol-chloroform-ammonia (50:49:1), by chemical reduction with sulphur dioxide, and by ultra-violet spectrophotometry and nuclear magnetic resonance spectroscopy. Incubation of metronidazole at 37 degrees C with rat liver 10,000g supernatant fortified with cofactors gave a product with identical chromatographic and UV spectral data suggesting that metronidazole like other tertiary amine drugs undergoes microsomal N-oxidation.

We investigated the effect of 4 days pretreatment with cimetidine (1.2 g daily) and ranitidine (0.3 g daily) on tolbutamide disposition in an open randomised, cross-over study design involving 8 healthy adult male volunteers. Control half-life of tolbutamide 6.29 h was not significantly altered by cimetidine (6.93 h) or ranitidine (6.97 h). The corresponding apparent oral clearance (ml.min-1.kg-1) were not significantly different: 0.26 (control), 0.24 (cimetidine) and 0.25 (ranitidine). Apparent volume of distribution was also unaltered 0.140 l.kg-1 (control), 0.141 l.kg-1 (cimetidine) and 0.146 l.kg-1 (ranitidine). It is suggested that the hepatic monooxygenase isozyme that catalyses the rate-limiting conversion of tolbutamide to its hydroxy derivative is not susceptible to the inhibitory effect of cimetidine or ranitidine.

The effect of placebo or cimetidine at a dose of 1 g daily on theophylline elimination was studied in a double-blind control manner in twelve healthy adult males aged 19-31 years. In a group of six, placebo had no effect on any of theophylline half-life (t1/2), volume of distribution (Vd), and total body clearance (CL). In another group of six, theophylline t1/2 rose significantly from 5.48 to 9.04 h (p less than 0.001) after 48 h and to 8.98 h (p less than 0.001) after a week pretreatment with cimetidine. Correspondingly, CL (ml min-1kg-1) fell to 0.66 (p less than 0.025) and 0.60 (p less than 0.01). Changes after 48 h pretreatment were not different from those after a week pretreatment. Seven days after the last cimetidine dose, theophylline disposition had reverted to the control level. There was no significant change in Vd. In five elderly subjects aged 56-68 years, a week of dosing with cimetidine caused a rise in t1/2 (7.17 h to 10.39 h; p less than 0.001) and a fall in CL (0.77 ml min-1kg-1 to 0.53 ml min-1kg-1; p less than 0.005) without significantly altering Vd. In two subjects, there was restoration of theophylline disposition to the control level 72 h after cessation of cimetidine intake. Changes in the elderly were not significantly different from those in the younger ones. Data indicate that cimetidine-induced impairment of theophylline disposition is of rapid onset, has rapidly attainable maximum effect, and is rapidly reversible. Furthermore elderly individuals are just as susceptible to it as the younger adults.