Electrochemical Redox Behavior of Omeprazole Using a Glassy Carbon Electrode

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Theoretical study of omeprazole behavior: Racemization barrier and decomposition reaction

omeprazole is a substituted benzimidazole which suppresses gastric-acid secretion by means of H+, K+-ATPase inhibition. It is an optically active drug with the sulfur of the sulfoxide being the chiral center. This pro-drug can be easily converted into its respective sulfenamide at low pH. In this work, omeprazole has been studied in relation to racemization barrier and decomposition reaction. Quantum chemistry coupled to PCA chemometric method were used to find all minimum energy structures. Conformational analysis and calculation of racemization barriers were carried out by PM3 semiempirical method (Gaussian 98). The average racemization energy barrier for all minimum energy structures (43.56 kcal mol(-1)) can be related to the velocity constant in Eyring's equation. The enormous half-life time at 100 degrees C (9.04 x 10(4) years) indicates that the process cannot be observed in human time scale. on the other hand, the difference of free energy change (Delta(Delta G) = -266.78 kcal mol(-1)) for the decomposition reaction shows that the process is favorable to the sulfenamide formation. The highly negative Delta(Delta G) obtained for the decomposition reaction shows that this process is extremely exothermic. This result explains why omeprazole decomposes and does not racemize. (C) 2008 Wiley Periodicals, Inc.

Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole

Subjects taking a hydrogen pump blocking agent (omeprazole) develop bacterial overgrowth of the small intestine. We tested the hypothesis that this bacterial overgrowth produces menaquinones, which would meet the Vitamin requirement in situations of vitamin K deficiency. In a crossover-type design, 13 healthy Volunteers eating a phylloquinone-restricted diet for 35 d were randomly assigned to take omeprazole during the first period of study or starting on day 15 until the end of the study. Coagulation times, serum osteocalcin [total osteocalcin and undercarboxylated osteocalcin (ucOC)], plasma phylloquinone, urinary gamma-carboxyglutamic acid, and plasma undercarboxylated prothrombin (PIVKA-II) were measured. Plasma phylloquinone concentrations declined 82% with dietary phylloquinone restriction (P < 0.05) and were not significantly different in the period when the diet was combined with omeprazole treatment (P > 0.05), the mean value for PIVKA-II during the phylloquinone-restricted diet significantly increased 5.7-fold from baseline (P < 0.05); however, the combination of omeprazole treatment and the phylloquinone-restricted diet significantly reduced PIVKA-II values by 21% (P < 0.05) compared with the diet period alone. There were no alterations in total or percentage ucOC concentrations during the phylloquinone-restricted diet or during the period of diet plus omeprazole treatment. Our data support the hypothesis that bacterial overgrowth results in the synthesis and absorption of menaquinones. These menaquinones contribute to vitamin K nutriture during dietary phylloquinone restriction, but not enough to restore normal vitamin K status.

Kinetic characterization of a membrane-specific ATPase from rat osseous plate and its possible significance on endochondral ossification

Treatment with phosphatidylinositol-specific phospholipase C of rat osseous plate membranes released up to 90-95% of alkaline phosphatase, but a specific ATPase activity (optimum pH = 7.5) remained bound to the membrane. The hydrolysis of ATP by this ATPase was negligible in the absence of magnesium or calcium ions. However, at millimolar concentrations of magnesium and calcium ions, the membrane-specific ATPase activity increased to about 560-600 U/mg, exhibiting two classes of ATP-hydrolysing sites, and site-site interactions. GTP, UTP, ITP, and CTP were also hydrolyzed by the membrane-specific ATPase. Oligomycin, ouabain, bafilomycin A(1), thapsigargin, omeprazole, ethacrynic acid and EDTA slightly affected membrane-specific ATPase activity while vanadate produced a 18% inhibition. The membrane-specific ATPase activity was insensitive to theophylline, but was inhibited 40% by levamisole. These data suggested that the membrane-specific ATPase activity present in osseous plate membranes, and alkaline phosphatase, were different proteins. (C) 1998 Elsevier B.V. B.V.

Ventilatory compensation of the alkaline tide during digestion in the snake Boa constrictor

The increased metabolic rate during digestion is associated with changes in arterial acid-base parameters that are caused by gastric acid secretion (the 'alkaline tide'). Net transfer of HCl to the stomach lumen causes an increase in plasma HCO3- levels, but arterial pH does not change because of a ventilatory compensation that counters the metabolic alkalosis. It seems, therefore, that ventilation is controlled to preserve pH and not P-CO2, during the postprandial period. To investigate this possibility, we determined arterial acid-base parameters and the metabolic response to digestion in the snake Boa constrictor, where gastric acid secretion was inhibited pharmacologically by oral administration of omeprazole. The increase in oxygen consumption of omeprazole-treated snakes after ingestion of 30% of their own body mass was quantitatively similar to the response in untreated snakes, although the peak of the metabolic response occurred later (36 h versus 24 h). Untreated control animals exhibited a large increase in arterial plasma HCO3- concentration of approximately 12 mmol 1(-1), but arterial pH only increased by 0.12 pH units because of a simultaneous increase in arterial P-CO2 by about 10 mmHg. Omeprazole virtually abolished the changes in arterial pH and plasma HCO3- concentration during digestion and there was no increase in arterial P-CO2. The increased arterial P-CO2 during digestion is not caused, therefore, by the increased metabolism during digestion or a lower ventilatory responsiveness to ventilatory stimuli during a presumably relaxed state in digestion. Furthermore, the constant arterial P-CO2, in the absence of an alkaline tide, of omeprazole-treated snakes strongly suggests that pH rather than P-CO2 normally affects chemoreceptor activity and ventilatory drive.

Effects of inhibition gastric acid secretion on arterial acid-base status during digestion in the toad Bufo marinus

Digestion affects acid-base status, because the net transfer of HCl from the blood to the stomach lumen leads to an increase in HCO3- levels in both extra- and intracellular compartments. The increase in plasma [HCO3-], the alkaline tide, is particularly pronounced in amphibians and reptiles, but is not associated with an increased arterial pH, because of a concomitant rise in arterial Pco(2) caused by a relative hypoventilation. In this study, we investigate whether the postprandial increase in Paco(2) of the toad Bufo marinus represents a compensatory response to the increased plasma [HCO3-] or a state-dependent change in the control of pulmonary ventilation. To this end, we successfully prevented the alkaline tide, by inhibiting gastric acid secretion with omeprazole, and compared the response to that of untreated toads determined in our laboratory during the same period. In addition, we used vascular infusions of bicarbonate to mimic the alkaline tide in fasting animals. Omeprazole did not affect blood gases, acid-base and haematological parameters in fasting toads, but abolished the postprandial increase in plasma [HCO3-] and the rise in arterial Pco(2) that normally peaks 48 h into the digestive period. Vascular infusion of HCO3-, that mimicked the postprandial rise in plasma [HCO3-], led to a progressive respiratory compensation of arterial pH through increased arterial Pco(2) Thus, irrespective of whether the metabolic alkalosis is caused by gastric acid secretion in response to a meal or experimental infusion of bicarbonate, arterial pH is being maintained by an increased arterial Pco(2). It seems, therefore, that the elevated Pco(2), occuring during the postprandial period, constitutes of a regulated response to maintain pH rather than a state-dependent change in ventilatory control. (C) 2003 Elsevier B.V. All rights reserved.

Avaliação do efeito antiparasitário do omeprazol na prevenção do desenvolvimento de lesões cutâneas em hamsters infectados por Leishmania brasiliensis

FUNDAMENTOS: A leishmaniose tegumentar americana permanece doença endêmica em diversas regiões brasileiras. A sobrevivência do parasita no interior dos macrófagos se deve, em parte, pela atividade de uma K+/H+-ATPase de membrana que pode ser inibida pelo omeprazol. OBJETIVOS: Avaliar a eficácia do omeprazol na prevenção do desenvolvimento de lesões de leishmaniose em hamsters. MÉTODOS: Empregaram-se 18 hamsters, divididos em três grupos: o grupo L recebeu apenas a inoculação de L. brasiliensis na pata anterior direita, o grupo O recebeu apenas doses diárias de 0,4mg de omeprazol subcutâneo, e o grupo L+O recebeu o inóculo de leishmanias e o tratamento com omeprazol desde o dia da inoculação. O estudo foi conduzido por 42 dias, realizaram-se medidas dos diâmetros das patas semanalmente, e, ao final do estudo, foram realizados esfregaços das lesões para verificação dos parasitas. RESULTADOS: Os hamsters dos grupos L e L+O desenvolveram lesões de leishmaniose tegumentar havendo ulceração em duas patas do grupo L e uma do grupo L+O. Ao final do estudo, a mobilidade e vitalidade no grupo L foram menores que em L+O, e estas menores que no grupo O. Os diâmetros das patas inoculadas nos grupos L e L+O foram significativamente maiores que no início do estudo (p<0.05). Não houve diferença significativa entre os diâmetros das patas dos grupos L e L+O ao final do estudo (p0,05), sendo detectados parasitas no esfregaço das lesões dos dois grupos. CONCLUSÕES: Omeprazol, no protocolo utilizado, não evitou o desenvolvimento de lesões de leishmaniose tegumentar em hamsters.

Conformational analysis: A new approach by means of chemometrics

In conformational analysis, the systematic search method completely maps the space but suffers from the combinatorial explosion problem because the number of conformations increases exponentially with the number of free rotation angles. This study introduces a new methodology of conformational analysis that controls the combinatorial explosion. It is based on a dimensional reduction of the system through the use of principal component analysis. The results are exactly the same as those obtained for the complete search but, in this case, the number of conformations increases only quadratically with the number of free rotation angles. The method is applied to a series of three drugs: omeprazole. pantoprazole, lansoprazole-benzimidazoles that suppress gastric-acid secretion by means of H(+), K(+)-ATPase enzyme inhibition. (C) 2002 John Wiley Sons. Inc.

Anti-ulcerogenic and analgesic activities of the leaves of Wilbrandia ebracteata in mice

Wilbrandia ebracteata (Cogn.) Cogn. is a medicinal plant belonging to the Cucurbitaceae family used popularly as an antiulcer and analgesic medicine. The hydromethanol extract of leaves was investigated to determine its anti-ulcerogenic (ethanol and indomethacin induced gastric damage) and analgesic (writhing and tail-flick tests) activities in mice (efficacy), its acute toxicity (safety), and its phytochemistry (quality control). Oral administration of leaf extract at a dose of 1000 mg/kg body wt. significantly reduced 73.3% of the total area of lesion in ethanol-induced gastric damage, but was inactive in an indomethacin-induced gastric damage test. The hydromethanol extract was also inactive in both analgesic tests. Oral administration of the leaf extract did not produce mortality in mice, while the LD50 value of the roots was 22.10 mg/kg body wt. in female mice and 58.31 mg/kg body wt. in male mice. Leaves of W. ebracteata reacted positively for steroids, flavonols, flavanones, saponins, tannins and xanthones and negative for other compounds, including cucurbitacins. Leaf extract of W. ebracteata was active as an anti-ulcerogenic, probably through increasing gastric defensive factors, and flavonoids might be the main constituent responsible for this activity.

Nerolidol, an antiulcer constituent from the essential oil of Baccharis dracunculifolia DC (Asteraceae)

In this study, the antiulcerogenic effect of essential oil from Baccharis dracunculifolia was evaluated using the model of acute gastric lesions induced by ethanol. The ulcerative lesion index (ULI) was significantly reduced by oral administration of the essential oil of B. dracunculifolia at doses of 50, 250 and 500 mg/kg which reduced the lesions by 42.79, 45.70 and 61.61%, respectively. The analysis of the chemical composition of the essential oil from B. dracunculifolia by GC showed that this was composed mainly of mono- and sesquiterpenes and the majority compound was nerolidol. Therefore, antiulcerogenic activity of nerolidol (50, 250 and 500 mg/kg) was investigated using ethanol-, indomethacin- and stress-induced ulcer models in rat. In the stress-induced ulcer model, a significant reduction of the ULI in animals treated with nerolidol (50, 250 and 500 mg/kg) and cimetidine (100 mg/kg) was observed, compared to the control group (p < 0.05). The percentage of inhibition of ulcer was 41.22, 51.31, 56.57 and 53.50% in groups treated with 50, 250, 500 mg/kg of nerolidol and 100 mg/kg of cimetidine (positive control), respectively. Regarding ethanol- and indomethacin-induced ulcer models, it was observed that the treatment with nerolidol (250 and 500 mg/kg) significantly reduced the ULI in comparison with the control group (p < 0.05). The dose of 50 mg/kg reduced the parameters analyzed but this was not statistically significant. In the ethanol-induced model percentage of inhibition of ulcer was 34.20, 52.63, 87.63 and 50.87% in groups treated with 50, 250, 500 mg/kg of nerolidol and 30 mg/kg of omeprazol (positive control), respectively. In indomethacin-ulcer the percentage of inhibition of ulcer was 34.69, 40.80, 51.02 and 46.93% in groups treated with 50, 250, 500 mg/kg of nerolidol and 100 mg/kg of cimetidine (positive control), respectively. The results of this study show that nerolidol displays antiulcer activity, as it significantly inhibited the formation of ulcers induced in different animal models. However, further pharmacological and toxicological investigations, to delineate the mechanism(s) of action and the toxic effects, are required to allow the use of nerolidol for the treatment of gastric ulcer. © 2007 Verlag der Zeitschrift für Naturforschung.

Contribuição do uso de medicamentos para a admissão hospitalar

According to the Word Health Organization, adverse drug reactions (ADR) are any harmful and non intentional answer which occurred in doses normally used in human beings. The ADR can be responsible for 2.4% to 11.5% of hospital admissions. Therefore, this study aimed at knowing the admitted patient's demographic profile due to possible ADR, identifying the most frequent drugs and complaints, and evaluating the incidence of hospital admission related to drug use. Patients who were 18 years old or more and were admitted during a period of one month to a medical clinical of a general hospital were interviewed for one month about drug use before being admitted, as well as regarding to the complaint which led them to hospital. These information were analyzed according to official data, like MICROMEDEX® and WHO criteria as well. It was observed that the admission due to drug use occurred in most part of the cases in elderly [47.5% (66/139)] and women [62% (87/139)]. The most frequent drugs used were: omeprazole (16), analgesics (31), antihypertensive (31), simvastatin (7) and formoterol fumarate (6), and the symptoms were normally associated to the digestive (20.5%), circulatory (20.2%), respiratory (18.2%) and central nervous systems (13.9%). It was estimated that 15.5% (139/897) of the hospital admission occurred possibly due to the drug use. The data found by present study suggests some strategies in order to prevent ADR in the context of primary health care services, such as monitoring drug therapy, manly for patients with chronic diseases, elderly and polimedicated people; and pharmaceutical care including dispensation and purchasing of the drugs, a lot of them dispensed over the counter (OTC).

Adverse drug reaction as cause of hospital admission of elderly people: a pilot study

The objective of this study was to estimate the prevalence of adverse drug reactions (ADR) related to hospital admission of elderly people, identifying the use of potentially inappropriate medication (PIM), the ADR and the risk factors associated with the hospitalization. A cross-sectional study was conducted in a private hospital of São Paulo State, Brazil. All patients aged ≥ 60 years, admitted in the general practice ward in May 2006 were interviewed about the drugs used and the symptoms/complaints that resulted in hospitalization. More than a half (54.5 %) of elderly hospitalizations were related with ADR. The therapeutic classes involved with ADR were: cardiovascular (37.7 %), central nervous (34.6 %) and respiratory (5.7 %). The ADR observed were disorders in circulatory (28.4 %), digestive (20.0 %) and respiratory (18.9 %) tracts. 27 elderly had made PIM and in 20 of them this was the cause of hospitalization. Polypharmacy was an ADR risk factor (p = 0.021).These data allows the healthcare professionals upgrade, qualifying them in pharmcovigilance.

Avaliação do efeito protetor e cicatrizante do extrato hidroalcóolico de folhas de Solanum paniculatum L. frente á úlceras pépticas

Pós-graduação em Biologia Geral e Aplicada - IBB

Ivabradine: Just another New Pharmacological Option for Heart Rate Control?

Ivabradine (IVB) is a heart rate lowering agent that acts via selective inhibition of the pacemaker funny current in sinoatrial nodal P cells, thus, reducing heart rate at rest and during exercise with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction. IVB exerts no effect on external respiratory function parameters and it may also play a role in patients with concurrent chronic obstructive pulmonary disease. This property constitutes an important advantage over β-blockers. IVB acts by reducing the heart rate in a mechanism different from β-blockers, calcium channel blockers or late sodium channel blockers, three commonly prescribed antianginal drugs. As clinical trials have shown, it is remarkably well-tolerated and offers an alternative for patients who cannot take β-blockers. The combination of IVB and atenolol at commonly used doses in patients with chronic stable angina produced additional efficacy with no untoward effect on safety or tolerability. Additionally, side effects are rare and largely limited to a luminous phenomenon or phosphenes. This sensation is thought to be due to a block of Ih in the retina, a current very similar to cardiac If channels. IVB is contraindicated in patients with sick sinus syndrome or sinus node dysfunction and in patients taking hepatic inhibitors of Cytochrome P450 family 3, subfamily A, polypeptide 4 (abbreviated CYP3A4), with exception of omeprazole or lansoprazole. This review briefly summarizes the main studies regarding this drug.

Avaliação do uso profilático de omeprazol em pacientes internados no hospital estadual Américo Brasiliense

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)