DSpace Community: Pharmacology & Therapeutics

DETERMINANTS OF RESPONSES TO ANTIMALARIAL DRUGS IN CHILDREN WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA

2011-05-01T00:00:00Z

Title: DETERMINANTS OF RESPONSES TO ANTIMALARIAL DRUGS IN CHILDREN WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA Authors: SIJUADE, A.O Abstract: Drug resistance is a challenge to malaria control efforts and several factors including parasite genetics, host factors and pharmacokinetics may contribute to the selection of drug resistant Plasmodium falciparum. Understanding the role of these factors in patient response to antimalarial drugs is therefore essential in the management of malaria. The aim of the study was to determine the factors contributing to delay in malaria Parasite Clearance (PC) in children and evaluating the effects of pharmacokinetic variability on treatment outcome. Children (n=2,752), aged 6 months -12 years, with falciparum malaria, were enrolled over a period of eight years and treated with standard doses of Chloroquine (CQ), Sulphadoxine-Pyrimethamine (SP) or Amodiaquine (AQ) given alone or in combination with artemisinin. Each patient was followed up for at least 14 days. Age, axillary temperature, parasite density and gametocytaemia were assessed for their potential association with delay in PC and treatment outcomes. Filter-paper blood samples were collected from some of the children (n=148) before treatment and on days 1-7, 14, 28 and 35 after treatment for determination of CQ and sulphadoxine concentrations. In another subset of patients (n=7), treated with amodiaquine, blood and saliva samples were collected over 35 days. High performance liquid chromatographic techniques were used to determine concentrations of sulphadoxine in whole blood as well as AQ and Desethyl amodiaquine (DEAQ) in saliva. Mean maximum drug concentration (Cmax), half-life (t1/2) and area under concentration-time curve (AUC0-28d) were assessed for their association and predictive value for treatment outcomes. Data were analyzed using descriptive statistics, ANOVA, Chi-square, Students’ t-test, Kruskal-Wallis and multiple regressions at p = 0.05. Age ≤ 2 years (Adjusted odds ratio [AOR] = 2.13), presence of fever (AOR = 1.33) and parasitaemia > 50,000/µl (AOR = 2.21) at enrolment were independent risk 3 factors for delay in PC, while a body temperature >38OC and parasitaemia >20,000/µl were predictors a day after treatment regardless of the drug used. Day 3 concentration ≤ 1750ng/ml and AUC0-28d ≤ 950ng/ml.h were associated with chloroquine treatment failure. In a multivariate analysis, a terminal elimination t½ ≤ 220h (AOR = 0.28) and AUC0-28d ≤ 950ng/ml.h (AOR = 4.12) were identified as independent pharmacokinetic predictors of chloroquine treatment failure. Age stratified analysis showed that SDX concentrations were significantly higher in children > 5years compared to children <5years: Cmax; 295 vs 125µg/ml, AUC0-28d; 1562 vs 812µg/ml.d. In patients who received AQ, there was a rapid conversion of AQ to DEAQ, which was detectable in plasma and saliva within 40 minutes of administration. The mean day 7 concentration of DEAQ was significantly higher in plasma than in saliva (247.8 vs 125.1ng/ml). The t1/2 of DEAQ were similar in plasma (167.25±43.4h) and saliva (146.12±17.2h). The decline phases of DEAQ in saliva concentration-time curves were approximately similar to that in plasma. Delay in parasite clearance is specific and related to drug resistance. In addition pharmacokinetic variability of sulphadoxine in children has potential impact on dosage regimen and treatment outcome. Description: A thesis in the Department of PHARMACOLOGY AND THERAPEUTICS submitted to the Faculty of Basic Medical Sciences in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF IBADAN

EVALUATION OF THE ANTIPSYCHOTIC PROPERTY OF MORIN AND ITS MECHANISMS OF ACTION IN EXPERIMENTAL MICE

2018-06-01T00:00:00Z

Title: EVALUATION OF THE ANTIPSYCHOTIC PROPERTY OF MORIN AND ITS MECHANISMS OF ACTION IN EXPERIMENTAL MICE Authors: BEN-AZU, B. Abstract: Psychosis is a chronic neuropsychiatric disease characterised by severe behavioural perturbations. Current drugs used in the management of the disease are associated with serious side effects. Therefore, compounds with psychotropic-antioxidant effects are currently being sought as alternatives. Morin, a naturally-occurring neuroactive flavonoid isolated from Morusalba possesses strong psychotropic and antioxidant properties, however the mechanism of the antipsychotic property has not been fully elucidated. This study was designed to investigate the antipsychotic-like activity of morin and its mechanisms of action in mice. Morin was administered intraperitoneally to male Swiss mice. Ninety mice randomised into 6 groups of each experiment (n=5): vehicle (normal saline, 10mL/kg), morin (25, 50, 100mg/kg), haloperidol (1mg/kg) and risperidone (0.5mg/kg); were pre-treated to assess the acute antipsychotic effects of morin on apomorphine-(2mg/kg), ketamine-(10mg/kg) induced stereotypes and woodblock-catalepsy test. For the chronic studies, fifty mice were given preventive treatments (n=5) with morin (100mg/kg/day), haloperidol (1mg/kg/day), risperidone (0.5mg/kg/day), or vehicle for 14 days prior to injection of ketamine (20mg/kg/day) from the 8th-14th day. For the reversal treatment, animals received ketamine for 14 days prior to the treatments. The antipsychotic and neuroinflammatory effects were also assessed in 25 mice following pretreatments with vehicle, morin, haloperidol and risperidone, in combination with lipopolysaccharide (0.1mg/kg/day) induced neuroinflammation for 14 days prior to ketamine (20mg/kg/day) treatment from the 8th-14th day. Schizophrenia-like behaviours in all chronic studies were evaluated using open-field, social-interaction and Y-maze tests. Thereafter, brain biomarkers of oxidative/nitrergic stress were determined, spectrophotometrically in specific-brain regions (striatum, prefrontal cortex and hippocampus) in preventive-reversal and neuroinflammatory studies. Specific-brain regions of dopamine, glutamate and serotonin concentrations, Glutamic Acid Decarboxylase-67 (GAD67), Brain-Derived Neurotrophic Factor (BDNF) and gp91-phox expressions were measured in the preventive-reversal study using ELISA or immunohistochemistry. Brain Tumor Necrosis Factor-alpha (TNF-α),interleukin-6 levels, cyclooxygenase-2 (COX-2) and Nuclear Factor-κB (NFκB) expressions were determined in the neuroinflammatory study using ELISA or immunohistochemistry. Dendritic arborization of the cortical pyramidal neurons of lipopolysaccharide-ketamine treated mice was assessed using silver-impregnation stain. Data were analysed using descriptive statistics and ANOVA at α0.05. Morin (25, 50, 100mg/kg) significantly suppressed stereotypy induced by apomorphine (23.4, 34.5 and 60.1%) and ketamine (33.7, 73.4 and 83.4%) relative to controls,and was devoid of extrapyramidal side effects in catalepsy test.Morin (100mg/kg) prevented and reversed ketamine-induced social and cognitive deficits relative to controls and ketamine-induced hyperlocomotion (61.6±5.2 vs109.8±5.3; 47.0±6.1 vs103.2±4.5), respectively. Morin prevented and reversed altered dopaminergic, glutamatergic, GABAergic and serotonergic neurotransmissions in the striatum, prefrontal cortex and hippocampus, respectively. Morin increased BDNF, glutathione, and decreased malondialdehyde, nitrite levels and pg91-phox expressions in the three brain regions. Morin reduced TNF-α (124.7±8.6 vs212.7±9.4; 117.3±9.7 vs278.5±13.9 pg/g tissue) in the striatum and prefrontal cortex, and morin also reduced interleukin-6 (321.3±24.2 vs704.7±26.3, 295.1±19.7 vs581.3±47.4 pg/g tissue) in the prefrontal cortex and hippocampus. It also reduced COX-2 and NFκB expressions in the three brain-regions, and increased dendritic arborization of the cortical-pyramidal neurons. Morin demonstrated antipsychotic-like activity via mechanisms related to modulation of neurotransmitters, enhancement of neurotrophin, inhibition of oxidative/nitrergic stress and neuroinflammation. Description: A thesis in the department of Pharmacology and Therapeutics, submitted to the Faculty of Basic Medical Sciences in partial fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY of the UNIVERSITY OF IBADAN

CATION CONTENT AND FLUXES IN RED CELLS OF NORMAL AND HYPERTENSIVE NIGERIANS

1978-08-01T00:00:00Z

Title: CATION CONTENT AND FLUXES IN RED CELLS OF NORMAL AND HYPERTENSIVE NIGERIANS Authors: ADEROUNMU, A. F. Abstract: RED CELL SODIUM AND POTASSIUM CONTENT AND FLUXES IN NORMAL AND HYPERTENSIVE NIGERIANS. 1. Erythrocyte sodium, potassium and water content have been determined in 908 Nigerians so as to: 1. establish normal values in Nigerians 2. compare values in Nigerians with known values in other blacks. 3. compare values in Nigerians with those of caucasians. Red cell sodiuum, potassium and water were also determined in 7 caucasians who had been resident in Nigeria for periods varying from 6 months to 18 years. The RBC sodium for Nigerians considerably higher than those of caucasians, but the RBC potassium and water did not show any significant difference. In the course of this work, the normal (control) subjects were grouped according to their genotypes. 3 genotypes were encountered: AA, AS and AC. There was no significant difference in the erythrocyte sodium, potassium and water of the individuals belonging to these 3 genotypes. The results were also analysed for sex and age differences, and none was found. Results of erythrocyte sodium, potassium and water from 3 siblings and their mother were also presented. These results differed, from one another, suggesting that environmental factors are also important and probably just as potent determinants of RBC sodium, potassium and water content as are genetic factors. 2. 100 hypertensive subjects were studied. They were all newly diagnosed, mostly symptomless ambulant subjects who were attending the medical out-patient department of the University College Hospital, Ibadan. Their main pathological finding systemic hypertension. They were followed up for periods varying from 18 months to 3 1/2 years. Investigations were performed on each patient which enabled their being grouped into hypertensives with normal renal function or hypertensives with abnormal renal function. Only those with normal renal function were included in the study. The results obtained for the red cell sodium and potassium were significantly different from those of the Controls. Their red cell water was also significantly different from that of the Controls, but the difference m RBC water was not sufficient to account for the differences in the RBC sodium and potassium. Here again, the RBC sodium and potassium were not related to age or sex. The RBC sodium and potassium content were in no way related to the mean blood pressures. Their values remained the same both before and during treatment. Adequate control and maintenance of the patients blood pressures within the normal range did not affect these two cations. 3. When red cells from Controls and red cells from Hypertensives were exposed to a high sodium load, the RBCs from hypertensive gained a lot more sodium and lost a lot more potassium than the RBCs from Controls. 4. Normal red cells lost their potassium into isotonic sucrose media seven times as fast as red cells from hypertensive subjects. 5. Normal red cells have a slightly higher a tive sodium flux per hour than red cells from hypertensive subjects, but the difference is not statistically significant. The rate constant for active sodium flux is higher for red cells of Controls than for red cells of hypertensive subjects, but the correlation between intracellular sodium content and rate constant is not good (r= -0.43). The rate constant for the red cells of the hypertensives is lower, but it correlates better with the red cell sodium (r =0.53). Description: A THESIS IN DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS SUBMITTED TO THE FACULTY OF MEDICINE IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DOCTOR OF PHILOSOPHY UNIVERSITY OF IBADAN

INTERACTION OF PROSTAGLANDIN E(2) (PGE(2)) WITH NORADRENALINE AND ITS ANTAGONISTS IN THE ISOLATED MESENTERIC ARTERY OF RAT

1980-07-01T00:00:00Z

Title: INTERACTION OF PROSTAGLANDIN E(2) (PGE(2)) WITH NORADRENALINE AND ITS ANTAGONISTS IN THE ISOLATED MESENTERIC ARTERY OF RAT Authors: ADEAGBO, A. S. O. Abstract: The effect of PGE(2), PGF(2a) and PGI(2) on constriction induced by different mechanisms was studied in the isolated rat mesenteric artery as described by McGregor (1965) Vasoconstriction was induced by mechanisms involving dif modes of calcium utilization viz: (i) Pharmacomechanical pathway by low doses of the adrenergic neurotransmitter, noradrenaline acting at α- receptor; (ii) electromechanical pathway by high potassium and (iii) agents which facilitate Ca(2t) influx e.g. A23187. The prostaglandins potentiated the vasoconstrictor effect of NA. Potentiation factors calculated from different doses of the prostaglandins showed the effects of the prostaglandins to be dose - dependent and PGE(2) to be significantly more potent (P>0.005) than PGF(2a) and PGI(2). The prostaglandins failed to potentiate high potassium - induced vasoconstriction. PGE(2) also failed to potentiate NA if the vasoconstrictor effects were evoked in Ca(2+) - free Krebs solution; but the degree of potentiation increased with increase in the concentration of Ca(2+) ions in the perfusion fluid. This result suggested strongly that the potentiation was associated with external calcium. Evidence is presented to show that potentiation was not prejunctional since cocaine, bretylium and reserpine pretreatment did not materially alter the effect of PGE(2). It was concluded that prostaglandins potentiated NA vasoconstriction by facilitating Ca(2a) influx. The mechanism of this facilitation is discussed. NA vasoconstriction was competitively antagonised by adrenoceptor antagonists-phentolamine, tolazoline, yohimbine and phenoxybenzamine (in low concentrations). The blockade caused by these antagonists was reversed by PGE(2). By comparing NA dose-ratios in the presence of antagonist with dose-ratios in the presence of antagonists plus different doses of PGB(2), I showed 1hat the degree of reversal was related to the dose of PGE. For example, the NA dose - ratio for yohimbine (1.28 x 10(-6)M) was reduced from 26.6 + 0.9 to 1.7 + 0.1 when PGE(2) (2.8 x 10(-8) M)was included in the perfusion fluid with the antagonist. The reverse of antagonism was not due to a change in the binding characteristics of the α- adrenoceptor since pA(2) values for the antagonist were not significantly different (P<0.05) when PGS was included with the antagonists. Evidence is presented which suggests that reversal of antagonism involved utilization of internally bound calcium since reversal of antagonism occured even after the omission of Ca(2+) from the external medium. In this sense, the mechanism of reversal was different from that of potentiation. Furthermore, the degree of reversal (measured as-reversal factor) was quantitatively greater than would be the case if reversal was simply a reflection of the enhgresponsiveness of the vascular muscle to NA. In contrast to the "competitive” α- adrenoceptor antagonists, PGE(2) did not reverse the block of NA vasoconstriction caused by phenoxybenzamine (high doses); verapamil, cinnarizine or prazosin. All these agents caused blockade of NA that was not competitive in nature. Since none of the competitive α- adrenoceptor antagonists prevent prostaglandin formation; the point is made, that a prostaglandin can reverse NA blockade even if the blockade did not involve inhibition of prostaglandin synthesis. Description: A THESIS IN THE DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS SUBMITTED TO THE FACULTY OF MEDICINE IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF IBADAN, IBADAN, NIGERIA