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Item DETERMINANTS OF RESPONSES TO ANTIMALARIAL DRUGS IN CHILDREN WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA(2011-05) SIJUADE, A.ODrug 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.Item EVALUATION OF THE ANTIPSYCHOTIC PROPERTY OF MORIN AND ITS MECHANISMS OF ACTION IN EXPERIMENTAL MICE(2018-06) BEN-AZU, B.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.Item Do Frequent Antenatal Care Visits Ensure Access and Adherence to Intermittent Treatment of Malaria in Pregnancy in an Urban Hospital in South West Nigeria?(2013-09) Olorunda, D. C; Ajayi, I. O; Falade, C. OThe relationship of antenatal clinic (ANC) attendance and factors that could affect intermittent preventive treatment (IPT) uptake among 339 parturient women was examined. Respondents were enrolled over a period of three months in a secondary healthcare facility within 24 hours of delivery. Demographic details, delivery and antenatal history, insecticide treated net (ITN) use, and history of IPTp-Sulfadoxine-Pyrimethamine (SP) use in the index pregnancy were recorded. Finger and heel pricks blood samples from mothers and neonates respectively were used to detect malaria parasitaemia and to determine packed cell volume (PCV). Median number of ANC visits made by the enrollees was 4.0 (IQR=2.0) with a range of 1-20 visits. Two hundred and eleven (62.2%) enrollees made ≥4 ANC visits. Primigravidae [70 (40.7%)] were more likely than multigravidae [67 (38.4%)] to make their first antenatal visits in the second trimester. Eighty-eight (26.0%) received at least one dose of IPT-SP while 17 (5.0%) received the recommended two doses (first dose after the first trimester and a month later). Adherence increased with the number of ANC visits. Adherence was significantly higher among those who had ≥4 ANC visits compared with those who had <4 ANC visits. Directly observed therapy (DOT) was reported in 35.3%. The main reasons given for not taking two doses of SP were: that SP was administered once, 27 (38.1%) and reasons unknown, 14 (19.7%). In this study, there was low IPT-SP uptake and adherence. Adequate supervision of health workers as well as health education of pregnant women is needed to encourage adherence to IPTp-SP.Item NEUROPHARMACOLOGICAL PROPERTIES OF ETHANOL EXTRACT OF Adenopus breviflorus (ROBERTY)FRUIT IN MICE(2014-06) OYEDEJI, K. O.Adenopus breviflorus is a perennial climber used locally as an anti-convulsant, sedative and pain-killer in West Africa. Several studies have reported gastrointestinal, reproductive and anti-microbial effects of extracts of Adenopus breviflorus, but there is dearth of information on its neurological effect. This study was therefore designed to investigate effect of Ethanol Extract of Adenopus breviflorus (EEAB) on central nervous system in mice. Three hundred gram of air-dried Adenopus breviflorus fruits were cold macerated in 70% ethanol and concentrated using rotary evaporator. One hundred and ninety-two Swiss male albino mice (20-25 g) were divided into control (distilled water), EEAB-treated (62.5, 125, 250, 500, 1000, 2000 mg/kg, p.o.) and diazepam-treated (2.0 mg/kg) groups (8 per group) for neurobehavioural studies; fifty-six mice(20-25 g) (8 per group) were used to evaluate mechanisms of action using different antagonists (0.5 mg/kg atropine, 0.5 mg/kg cyproheptadine, 0.2 mg/kg haloperidol, 2.0 mg/kg naloxone, 0.2 mg/kg propranolol and 1.0 mg/kg yohimbine). Sixty-four mice (20-25 g) were divided into control and EEAB-treated groups (62.5, 125, 250, 500, 1000, 2000 mg/kg, p.o.) (8 per group) for Y-maize test. One hundred and sixty mice (20-25 g) (8 per group) were divided into control and EEAB-treated groups (250, 500, 1000, 2000 mg/kg, p.o.) for analgesic study; 32 mice (8 per group) were used to evaluate mechanism of action using naloxone (2 mg/kg). Neurobehavioural studies were carried out using novelty-induced rearing, grooming and locomotor activity in open-field. Head dips rate was determined using hole-board. Effect on memory was performed using Y-maze test. Analgesic activity was carried out using hot plate, tail immersion, formalin and acetic acid-induced writhing tests. Data were analysed using descriptive statistics and ANOVA at p=0.05. The EEAB (250-2000 mg/kg) significantly decreased rearing (86.6+2.1, 84.6+2.7, 62.8+2.4, 23.6+2.8, relative to control 131.2+2.9). Diazepam also significantly decreased rearing (11.0+2.6 relative to control 131.2+2.9). The EEAB (62.5-2000 mg/kg) significantly decreased grooming, locomotor activity and head dips relative to controls (32.8-8.0 versus 36.2+2.6, 77.8-29.8 versus 121.0+3.4 and 15.0-6.8 versus 32.6+1.8 respectively). Diazepam also significantly decreased grooming, locomotor activity and head dips relative to controls (14.4+1.7 versus 36.2+2.6, 49.6+1.3 versus 121.0+3.4 and 6.2+1.1 versus 32.6+1.8 respectively). Three antagonists (2 mg/kg naloxone, 0.2 mg/kg propranolol, 1.0 mg/kg yohimbine) reversed effect of EEAB (2000 mg/kg) on rearing relative to controls (112.4+2.9 versus 131.2+2.9, 113.8+2.8 versus 131.2+2.7 and 110.4+1.3 versus 131.2+2.7 respectively). The EEAB (62.5-2000 mg/kg) significantly increased memory (65.4+1.8, 66.0+2.9, 66.6+1.6, 68.4+2.3, 74.2+2.1, 77.6+2.9 relative to control 58.2+2.7). The EEAB (250-2000 mg/kg) significantly increased reaction time (min) to thermal stimulus of hot plate (2.2+0.2, 2.8+0.4, 2.80+0.4, 3.6+0.3 relative to control 1.0+0.0) and hot water (2.8+0.3, 2.8+0.3, 3.4+0.4, 20.0+0.1 relative to control 1.0+0.0). The EEAB (250-2000 mg/kg) also significantly reduced acetic acid-induced writhes (33.6+1.1, 15.8+1.1, 13.8+0.9, 4.0+0.5 relative to control 41.4+1.8) and decreased paw-licking time (sec) in formalin-induced neurogenic pain (44.0+2.6, 38.2+2.8, 27.6+2.8, 4.6+0.6 relative to control 76.0+3.7) which were all reversed by naloxone (2 mg/kg). Adenopus breviflorus had central nervous system depressant and analgesic effects which could be mediated via µ-receptor, β and α2- adrenergic receptors.