Peroxynitrite stimulates pulmonary artery endothelial and smooth muscle cell proliferation: involvement of ERK and PKC.

BACKGROUND: There is evidence that peroxynitrite is generated in pulmonary hypertension and we have therefore investigated whether peroxynitrite can cause proliferation of pulmonary artery cells. METHODS: Bovine pulmonary artery endothelial (PAEC) and smooth muscle cells (PASMC) were exposed to peroxynitrite solution or to the peroxynitrite generating compound, 3-morpholinosydnonimine (SIN-1). Vascular cell proliferation was determined by cell count and (3)H-thymidine incorporation. Protein biochemistry was by western blot analysis. RESULTS: Transient exposure to peroxynitrite stimulated the proliferation of PASMC (peroxynitrite 0.2 nM-2 µM) and PAEC (peroxynitrite 0.2 µM). Peroxynitrite 0.2 µM stimulated DNA synthesis in PASMC cell by 200 ± 22% and in PAEC by 137 ± 4%. DNA synthesis in PAEC and PASMC was also stimulated by the peroxynitrite generator SIN-1 2 µM. Cell proliferation was accompanied by activation of ERK, which peaked at 15 min and remained elevated for 12 h in PASMC. However peroxynitrite at the concentrations used in this study did not activate the stress pathways p38 mitogen activated protein kinase (MAPK) or Jun N-terminal kinase (JNK). Peroxynitrite-induced proliferation and ERK phosphorylation in PASMC were abolished by the peroxynitrite scavenger ebselen 5 µM. Peroxynitrite-induced proliferation and extracellular signal-regulated kinase (ERK) phosphorylation in PASMC was prevented by selective inhibitors of MAP kinase kinase (MEK) (U0126 5 µM, PD98059 50 µM), Raf-1 (Raf-1 kinase inhibitor 10 µM), Ras (FPT II and FPT III 10 µM) and protein kinase C (PKC) (GF109203X 10 µM). Inhibition of EGF or PDGF receptor signaling using AG-1296, AG-1478 or imatinib prevented peroxynitrite-induced cell proliferation and ERK phosphorylation in PASMC. CONCLUSION: Peroxynitrite can stimulate proliferation of pulmonary artery cells, involving ERK, PKC and EGF or PDGF receptors.

Positive benefits of a pharmacist-managed hypertension clinic in Nigeria.

OBJECTIVE: The aim of this study was to determine whether the provision of further practice-based support by pharmacists will bring about improved outcomes for blood pressure (BP) control in middle-aged and elderly Nigerian hypertensive patients managed with combination diuretics (amiloride hydrochloride 5 mg+hydrochlorothiazide 50 mg) and/or methyl dopa at the primary care level. DESIGN AND SETTING: This was a 1-year prospective, randomized cohort study of the outpatients of a state comprehensive health centre in South-western Nigeria. Free primary health services including free drugs were provided for all patients. PATIENTS AND METHOD: The study population comprised 51 Nigerian patients with uncomplicated hypertension aged 45 years or more, with a 0.2-3.0-year history of hypertension, registered at the Comprehensive Health Centre, Ife between October 2002 and March 2003. They were invited into the pharmacist-managed hypertension clinic and followed for the study period. Participating pharmacists counselled for current medication, personalized goals of lifestyle modification stressing weight loss and/or increased activity, increased patient awareness by providing relevant education about hypertension and associated/related diseases, adjusted drug therapy to optimize effectiveness and minimize adverse events, utilized treatment schedules that enhanced patients' adherence to therapy, and monitored treatment outcomes between enrollment and return visits. Patient satisfaction and the number of treatment failures within 6 months post enrollment were compared with retrospective data from our earlier study involving physician-managed patients under a similar setting. RESULTS: Uncontrolled BP reduced from 92 to 36.2% by 10.15+/-5.02 days after enrollment. Treatment failures were observed at 5.9% of the total return visits (n=184) within 6 months. CONCLUSION: Pharmacist-managed hypertension clinics can improve BP control, reduce treatment failure and increase patient satisfaction.

Prevalence of Hypertension in a University Community in South West Nigeria

A worksite study of hypertension prevalence was carried out in a university community in Southwestern Nigeria. Overall crude prevalence was 21% in the respondent population. About 16% of these were already on treatment with medicines. The study established no significant (p>0.05) relationship between coffee consumption and hypertension.Prevalence was 32% in subjects with over 3 children, while among subjects witheye problem, diabetics and those who took local kola nutsand it was 18.6%, 1.9% and 7.4%, respectively. There is need for increased awareness of the disease and other cardiovascular risk factors within the populace and to encourage the possession or provision of self-measurement blood pressure devices

Malaria Prevention: Knowledge, Attitude And Practice In A Southwestern Nigerian Community

Assessing and analyzing local malaria problems are a prerequisite for successful control interventions. We sought to assess the knowledge of the symptoms of malaria, attitude towards preventive measures as well as treatment seeking behaviors among members of the Ile-Ife community in southwestern Nigeria.A cross sectional study was carried out using a questionnaire, which was self or researcher administered to community members of semi-urban Ile-Ife.Analysis of "what respondents will do first" during malaria attack showed that 35.5%, 0.9% and 13.4% of respondents will use synthetic anti-malarials, consult a herbalist and use local herb, respectively, while 27.3%, 1.7% and 18.2% will go to the hospital, take spiritual/ritual waters for cure and just pray, respectively, with 3.0% of the respondents indicating that they will ignore the signs. Factors influencing respondents' choice of malaria treatment and preventive methods included cost, religious beliefs, perceived safety, convenience and respondents' state of health for 22.7%, 5.4%, 20.8%, 26.5% and 24.6% of the respondents, respectively. The use of insecticide impregnated net are uncommon amongst the respondents (0%). Treatment seeking practice in malaria was related to level of education and religion. We found that convenience and the severity of the disease affected respondents' choice of treatment in more than 50% of the cases. We suggest that malaria public enlightenment efforts should be intensified, effective malaria preventive methods be made affordable and that support be provided to make malaria treatments at public hospitals free

Effects of autacoid inhibitors and of an antagonist on malaria infection in mice

The effects of p-chlorophenylalanine, an inhibitor of serotonin synthesis, indomethacin, an inhibitor of prostaglandin synthesis, cyproheptadine, a serotonin, bradykinin and histamine antagonist, were assessed separately and in combination with chloroquine (CQ) in Vom strains of Swiss albino mice (18-22 g) of either sex infected intraperitoneally with 1 x 10(7) Plasmodium yoelii nigeriensis-induced malaria. As prophylactic, these agents reduced from 31.9 ± 4.5 to 16.1 ± 8.1 percent the level of parasitemia relative to control but had no appreciable activity as curative agents when administered subcutaneously once daily for 4 days after 72 h of parasites innoculum in vivo. However, CQ alone and the combination of these agents with CQ in curative and prophylactic treatments significantly reduced (from 50.3 ± 5.8 to 4.9 ± 0.75 percent) the level of parasitemia (P < 0.05), which was taken only once 72 h after the parasites innoculum. The prophylactic result was shown to produce better results than the curative treatment. The data indicate that inhibitors and an antagonist can reduce the parasitemia load (the extent of damage and the severity of infection) as well as enhance the effects of CQ when combined with it for malaria therapy. The study reveals that the production of autacoids in established infection renders autacoid inhibitors and an antagonist ineffective for radical cure in malarial mice; however, selective inhibition of local hormones implicated in the pathological manifestations of malaria infection by autacoid inhibitors and an antagonist may be a possible pathway to reduce the severity of infection and the associated tissue damage and to enhance the efficacy of available anti-malarials.

Effects of autacoid inhibitors and of an antagonist on malaria infection in mice.

The effects of p-chlorophenylalanine, an inhibitor of serotonin synthesis, indomethacin, an inhibitor of prostaglandin synthesis, cyproheptadine, a serotonin, bradykinin and histamine antagonist, were assessed separately and in combination with chloroquine (CQ) in Vom strains of Swiss albino mice (18-22 g) of either sex infected intraperitoneally with 1 x 10(7) Plasmodium yoelii nigeriensis-induced malaria. As prophylactic, these agents reduced from 31.9 +/- 4.5 to 16.1 +/- 8.1% the level of parasitemia relative to control but had no appreciable activity as curative agents when administered subcutaneously once daily for 4 days after 72 h of parasites innoculum in vivo. However, CQ alone and the combination of these agents with CQ in curative and prophylactic treatments significantly reduced (from 50.3 +/- 5.8 to 4.9 +/- 0.75%) the level of parasitemia (P < 0.05), which was taken only once 72 h after the parasites innoculum. The prophylactic result was shown to produce better results than the curative treatment. The data indicate that inhibitors and an antagonist can reduce the parasitemia load (the extent of damage and the severity of infection) as well as enhance the effects of CQ when combined with it for malaria therapy. The study reveals that the production of autacoids in established infection renders autacoid inhibitors and an antagonist ineffective for radical cure in malarial mice; however, selective inhibition of local hormones implicated in the pathological manifestations of malaria infection by autacoid inhibitors and an antagonist may be a possible pathway to reduce the severity of infection and the associated tissue damage and to enhance the efficacy of available anti-malarials.

Is Berlina grandiflora (Leguminosae) toxic in rats?

The toxicity profile of the aqueous methanolic extract of Berlina grandiflora (BG) stem bark was studied in rats. The rats were administered graded doses (125-500 mg/kg p.o) of the extract daily for 21 days and the effects on body weight, organ weight, clinical signs, gross pathology, hematology, histology and serum biochemical parameters were measured. The relative weights of the heart, liver, kidneys and lungs of treated rats were unaffected but there were significant changes in the relative weights of the spleen and testes. The packed cell volume and hemoglobin concentrations were slightly reduced whereas total leucocytes counts were increased remarkably. Alkaline phosphatase and Creatine Kinase levels were reduced in all the groups but Glutamate oxaloacetate was significantly elevated. Total proteins and albumin levels remained normal. BG elicited a significant increase in gamma glutamyl transferase concentrations at 250 mg/kg. No significant changes occurred in urea, uric acid and BUN concentrations but calcium levels shot up remarkably. Histological findings did not reveal any treatment-related effects. The acute toxicity LD50 was estimated to be >2000 mg/kg but dose-related mortality rates of 16.7, 33.4 and 50% were observed during the sub-acute toxicity studies. These findings have once more highlighted the limitations of acute toxicity LD50 testing and suggest that BG may exert varied toxicological effects when administered orally in rats.

Studies on the acute and sub-chronic toxicity of the essential oil of Ocimum gratissimum L. leaf.

Oral and intra-peritoneal acute toxicity and the sub-chronic intra-peritoneal toxicity of the essential oil of Ocimum gratissimum Linn, Lamiaceae (Ocimum oil), was investigated. The acute toxicity test involved the oral and intra-peritoneal administration of graded doses of Ocimum oil prepared as a 4% v/v emulsion to 2 groups each of 30 rats and mice. LD50 and LD100 were determined for both routes and species. In the sub-chronic toxicity study, 25 male Sprague-Dawley rats were randomized into 4 test groups (treated with three graded sub-lethal doses of Ocimum oil prepared as a 4% v/v emulsion) and a control. Organs and blood samples were taken for analyses after a 30 day treatment period. A dose-dependent sedative effect of Ocimum oil was observed during the acute toxicity study in mice and rats and in the sub-chronic test in rats. Evidence of treatment, route, and dose-dependent toxicity were detected in both studies. Changes in weight of the testes, hearts, kidneys, intestines and lungs of the rats were statistically insignificant (ANOVA P < 0.05). Data analyses of blood biochemical, haematological and histopathological findings showed significant differences between control and treated groups and revealed that Ocimum oil is capable of invoking an inflammatory response that transits from acute to chronic on persistent administration. While the study revealed that Ocimum oil might be better tolerated when administered orally for systemic delivery, the oil has toxic potentialities that should not be overlooked.

An investigation into the wound-healing properties of essential oil of Ocimum gratissimum linn.

OBJECTIVE: To investigate the effects of Ocimum oil and two antibacterial preparations, Cicatrin (GlaxoWellcome) and Cetavlex (AstraZeneca), on the healing of full-thickness excisional and incisional wounds, created under anaesthesia, on the back of test and control groups of adult albino rabbits. METHOD: Treatment was by topical application of the test substances onto the wound surface for 15 days. Observation continued for a further six days. Quantitative parameters of wound healing were determined daily. Swabs were taken from wound sites that appeared not to be healing for identification of wound contaminants and sensitivity tests. RESULTS: There was a marked enhancement in the inflammatory and proliferative phases of wound healing in the rabbits treated with Ocimum oil, suggesting that the oil facilitated the healing process to a greater extent than the control and reference products. Wounds treated with Cetavlex showed no sign of healing for eight days but responded to Ocimum oil after a three-day wash-out period. CONCLUSION: The essential oil Ocimum gratissimum can promote wound healing. However, large studies will need to be carried out using domestic pigs, followed by clinical trials on human wounds. DECLARATION OF INTEREST: None.

Managing hypertension with combination diuretics and methyldopa in nigerian blacks at the primary care level.

OBJECTIVE: To gain insight into the control of hypertension and to suggest possible interventions within a selected black population treated with combination diuretics (amiloride 5mg + hydrochlorothiazide 50mg) and/or methyldopa for uncomplicated essential hypertension. DESIGN AND SETTING: A 2-year retrospective cohort review of the outpatient medical records of a State Comprehensive Health Center in southwestern Nigeria. Free primary health service, including free drugs, is provided in the health facility for all patients. PATIENTS AND METHODS: The study population included outpatients continuously registered at the health centre between June 1999 and June 2002, aged >/=36 years, with 2-6 months' history of hypertension or newly diagnosed hypertension and followed for 6 months after diagnosis. They were managed with methyldopa 250mg and/or combination diuretics (amiloride 5mg + hydrochlorothiazide 50mg) or a combination in two different regimens for at least 6 months. Participating physicians measured patients' blood pressure with a validated device and recorded demographics and medical history. Patients were considered to have hypertension if systolic blood pressure was >140mm Hg and diastolic blood pressure was >90mm Hg. RESULTS: Bivariate regression analysis revealed that systolic blood pressure contributed moderately to the variances of drug and regimen decisions. Among the 128 hypertensive patients with average and modal ages of 57.2 +/- 11.1 and 60 years, respectively, only 37.5% had controlled blood pressure after the first treatment; with 10.2% and 4% of the study population needing, respectively, three and five re-treatments within 6 months to achieve target blood pressure levels. CONCLUSION: A high percentage of uncontrolled blood pressure and re-treatment rates were observed within the study population. A more aggressive management strategy that individualises diuretic therapy by titrating dose to systolic blood pressure and prioritises lifestyle modification in middle-aged and elderly black hypertensive patients is suggested.