The role of adiponectin in endothelial dysfunction and hypertension.

It has been two decades since the discovery of adiponectin, and today its role in insulin resistance, inflammation, and atherosclerosis are areas of major interest. Production of adiponectin is reduced in all inflammatory processes and states of insulin resistance such as obesity, type 2 diabetes mellitus, and coronary artery disease. Adiponectin regulates carbohydrate metabolism, and may also regulate vascular homeostasis by affecting important signaling pathways in endothelial cells and modulating inflammatory responses in the subendothelial space. Clinical studies have demonstrated a relationship between serum adiponectin concentrations and the activity of the renin-angiotensin-aldosterone system (RAAS), causing changes in blood pressure. Antihypertensive therapy with angiotensin II receptor blockers (ARBs) has been demonstrated to increase adiponectin levels in 3-6 months. Adiponectin has also been shown to play a role in cardiac injury in modulation of pro-survival reactions, cardiac energy metabolism, and inhibition of hypertrophic remodeling. The effects of adiponectin on the cardiovascular system are believed to be partially mediated by the activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and cyclooxygenase-2 (COX-2) pathways, reducing endothelial cell apoptosis, promoting nitric oxide production, decreasing tumor necrosis factor-alpha (TNF-α) activity, and preventing atherosclerotic proliferation and smooth muscle cell migration. Further evaluation of biologically active forms of adiponectin and its receptor should help to clarify how obesity affects the cardiovascular system.

Toxoplasmosis--a global threat. Correlation of latent toxoplasmosis with specific disease burden in a set of 88 countries.

BACKGROUND: Toxoplasmosis is becoming a global health hazard as it infects 30-50% of the world human population. Clinically, the life-long presence of the parasite in tissues of a majority of infected individuals is usually considered asymptomatic. However, a number of studies show that this 'asymptomatic infection' may also lead to development of other human pathologies. AIMS OF THE STUDY: The purpose of the study was to collect available geoepidemiological data on seroprevalence of toxoplasmosis and search for its relationship with mortality and disability rates in different countries. METHODS AND FINDINGS: Prevalence data published between 1995-2008 for women in child-bearing age were collected for 88 countries (29 European). The association between prevalence of toxoplasmosis and specific disease burden estimated with age-standardized Disability Adjusted Life Year (DALY) or with mortality, was calculated using General Linear Method with Gross Domestic Product per capita (GDP), geolatitude and humidity as covariates, and also using nonparametric partial Kendall correlation test with GDP as a covariate. The prevalence of toxoplasmosis correlated with specific disease burden in particular countries explaining 23% of variability in disease burden in Europe. The analyses revealed that for example, DALY of 23 of 128 analyzed diseases and disease categories on the WHO list showed correlations (18 positive, 5 negative) with prevalence of toxoplasmosis and another 12 diseases showed positive trends (p<0.1). For several obtained significant correlations between the seroprevalence of toxoplasmosis and specific diseases/clinical entities, possible pathophysiological, biochemical and molecular explanations are presented. CONCLUSIONS: The seroprevalence of toxoplasmosis correlated with various disease burden. Statistical associations does not necessarily mean causality. The precautionary principle suggests however that possible role of toxoplasmosis as a triggering factor responsible for development of several clinical entities deserves much more attention and financial support both in everyday medical practice and future clinical research.

Antimicrobial properties of honey.

Honey has been widely accepted as food and medicine by all generations, traditions, and civilizations, both ancient and modern. For at least 2700 years, honey has been used by humans to treat a variety of ailments through topical application, but only recently have the antiseptic and antimicrobial properties of honey been discovered. Honey has been reported to be effective in a number of human pathologies. Clinical studies have demonstrated that application of honey to severely infected cutaneous wounds rapidly clears infection from the wound and improves tissue healing. A large number of in vitro and limited clinical studies have confirmed the broad-spectrum antimicrobial (antibacterial, antifungal, antiviral, and antimycobacterial) properties of honey, which may be attributed to the acidity (low pH), osmotic effect, high sugar concentration, presence of bacteriostatic and bactericidal factors (hydrogen peroxide, antioxidants, lysozyme, polyphenols, phenolic acids, flavonoids, methylglyoxal, and bee peptides), and increase in cytokine release, and to immune modulating and anti-inflammatory properties of honey; the antimicrobial action involves several mechanisms. Despite a large amount of data confirming the antimicrobial activity of honey, there are no studies that support the systemic use of honey as an antibacterial agent.

Cytotoxicity of alkaloids isolated from Peganum harmala seeds.

ETHNOPHARMACOLOGICAL RELEVANCE: Peganum harmala is used in traditional medicine to treat a number of diseases including cancer. Our preliminary studies show that the alkaloidal extract of PH seed is cytotoxic to several tumor cell lines in vitro and has antitumor effect in a tumor model in vivo. The present investigation was aimed at extending our previous studies in identifying the components in P. harmala seed-extract responsible for the cytotoxic effects, and study the cytotoxic and antiproliferative activity of isolated alkaloids and total alkaloidal fraction (TAF) in several tumor cell lines. Four alkaloids: harmalicidine, harmine, peganine (vasicine) and vasicinone were isolated from the P. harmala seed-extract and their activity and that of TAF were tested a) for their cytotoxic activity against four tumor cell lines [three developed by us by chemical-induction in Wistar rats: 1) Med-mek carcinoma ; 2) UCP-med carcinoma ; 3) UCP-med sarcoma] ; and 4) SP2/O-Ag14, and b) for antiproliferative effect on cells of Jurkat, E6-1 clone (inhibition of incorporation of {(3)H-thymidine} in cellular DNA). The alkaloids and TAF inhibited the growth of tumor cell lines to varying degrees; Sp2/O-Ag14 was the most sensitive, with IC50 values (concentration of the active substance that inhibited the growth of the tumor cells by 50%) ranging between 2.43 µg/mL and 19.20 µg/mL, while UCP-med carcinoma was the least sensitive (range of IC50 = 13.83 µg/mL to 59.97 µg/mL). Of the substances evaluated, harmine was the most active compound (IC50 for the 4 tumor cell lines varying between 2.43 µg/mL and 18.39 µg/mL), followed by TAF (range of IC50 = 7.32 µg/mL to 13.83 µg/mL); peganine was the least active (IC50 = 50 µg/mL to > 100 µg/mL). In terms of antiproliferative effect, vasicinone and TAF were more potent than other substances: the concentration of vasicinone, and TAF needed to inhibit the incorporation of {(3)H-TDR} in the DNA cells of Jurkat, E6-1 clone by 50% (IC50) were 8.60 ± 0.023 µg/mL and 8.94 ± 0.017 µg/mL, respectively, while peganine was the least active (IC50 >100 µg/mL). The IC50 values for harmalacidine (27.10 ± 0.011 µg/mL) and harmine (46.57 ± 0.011 µg/mL) were intermediate. The harmala alkaloids inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies. Harmine was the most potent in inhibiting cell growth, and vasicinone was most active as antiproliferating substance. The TAF had significant cytotoxic as well as antiproliferating activity.

Hypoglycemic and hypolipidemic effects of Coriandrum sativum L. in Meriones shawi rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of an aqueous extract of coriander (Coriandrum sativum L.; Apiaceae, Umbelliferae) seeds (CS-extract) in Moroccan traditional treatment of diabetes remains to be experimentally validated. AIM OF THE STUDY: The study aim was to investigate potential hypoglycemic (and hypolipidemic) activity of CS-extract after a single oral dose and after daily dosing for 30 days (sub-chronic study) in normal and obese-hyperglycemic-hyperlipidemic (OHH) Meriones shawi rats. MATERIALS AND METHODS: After a single oral dose of CS-extract (20mg/kg; predetermined as optimum), plasma glucose, insulin, total cholesterol (TC), and triglycerides (TG) were measured in normal and OHH rats (hypercaloric diet and forced limited physical activity); glibenclamide (GLB; 2.5mg/kg) was used as reference. In the sub-chronic study, the effect of CS-extract and GLB (at the above doses) on body weight (BW), plasma glucose, insulin, TC, LDL-cholesterol, HDL-cholesterol, TG, urea and creatinine was determined in normal and OHH rats; insulin resistance (IR as HOMA-IR), atherosclerotic and cardioprotective indices were calculated. RESULTS: A single dose of CS-extract or GLB suppressed hyperglycemia in OHH rats, and normo-glycemia was achieved at 6-h post-dose; there was no effect on lipids, TG or insulin, but IR decreased significantly. The hypoglycemic effect was lower in normal rats. In the sub-chronic study in OHH rats, the test substances (CS-extract>GLB) reduced plasma glucose (normoglycemia on Day 21), insulin and IR, TC, LDL-cholesterol, and TG. Atherosclerotic index decreased while cardioprotective indices increased only by CS-extract, with no effect on BW, urea or creatinine. CONCLUSION: Sub-chronic administration of CS-extract in OHH Meriones shawi rats normalized glycemia and decreased the elevated levels of insulin, IR, TC, LDL-cholesterol and TG. Since, the CS-extract decreased several components of the metabolic syndrome and decreased atherosclerotic and increased cardioprotective indices, CS-extract may have cardiovascular protective effect. The present study validates the traditional use of coriander in diabetes.

Advances in the treatment of type 2 diabetes mellitus.

There is a rising worldwide prevalence of diabetes, especially type 2 diabetes mellitus (T2DM), which is one of the most challenging health problems in the 21st century. The associated complications of diabetes, such as cardiovascular disease, peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure, and blindness result in increasing disability, reduced life expectancy, and enormous health costs. T2DM is a polygenic disease characterized by multiple defects in insulin action in tissues and defects in pancreatic insulin secretion, which eventually leads to loss of pancreatic insulin-secreting cells. The treatment goals for T2DM patients are effective control of blood glucose, blood pressure, and lipids (if elevated) and, ultimately, to avert the serious complications associated with sustained tissue exposure to excessively high glucose concentrations. Prevention and control of diabetes with diet, weight control, and physical activity has been difficult. Treatment of T2DM has centered on increasing insulin levels, either by direct insulin administration or oral agents that promote insulin secretion, improving sensitivity to insulin in tissues, or reducing the rate of carbohydrate absorption from the gastrointestinal tract. This review presents comprehensive and up-to-date information on the mechanism(s) of action, efficacy, pharmacokinetics, pleiotropic effects, drug interactions, and adverse effects of the newer antidiabetic drugs, including (1) peroxisome proliferator-activated-receptor-γ agonists (thiazolidinediones, pioglitazone, and rosiglitazone); (2) the incretin, glucagon-like peptide-) receptor agonists (incretin-mimetics, exenatide. and liraglutide), (3) inhibitors of dipeptidyl-peptidase-4 (incretin enhancers, sitagliptin, and vildagliptin), (4) short-acting, nonsulfonylurea secretagogue, meglitinides (repaglinide and nateglinide), (5) amylin anlog-pramlintide, (6) α-glucosidase inhibitors (miglitol and voglibose), and (7) colesevelam (a bile acid sequestrant). In addition, information is presented on drug candidates in clinical trials, experimental compounds, and some plants used in the traditional treatment of diabetes based on experimental evidence. In the opinion of this reviewer, therapy based on orally active incretins and incretin mimetics with long duration of action that will be efficacious, preserve the ß-cell number/function, and block the progression of diabetes will be highly desirable. However, major changes in lifestyle factors such as diet and, especially, exercise will also be needed if the growing burden of diabetes is to be contained.

Acute and sub-chronic toxicity of a lyophilised aqueous extract of Centaurium erythraea in rodents.

ETHNOPHARMACOLOGICAL RELEVANCE: An aqueous concoction made from centaury (Centaurium erythraea (L.) Rafn., (Gentianaceae) whole plant is used in the Moroccan traditional medicine for the treatment of diabetes, as well as a number of other diseases. No systematic study of the potential toxicity of the plant has been described. AIM OF THE STUDY: The present investigation was carried out to evaluate the safety of an aqueous extract of Centaurium erythraea whole plant (CE-extract) by determining its potential toxicity after acute and sub-chronic administration in rats and mice. MATERIALS AND METHODS: For the acute study, the lyophilised CE-extract was administered to adult IOPS OFA mice in single oral doses of 1-15 g/kg given by gavage, and single intraperitoneal (i.p.) doses of 1-14 g/kg. General behavioral adverse effects, mortality, and latency of mortality were determined for up to 14 days. In the sub-chronic dose study, the CE-extract was administered orally at doses of 100, 600 and 1200 mg/kg daily for 90 days to Wistar rats. Body weight and selected biochemical and hematological parameters were determined every 30 days and at the end of 90 days of daily administration; sections of liver and kidney were examined histologically for any signs of organ damage at the end of the treatment. RESULTS: In the acute study in mice, there were no deaths or any signs of toxicity observed after oral administration of single doses of the CE-extract at any dose level up to the highest dose tested (15 g/kg), which was the no-observed-adverse-effect level (NOAEL). However, the mortality rate as well as the acute toxicity of the i.p. administered CE-extract increased progressively with increasing dose. The NOAEL for the i.p. dose was 6 g/kg while the lowest-observed-adverse-effect level (LOAEL) was 8 g/kg; the calculated acute toxicity (LD(50)) of i.p. administered CE-extract in mice was 12.13 g/kg. In sub-chronic studies in rats, the CE-extract (administered orally at daily doses of 100, 600 and 1200 mg/kg for 90 days), did not cause any changes in hematological and biochemical parameters, except a small reduction of mean corpuscular volume, and a decrease in serum glucose and triglyceride levels at the higher doses. Histopathological examination of the liver and kidneys at the end of the study showed normal architecture suggesting no morphological disturbances. CONCLUSIONS: Because of the lack of toxicity of the CE-extract given by the oral route, and relatively high NOAEL values for the i.p. dose in the acute study in mice, as well as lack of mortality or clinically significant adverse changes in the biological and hematological parameters, and the morphology of liver and kidneys in rats after 90 days of daily dosing, it may be concluded that the CE-extract is relatively non-toxic. Also, in view of the doses consumed empirically in traditional medicine in Morocco, there is a wide margin of safety for the therapeutic use of Centaurium erythraea.

Direct renin inhibitors as antihypertensive agents.

Hypertension, a serious disease affecting almost a billion people (25% of adults) worldwide, is a major modifiable risk factor for cardiovascular (CV) and renal disease. Despite numerous advances in the pharmacologic treatment of high blood pressure (BP) and availability of several antihypertensive drugs to treat hypertension, a significant proportion of treated hypertensive patients still have uncontrolled high BP, and thus, face serious morbidity and mortality. Furthermore, it is not sufficient to aim for optimum BP control, but to treat all CV risk factors, protect end-organ damage, prevent progression of disease, and prevent long-range adverse effects of the drugs. Therefore, new therapeutic modalities have to be developed to achieve the above objectives. Some years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiologic effects occur when renin and prorenin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive but molecular modeling was used to develop aliskiren and other renin inhibitors that produce sustained suppression of plasma renin activity after oral administration with a dose-dependent BP. Additional studies will ultimately determine the place of renin inhibition in the treatment of hypertension and related CV disorders.

Hypoglycemic and hypolipidemic effects of an aqueous extract of Chamaerops humilis leaves in obese, hyperglycemic and hyperlipidemic Meriones shawi rats.

ETHNOPHARMACOLOGICAL RELEVANCE: An aqueous concoction made from the leaves of Chamaerops humilis (L.) (dwarf fan palm), is used in the Moroccan traditional medicine for the treatment of diabetes, as well as a number of other diseases. The aim of the study was to experimentally validate the use of C. humilis in the folk treatment of diabetes as well as to determine if the aqueous leaf extract of this plant has hypolipidemic properties in an animal model of obesity, hyperglycemia and hyperlipidemia. The animal model consisted of experimentally induced obesity, hyperglycemia and hyperlidemia (OHH) in Meriones shawi rats. In the acute study, OHH M. shawi rats (n = 8) were given a single oral dose (10 mg/kg) of an aqueous extract of C. Humilis leaves (plant-extract); taurine (8 mg/kg) was used as the positive control. Plasma glucose levels were determined at 2-, 4- and 6-hr after the dose. In the sub-chronic study, groups of OHH rats (n = 8 for each group) were given daily oral doses of the plant-extract and taurine (at the above doses) for 30 days. Body weight (BW), plasma glucose, total cholesterol and triglycerides were measured at 15 and 30 days of dosing. The M. shawi rats developed OHH when maintained on a hypercaloric diet and forced physical inactivity for 90 days. A single oral dose of the plant-extract decreased plasma glucose levels with the maximum effect occurring at 4-hr after the dose (6.88 +/- 1.38 mmol/L compared to baseline 12.04 +/- 0.94 mmol/L; P<0.01). Taurine also decreased plasma glucose (from 12.26 +/- 1.27 mmol/L to 9.15 +/- 1.27 mmol/L; P<0.05); water treated control group did not show any effect. In normal M. shawi (normal) rats, none of the treatments had significant effect on glucose levels. In the sub-chronic study, daily oral administration of the plant-extract or taurine for 30 days to the OHH rats resulted in a significant decrease in BW (from 241 +/- 8 g to 165 +/- 11 g; P<0.001 for the extract, and from 221 +/- 13 g to 189 +/- 11 g; P<0.05 for taurine); water treated control rats showed no effect. In normal rats, administration of the plant-extract or taurine for 30 days resulted in an insignificant decrease in BW, while water administration caused a small (normal) increase in the weight. Plasma glucose levels of the OHH rats decreased significantly with daily dosing with the plant-extract [from baseline 12.04 +/- 0.94 mmol/L to 6.10 +/- 0.27 mmol/L (P<0.05) after 15 days, and to 4.84 +/- 0.22 mmol/L (P<0.001) after 30 days]. Taurine was less effective (P<0.05), while water treated control group did not show any effect. In the normal rats, administration of the plant-extract or taurine for 30 days resulted in a small decrease in glycemia. Administration of plant-extract caused a significant decrease in plasma levels of total cholesterol [from baseline of 3.46 +/- 0.21 mmol/L to 1.05 +/- 0.06 mmol/L (p<0.01) after 15 days and to 0.62 +/- 0.02 mmol/L (p<0.001)] after 30 days, and triglycerides [from baseline of 1.15 +/- 0.17 mmol/L to 0.47 +/- 0.04 mmol/L (p<0.001) after 15 days and to 0.37 +/- 0.03 mmol/L (p<0.001) after 30 days]. Taurine was less effective, while water treated control group did not show any effect. There was no effect of these treatments on lipid levels in normal rats. The results of this study validate the traditional use of the leaves of C. humilis in the treatment of diabetes in Morocco. Since, the aqueous leaf extract also decreased total cholesterol and triglycerides, the plant may also be useful in the management of secondary complications of diabetes (dyslipidemia). Furthermore, the plant may become a good source of antidiabetic medication.

Latent Autoimmune Diabetes in Adults: a case report.

Latent Autoimmune Diabetes in Adults (LADA) is an autoimmune endocrine disorder in which despite the presence of antipancreatic islets antibodies in the moment of diagnostics, the progression to beta-cell secretory insufficiency is slow. It is often confused with others types of diabetes and therefore the management is frequently inadequate. We report a clinical case of a 23-year-old man with diagnosis of type 2 diabetes since 6 months ago, poorly controlled with a sulfonylurea, who initially presented 2 months ago from polyuria, polydipsia, and asthenia and 6 kg weight loss. History of past illness was negative, however, his mother relates exclusive breastfeeding during the first 15 days of life and later (until the 6 months) he was fed with infant formula (S-26). Family history revealed a first-degree relative (father) with diabetes mellitus secondary to steroid administration due to diagnosis of bone marrow hypoplasia. Also presents second-degree family history (uncle and grandfather) of type 2 diabetes mellitus. There were no pathologic findings at the physical examination. Anthropometry and laboratory tests were as follows: body mass index (BMI) = 19.66 kg/m, basal and postprandial glycemia = 108, and 276 mg/dL respectively, glycated haemoglobin = 8.9%, basal and postprandial C-peptide (2 hours) = 1.9, and 3.2 ng/mL, homeostasis model assessment of beta cell function: 87.5%, homeostasis model assessment of insulin resistance: 1.6. LADA presumptive diagnosis was confirmed with presence of autoantibodies anti-tyrosin-phosphatase and GAD65. At the time of diagnosis, individuals with LADA present an onset age <50, BMI <25 kg/m2, low magnitude postprandial and basal hyperglycemia, normal or close to normal C-peptide values, and thus not occur with acute hyperglycemic crises. Insulin therapy preserves pancreatic b-cell function, at the point that eventually prescribed insulin doses need to be reduced.

Ethnopharmacology of the plants of genus Ajuga.

The plants of genus Ajuga are evergreen, clump-forming rhizomatous perennial or annual herbaceous flowering species, with Ajuga being one of the 266 genera of the family Lamiaceae. There are at least 301 species of the genus Ajuga with many variations. These plants, growing in Europe, Asia, Africa, Australia and North America, are used in gardens as ground cover or border for their foliage and beautiful flowers. Many of these plants have been used in traditional medicine as a remedy for fever, toothache, dysentery, malaria, high blood pressure, diabetes, gastrointestinal disorders, as anthelmintic, diuretic and antifungal, anti-inflammatory, and antimycobacterial agents. They are also used as insect growth inhibitor s. A large number of compounds have been isolated from the Ajuga plants, including phytoecdysteroids, neo-clerodane-diterpenes and diterpenoids, triterpenes, sterols, anthocyanidin-glucosides and iridoid glycosides, withanolides, flavonoids, triglycerides and essential oils. These compounds possess a broad spectrum of biological, pharmacological and medicinal properties, such as anabolic, analgesic, antibacterial, antiestrogenic, antifungal, anti-inflammatory, antihypertensive, antileukemic, antimalarial, antimycobacterial, antioxidant, antipyretic, cardiotonic, cytotoxic, hypoglycemic, and vasorelaxing activity, as well as antifeedant and insect growth-inhibitory properties. Thus, genus Ajuga has significant medicinal and economic importance.

Acute and sub-chronic toxicity of an aqueous extract of the leaves of Herniaria glabra in rodents.

AIM OF THE STUDY: The present investigation was carried out to evaluate the safety of an aqueous extract of Herniaria glabra (caryophyllaceae) (HG) plant by determining its potential toxicity after acute and sub-chronic administration in rodents. MATERIALS AND METHODS: For the acute study, a lyophilized aqueous extract of HG plant was administered to adult IOPS OFA mice in single doses of 5-14.5 g/kg given by gavage. General behavior adverse effects and mortality were determined for up to 14 days. In the sub-chronic dose study, the HG-extract was administered orally at doses of 1, 2 and 4 g/kg daily for 90 days to Wistar rats. Selected biochemical and hematological parameters were determined after 30 and 60 days, and then at the end of 90 days of daily administration. RESULTS: In the acute study in mice, the crude aqueous extract of HG plant caused dose-dependent general behavior adverse effects and mortality. The no-observed adverse effect levels (NOAEL) of the HG extract was 5 g/kg and the lowest-observed adverse effect levels (LOAEL) was 5.5 g/kg. Mortality increased with increasing doses: the calculated LD50 was 8.50 +/- 0.42 g/kg in mice. In the sub-chronic study in rats, daily oral administration of the crude HG extract for up to 90 days resulted in a significant attenuation of the normal increase in the body weight. At the highest dose, the HG-extract caused a significant increase in erythrocytes, leukocytes (WBC), platelets, and eosinophils, but it had no effect on the differential WBC counts (lymphocytes, monocytes, neutrophils and basophils). Only at the highest dose, the HG-extract caused a significant increase in serum levels of the liver enzymes, alanine aminotransferase and aspartate aminotransferase, as well as serum creatinine, indicating toxic effect of the high dose of the extract on the liver and kidney. The organ toxicity was confirmed by histopathological examination, which showed centrolobular sinusoidal congestion, disruption of the central vein and hepatocellular necrosis in the liver, and interstitial and intraglomerular congestion, tubular atrophy, and inflammation in the kidney. This study also revealed the hypoglycemic activity of the HG-extract in normoglycemic rats. The suppression of the normal weight gain and the hypoglycemic action of HG-extract should be investigated further for possible therapeutic implications. CONCLUSIONS: Because of the relatively high NOAEL values in the acute study in mice, and lack of mortality or clinically significant changes in the biological (except for hypoglycemia) and hematological parameters in rats after 90 days of daily dosing, it may be concluded that the HG extract does not appear to have significant toxicity (except at high doses). In view of the doses consumed empirically in traditional medicine in Morocco, there is a wide margin of safety for the therapeutic use of Herniaria glabra.

Acute and chronic toxicity of a lyophilised aqueous extract of Tanacetum vulgare leaves in rodents.

AIM OF THE STUDY: The present investigation was carried out to evaluate the safety of an aqueous extract of tansy (Tanacetum vulgare L.) leaves by determining its potential toxicity after acute and chronic administration in rodents. MATERIALS AND METHODS: For the acute study, a lyophilized aqueous extract of tansy leaves was administered to mice in single doses of 0-13 g/kg given by gavage as well as intraperitoneal doses of 0-4.5 g/kg. General behavior adverse effects and mortality were determined for up to 14 days. In the chronic dose study, the extract was administered orally at doses of 0, 100, 300 and 600 mg/kg daily for 90 days to rats. Biochemical and hematological parameters were determined after 30 and 60 days, and then at the end of 90 days of daily administration. RESULTS: In the acute study in mice, the crude aqueous extract of tansy leaves caused dose-dependent general behavior adverse effects and mortality. The no-observed adverse effect levels (NOAEL) of the tansy extract were 7.0 g/kg and 1.0 g/kg, and the lowest-observed adverse effect levels (LOAEL) were 9.0 g/kg and 1.5 g/kg, when given by the oral and intraperitoneal routes, respectively. Mortality increased with increasing doses, with LD(50) of 9.9 g/kg and 2.8 g/kg for the oral and intraperitonal modes of administration, respectively. In the chronic study in rats, daily oral administration of the crude aqueous extract of tansy leaves for up to 90 days did not result in death or significant changes in the biological (except for hypoglycemia) and hematological parameters. CONCLUSIONS: Because of the relatively high NOAEL values in the acute study in mice, and lack of significant effect on biological and hematological parameters in rats after 90 days of daily doses, the tansy extract does not appear to have significant toxicity. In view of the dose of tansy consumed in traditional medicine, there is a wide margin of safety for the therapeutic use of the aqueous extract of Tanacetum vulgare leaves.

Acute diuretic effect of continuous intravenous infusion of an aqueous extract of Coriandrum sativum L. in anesthetized rats.

AIM OF THE STUDY: The present investigation was carried out to evaluate the acute diuretic activity of continuous intravenous infusion of an aqueous extract of the seed of Coriandrum sativum L. Apiaceae (coriander) in rats. MATERIALS AND METHODS: The aqueous extract of coriander seed was administered by continuous intravenous infusion (120 min) at two doses (40 and 100mg/kg) to anesthetized Wistar rats. Furosemide (10mg/kg), a standard diuretic was used as the reference drug. Excretion of water and electrolytes (sodium, potassium and chloride) in urine was measured, and glomerular filtration rate (equal to creatinine clearance) was determined. RESULTS: The crude aqueous extract of coriander seeds increased diuresis, excretion of electrolytes, and glomerular filtration rate in a dose-dependent way; furosemide was more potent as a diuretic and saluretic. The mechanism of action of the plant extract appears to be similar to that of furosemide. CONCLUSIONS: The aqueous extract of coriander seed possesses diuretic and saluretic activity, thus, validating the use of coriander as a diuretic plant in Moroccan pharmacopoeia.

Metabolic syndrome: treatment of hypertensive patients.

Metabolic syndrome (MetSyndr), a constellation of abnormalities [obesity, glucose intolerance, insulin resistance (IR), dyslipidemia (low HDL-cholesterol, high LDL-cholesterol and triglycerides (TG)], and elevated blood pressure (BP)], increases the risk of cardiovascular (CV) disease and premature death. From 10% to 30% of the adult population in industrialized countries has MetSyndr, which effectively predicts the development of type 2 diabetes mellitus (T2D) and CV disease. Because of the complex etiology of MetSyndr, a multi-targeted, integrated therapeutic approach is required to simultaneously treat high BP, obesity, lipid disorders and T2D (if present), to fully protect CV, cerebrovascular and renal systems. If lifestyle modification (weight control, diet, exercise, smoking cessation, moderation of alcohol intake) is ineffective, pharmaco-theraphy should be added to treat simultaneously the lipid- and non-lipid CV risk factors. Patients with HTN and MetSyndr should be started on angiotensin-converting enzyme (ACE) inhibitors, unless contraindicated. The ACE inhibitors and angiotensin receptor blockers (ARBs) reduce the odds of developing new onset T2D and also decrease albuminuria. The ACE inhibitors provide cardioprotective and renoprotective benefits beyond their effect on BP; they also improve IR. The ARBs are renoprotective in addition to being cardioprotective. Long-acting calcium channel blockers are also recommended in hypertensive patients with MetSyndr; these drugs also improve IR. Thiazides (at low doses) and selected ss-blockers can be given to patients with HTN and MetSyndr. Celiprolol in combination with diuretics has a favorable effect on glucose tolerance and IR in patients with HTN and MetSyndr, and spironolactone added to ACE inhibitor or ARB therapy provides additional reno- and CV protective benefits in patients with diabetic nephropathy. Carvedilol, a ss-blocker with vasodilating properties, added to ACE inhibitor or ARB therapy, is effective in preventing worsening of microalbuminuria in patients with HTN and MetSyndr; it also improves IR and glycemic control. Most patients eventually require two or more antihypertensive drugs to reach BP goal. It is recommended that therapy in patients whose BP is more than 20/10 mm Hg above target at diagnosis be initiated with a combination of antihypertensive drugs, administered either as individual drugs or as fixed-dose formulations. Treatment with fixed-dose combinations, such as irbesartan + hydrochlorothiazide provides good BP control in more than two-thirds of hypertensive patients with MetSyndr. Lipid and BP targets are reached in a high percent of patients with HTN and CV disease treated with a combination of amlodipine + atorvastatin. In conclusion, hypertensive patients with the MetSyndr be treated aggressively for each component of the syndrome to provide CV, cerebrovascular and renal protection.

Acute hypoglycemic, hypocholesterolemic and hypotriglyceridemic effects of continuous intravenous infusion of a lyophilised aqueous extract of Ajuga iva L. Schreber whole plant in streptozotocin-induced diabetic rats.

The hypoglycemic and hypolipidemic effect of continuous intravenous infusion of a lyophilised aqueous extract of the whole plant Ajuga iva (L.) Schreber (Labiatae) (AI-extract) was investigated in anesthetized normal and streptozotocin (STZ)-induced diabetic rats. The AI-extract was administered to a group of rats by continuous intravenous infusion for 4 h at a dose of 4.2 microg/min/100 g body weight; another group was infused with taurine, the reference compound, at the same dose. In normal rats, AI-extract infusion had no effect on plasma glucose or triglycerides, but plasma cholesterol levels were significantly decreased (22%; P<0.05). However, taurine infusion produced significant hypoglycemic, hypocholesterolemic and hypotriglyceridemic effects (all changes, P<0.05). In STZ-diabetic rats, AI-extract infusion reduced plasma levels of glucose by 24 % (P<0.05), cholesterol by 35% (P<0.01) and triglycerides by 13% (P<0.05). Infusion with taurine produced a greater fall in plasma glucose (72%, P<0.01), cholesterol (54%; P<0.001) and triglyceride (24%; P<0.001) levels. Our results indicate that intravenously administered AI-extract exerts hypoglycemic and hypolipidemic effects in diabetic rats by mechanism(s) which appear to be similar to that of taurine, which involve insulin sensitization or an insulin-like effect. The identity and the exact mechanism(s) of action of the active component(s) of the AI-extract are not known. Ajuga iva appears to be a useful plant in the therapy of diabetes, a condition in which hyperglycemia and dyslipidemia coexist quite often.

The future of antihypertensive treatment.

Despite progress in recent years in the prevention, detection, and treatment of high blood pressure (BP), hypertension remains an important public health challenge. Hypertension affects approximately 1 billion individuals worldwide. High BP is associated with an increased risk of mortality and morbidity from stroke, coronary heart disease, congestive heart failure, and end-stage renal disease; it also has a negative impact on the quality of life. Hypertension cannot be eliminated because there are no vaccines to prevent the development of hypertension, but, its incidence can be decreased by reducing the risk factors for its development, which include obesity, high dietary intake of fat and sodium and low intake of potassium, physical inactivity, smoking, and excessive alcohol intake. For established hypertension, efforts are to be directed to control BP by lifestyle modification (LSM). However, if BP cannot be adequately controlled with LSM, then pharmacotherapy can be instituted along with LSM. Normalization of BP reduces cardiovascular risk (for cardiovascular death, myocardial infarction, and cardiac arrest), provides renoprotection (prevention of the onset or slowing of proteinuria and progression of renal dysfunction to end-stage renal disease in patients with hypertension, diabetes mellitus types 1 and 2, and chronic renal disease), and decreases the risk of cerebrovascular events (stroke and cognition impairment), as has been amply demonstrated by a large number of randomized clinical trials. In spite of the availability of more than 75 antihypertensive agents in 9 classes, BP control in the general population is at best inadequate. Therefore, antihypertensive therapy in the future or near future should be directed toward improving BP control in treated hypertensive patients with the available drugs by using the right combinations at optimum doses, individually tailored gene-polymorphism directed therapy, or development of new modalities such as gene therapy and vaccines. Several studies have shown that BP can be reduced by lifestyle/behavior modification. Although, the reductions appear to be trivial, even small reductions in systolic BP (for example, 3-5 mm Hg) produce dramatic reduction in adverse cardiac events and stroke. On the basis of the results of clinical and clinical/observational studies, it has been recommended that more emphasis be placed on lifestyle/behavior modification (obesity, high dietary intake of fat and sodium, physical inactivity, smoking, excessive alcohol intake, low dietary potassium intake) to control BP and also to improve the efficacy of pharmacologic treatment of high BP. New classes of antihypertensive drugs and new compounds in the established drug classes are likely to widen the armamentarium available to combat hypertension. These include the aldosterone receptor blockers, vasodilator beta-blockers, renin inhibitors, endothelin receptor antagonists, and dual endopeptidase inhibitors. The use of fixed-dose combination drug therapy is likely to increase. There is a conceptual possibility that gene therapy may yield long-lasting antihypertensive effects by influencing the genes associated with hypertension. But, the treatment of human essential hypertension requires sustained over-expression of genes. Some of the challenging tasks for successful gene therapy that need to be mastered include identification of target genes, ideal gene transfer vector, precise delivery of genes into the required site (target), efficient transfer of genes into the cells of the target, and prompt assessment of gene expression over time. Targeting the RAS by antisense gene therapy appears to be a viable strategy for the long-term control of hypertension. Several problems that are encountered in the delivery of gene therapy include 1) low efficiency for gene transfer into vascular cells; 2) a lack of selectivity; 3) problem in determining how to prolong and control transgene expression or antisense inhibition; and 4) difficulty in minimizing the adverse effects of viral or nonviral vectors. In spite of the hurdles that face gene therapy administration in humans, studies in animals indicate that gene therapy may be feasible in treating human hypertension, albeit not in the near future. DNA testing for genetic polymorphism and determining the genotype of a patient may predict response to a certain class of antihypertensive agent and thus optimize therapy in individual patients. In this regard, there are some studies that report the effectiveness of antihypertensive therapy based upon the genotype of selected patients. Treatment of human hypertension with vaccines is feasible but is not likely to be available in the near future.

Effect of losartan therapy on endothelial function in hypertensive patients.

The aim of the study was to evaluate the effect of losartan therapy on endothelial function by measuring serum nitric oxide (NO) levels and urinary excretion of NO in patients with essential hypertension. A group of 30 untreated stage 2 hypertensive patients (15 males and 15 females; age, 51.3 +/- 1.5 years) were included in the study. Office systolic and diastolic blood pressure (BP) was measured by using a mercury sphygmomanometer according to phase I and V of Korotkoff sounds. NO levels in serum and 24-hour urine were determined at baseline and after 6 weeks of daily dosing with losartan (50-100 mg). Losartan therapy resulted in a significant fall in systolic/diastolic BP (from 169.7 +/- 4.1/105 +/- 1.8 mm Hg at baseline to 146 +/- 2.7/91 +/- 1.9 mm Hg at the end of losartan treatment; P < 0.001). The therapy also caused significant increases in both serum NO level (32.74 +/- 3.01 microM/L at baseline versus 79.04 +/- 5.17 microM/L; P < 0.001 after therapy) and urinary NO excretion (58.21 +/- 3.72 microM/L at baseline versus 113.21 +/- 8.63 microM/L; P < 0.001 after therapy). Losartan therapy also reduced serum malondialdehyde (MDA), which is a measure of oxidative stress, by 0.201 nM (15.3%; P = 0.009). Losartan at a dose of 50 to 100 mg per day was effective in reducing elevated BP. The increase in serum NO levels and urinary NO excretion and a decrease in serum MDA levels by losartan treatment indicate a reduction in oxidative stress and enhances NO availability, both of which improve endothelial function. Thus, losartan therapy improves endothelial function in hypertensive patients with essential hypertension.

Update of diuretics in the treatment of hypertension.

Diuretics, which are primarily used to modify the volume and the composition of body fluids, are widely used to treat hypertension. The diuretics include a) the thiazides and thiazide-like agents, which are the most common drugs used to treat high blood pressure (these drugs inhibit sodium reabsorption in the early distal convoluted tubule); b) loop diuretics, such as furosemide, block chloride and sodium reabsorption by inhibition of the Na/K/2Cl cotransport system in the thick ascending limb of the loop of Henle; and c) potassium-sparing (retaining) diuretics, including aldosterone receptor blockers (such as spironolactone and eplerenone) and epithelial sodium channel blockers (such as amiloride and triamterene, which interfere with the reabsorption of sodium and excretion of potassium and hydrogen that takes place in the late distal tubule, the connecting tubule, and the cortical collecting duct). Hydrochlorothiazide 12.5 mg once daily or equivalent low dosages of other similar agents reduce blood pressure in approximately one-half to two-thirds of patients who are responsive to this class of drugs; higher doses add little to the effect on blood pressure and also increase side effects. Some combinations of very small doses of thiazide diuretics - for example, 6.25 mg hydrochlorothiazide or 0.625 mg indapamide, with a low dose of an antihypertensive drug of a different class - have average antihypertensive efficacy when used once daily. Furosemide is used in patients with renal failure or severe heart failure and is best given by continuous intravenous infusion. The potassium-sparing diuretics are generally used in combination with thiazide diuretics to treat hypertension. Side effects occur at about the same frequency and severity with equipotent doses of all diuretics. The incidence of side effects is dose-dependent and also increases as a function of the duration of the renal excretory and antihypertensive actions. However, longer-acting diuretics provide better 24-hour control of blood pressure and increase compliance and adherence to the treatment regimen.