To evaluate the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin or metformin in combination with sulphonylurea.
To examine the clinical safety and effectiveness of insulin aspart (IAsp) therapy in type 2 diabetes (T2D) patients from the ASEAN cohort of the international, 24-week, non-interventional A₁chieve study.
T2D patients from Indonesia, Malaysia, Philippines and Singapore, who started IAsp therapy with or without oral glucose-lowering drugs, were included. The primary endpoint was the incidence of serious adverse drug reactions (SADRs), including major hypoglycaemic events. Secondary endpoints included hypoglycaemia, glycated haemoglobin A1c [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPPG], systolic blood pressure [SBP], body weight and lipids. Quality of life (QoL) was assessed using the EQ-5D questionnaire.
Overall, 312 T2D patients (222 insulin-naive and 90 insulin-experienced) with a mean ± SD age of 56.6 ± 11.2 years, BMI of 24.2 ± 3.9 kg/m(2) and diabetes duration of 7.0 ± 5.7 years were included. The mean daily IAsp dose was 0.51 ± 0.31 U/kg at baseline titrated up to 0.60 ± 0.29 U/kg at Week 24. No SADRs or major hypoglycaemic events were reported in the entire subgroup. The proportion of patients who reported overall hypoglycaemia decreased from baseline to Week 24 (7.1% vs. 0.3%, p < 0.0001). The mean HbA1c improved from 9.5 ± 1.6% at baseline to 7.6 ± 1.3% after 24 weeks (p < 0.001). The mean FPG, post-breakfast PPPG and SBP also improved (p < 0.001). Health-related QoL scores increased in the entire subgroup (mean increase: 9.8 ± 14.6 points, p < 0.001).
Starting IAsp therapy was well-tolerated and was associated with significantly improved overall glycaemic control in the ASEAN cohort.
Mango is a highly perishable seasonal fruit and large quantities are wasted during the peak season as a result of poor postharvest handling procedures. Processing surplus mango fruits into flour to be used as a functional ingredient appears to be a good preservation method to ensure its extended consumption.
Most cases of adenylosuccinate lyase (ADSL OMIM 103050) deficiency reported to date are confined to the various European ethnic groups. We report on the first Malaysian case of ADSL deficiency, which appears also to be the first reported Asian case. The case was diagnosed among a cohort of 450 patients with clinical features of psychomotor retardation, global developmental delay, seizures, microcephaly and/or autistic behaviour. The patient presented with frequent convulsions and severe myoclonic jerk within the first few days of life and severe psychomotor retardation. The high performance liquid chromatography (HPLC) profile of the urine revealed the characteristic biochemical markers of succinyladenosine (S-Ado) and succinyl-aminoimidazole carboximide riboside (SAICAr). The urinary S-Ado/SAICAr ratio was found to be 1.02 (type I ADSL deficiency). The patient was compound heterozygous for two novel mutations, c.445C > G (p.R149G) and c.774_778insG (p.A260GfsX24).
Attention has been paid to neurobehavioral effects of occupational and environmental exposures to chemicals such as pesticides, heavy metals and organic solvents. The area of research that includes neurobehavioral methods and effects in occupational and environmental health has been called "Occupational and Environmental Neurology and Behavioral Medicine." The methods, by which early changes in neurological, cognitive and behavioral function can be assessed, include neurobehavioral test battery, neurophysiological methods, questionnaires and structured interview, biochemical markers and imaging techniques. The author presents his observations of neurobehavioral and neurophysiological effects in Tokyo subway sarin poisoning cases as well as in pesticide users (tobacco farmers) in Malaysia in relation to Green Tobacco Sickness (GTS). In sarin cases, a variety effects were observed 6-8 months after exposure, suggesting delayed neurological effects. Studies on pesticide users revealed that organophosphorus and dithiocarbamate affected peripheral nerve conduction and postural balance; subjective symptoms related to GTS were also observed, indicating the effects of nicotine absorbed from wet tobacco leaves. In addition, non-neurological effects of pesticides and other chemicals are presented, in relation to genetic polymorphism and oxidative stress.
Postmenopausal estrogen deficiency often causes bone density loss and osteoporosis. This study evaluated the effects of an oral administration of oil palm leaf extract (OPL) on bone calcium content and structure, bone density, ash weights, and serum total alkaline phosphatase (T-ALP) of estrogen-deficient ovariectomized (OVX) rats.
BACKGROUND: WHO has targeted that medicines to prevent recurrent cardiovascular disease be available in 80% of communities and used by 50% of eligible individuals by 2025. We have previously reported that use of these medicines is very low, but now aim to assess how such low use relates to their lack of availability or poor affordability.
METHODS: We analysed information about availability and costs of cardiovascular disease medicines (aspirin, β blockers, angiotensin-converting enzyme inhibitors, and statins) in pharmacies gathered from 596 communities in 18 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. Medicines were considered available if present at the pharmacy when surveyed, and affordable if their combined cost was less than 20% of household capacity-to-pay. We compared results from high-income, upper middle-income, lower middle-income, and low-income countries. Data from India were presented separately given its large, generic pharmaceutical industry.
FINDINGS: Communities were recruited between Jan 1, 2003, and Dec 31, 2013. All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low-income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0·14% of households in high-income countries (14 of 9934 households), 25% of upper middle-income countries (6299 of 24,776), 33% of lower middle-income countries (13,253 of 40,023), 60% of low-income countries (excluding India; 1976 of 3312), and 59% households in India (9939 of 16,874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio [OR] 0·16, 95% CI 0·04-0·57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0·16, 0·04-0·55).
INTERPRETATION: Secondary prevention medicines are unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle-income, and low-income countries, which have very low use of these medicines. Improvements to the availability and affordability of key medicines is likely to enhance their use and help towards achieving WHO's targets of 50% use of key medicines by 2025.
FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.
Tamm-Horsfall glycoprotein (THP) and uromodulin are the most abundant glycoproteins in non-pregnant women's/men's and pregnant women's urine, respectively. However, the bioactivities of these glycoproteins are still unclear.
PIP: The findings of the final phase of a 3-phase multivariate areal analysis study undertaken by the Economic and Social Commission for Asia and the Pacific (ESCAP) in 5 countries of the Asian and Pacific Region, including Malaysia, to examine the impact of family planning programs on fertility and reproduction are reported. The study used Malaysia's administrative district as the unit of analysis because the administration and implementation of socioeconomic development activities, as well as the family planning program, depend to a large extent on the decisions of local organizations at the district or state level. In phase 1, existing program and nonprogram data were analyzed using the multivariate technique to separate the impact of the family planning program net of other developmental efforts. The methodology in the 2nd phase consisted of in-depth investigation of selected areas in order to discern the dynamics and determinants of efficiency. The insights gained in phase 2 regarding dynamics of performance were used in phase 3 to refine the input variables of the phase 1 model. Thereafter, the phase 1 analysis was repeated. Insignificant variables and factors were trimmed in order to present a simplified model for studying the impact of environmental, socioeconomic development, family planning programs, and related factors on fertility. The inclusion of a set of family planning program and development variables in phase 3 increased the predictive power of the impact model. THe explained variance for total fertility rate (TFR) of women under 30 years increased from 71% in phase 1 to 79%. It also raised the explained variance of the efficiency model from 34% to 70%. For women age 30 years and older, their TFR was affected directly by the ethnic composition variable (.76), secondary educational status (-.45), and modern nonagricultural occupation (.42), among others. When controlled for other socioeconomic development and environmental indicators, the nonagricultural activities had a positive direct effect on TFR. No direct effects were found to come from other socioeconomic development indicators, once these factors were controlled. The 3 factors that had direct effects on the fertility of women below age 30 were ethnic composition (.33), contraceptive pevalence (-.32), and secondary educational status (-.25). Other family planning program variables (contraceptive knowledge) and socioeconomic development indicators (exposure to modernization as measured by television ownership and health/living conditions as measured by infant mortality rate) affected fertility significantly but indirectly.
PIP: Morality in Peninsular Malaysia has reached a level that is quite similar to that prevailing in the low mortality countries. This article systematically documents changes in mortality levels and differentials in Malaysia over time and relates these to changes in development indicators and health-related policies. Remedial measures undertaken by the authorities including the expansion of hospital and health services into the estates, together with a comprehensive malaria-eradication program, improvements in sanitation laws, and increased provision of public utilities and education, resulted in beriberi being eliminated and the incidence of malaria, typhus, and smallpox being greatly reduced by the time of World War II. The gain in life expectancy over the period of 1957-1979 was greatest for the Malay, the most significant period being 1957-1967, which saw the introduction of rural health programs. The infant mortality rate and the neonatal and post-neonatal rates declined substantially for all ethnic groups in Peninsular Malaysia for the same time period. Although the lower infant mortality of the Chinese can be explained by their advantageous socioeconomic position the same reason cannot explain the lower decline in infant mortality levels of the Indians. Much still needs to be done to narrow, if not to eliminate, the existing mortality differentials of different groups in the country. Overall, the quality of life of the general population can be further enhanced by reducing the high mortality level of disadvantaged groups.
BACKGROUND:Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke.
METHODS:We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals.
FINDINGS: Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001).
INTERPRETATION: Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke.
FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.
Malaysia is a rapidly developing country with a very young population, about 36% of which are below the age of 15 years. The standard of child health has improved greatly. However, there are great changes in the morbidity and mortality patterns of childhood diseases relating mainly to an improved standard of living; availability of safe water supply and adequate sanitary latrines; a higher literacy rate; rapid industrialisation and urban migration. The infant mortality rate has droppedfrom 50.1 per 1,000 livebirths in 1986 to 10.4 in 1995, and similar trends apply also to neonatal, perinatal and toddler mortality rates. Nevertheless, current major child health problems are those relating to events in the perinatal period and to infections. Despite improvements in the standard of neonatal care with the use ofhigh technology, the commonest cause of certified deaths still occur in the neonatal period. A rapid and inexpensive screening test for G6PD deficiency, a disease present in 2-3% of the population, is now widely available and, together with the use of phototherapy is largely responsible for the declining incidence of kernicterus in the country. Infections remain an important cause of morbidity and mortality although their patterns have changed. The very high (>95%) WHO-EPI-vaccines coverage rate is linked to the great reduction in the incidence of diphtheria, pertussis, tetanus, poliomyelitis and measles. Childhood tuberculosis is less common now, with about 250 - 300 reported cases per year and TB meningitis is rare with about 30-40 reported cases/year. The hepatitis B carrier rate is high (5%) and the introduction of routine newborn hepatitis B vaccination in 1989 is expected to have a positive impact as is the immunisation of young girls against rubella introduced in 1985 in reducing the incidence of congenital rubella syndrome. The incidence of malaria has declined but remains prevalent in the interiors of PeninsularMalaysia and in Sabah and Sarawak. Filariasis is largely under control. Unfortunately, despite great efforts at mosquito control, dengue virus infection remains a major problem with thousands of cases reported every year. Children are most susceptible to dengue haemorrhagic fever with many dying from the shock syndrome. The incidence of acute gastroenteritis has also dropped with most cases being due to a viral aetiology. Acute respiratory infections, mostly viral in origin, account for most attendances at paediatric outpatient services. Although staphylococcal and streptococcal impetigo and pneumonia are common, the incidence of streptococcal related diseases like rheumatic fever and acute glomendonephritis is rapidly declining. The nutritional status of children has improved in tandem with the rise in the standard of living, but subclinical malnutrition is prevalent, particularly among urban squatters and the rural poor. There is a disturbing decline in breastfeeding among urban working mothers. Poor weaning practices and food habits are responsible for the common occurrence of nutritional anaemia (5%) among infants and young children. Greater prosperity, rapid industrialisation and urbanisation have resulted in changes in the childhood disease pattern where non-communicable diseases assume greater importance as the problems of malnutrition and infection are gradually overcome. Road traffic accidents are a major killer and home accidents, largely preventable, are an important cause of morbidity and mortality. Childhood cancer, with about 550 new cases a year, is an important cause of death beyond infancy. Major congenital malformations, with a 1% prevalence rate, cause much ill-health. Thalassaemia is a particularly common genetic disease with fl thalassaemia gene frequency of about 5%. The prevalence of asthma is increasing, with a rate of 13.9% in the Kiang Valley but the prevalence of asthma-related symptoms is much higher. Physical, sexual child abuse and neglect, abandoned babies, substance abuse are but signs of stress of modern city living and peoples inability to cope with it. Although the general standard of child health has greatly improved, there are several states where it is still not satisfactory. In Sabah where there is a large illegal immigrant population, the infant mortality and infection rates are relatively high. In Kelantan and Trengganu, it is common for parents to refuse permission for a lumbar puncture required to treat meningitis. Other still deeply entrenched, culturally-related adverse health practices include : a fatalistic attitude to illness; a preference for traditional practitioners of medicine resulting in late treatment; and 'doctor-hopping' with unrealistic expectations of 'instant cure'. Childhood illnesses that are uncommon in Malaysia include: cystic fibrosis, coeliac disease, ulcerative colitis, Crohns disease, Sudden Infant Death Syndrome, Encopresis, enuresis and epiglottitis due to Haemophilus Influen:ae.
A 36-year-old Danish man, living in Asia, was diagnosed with Pneumocystis pneumonia (PCP) and HIV in 2013 (CD4+ count: 6 cells/µL; viral load: 518 000 copies/mL). He initiated combination antiretroviral therapy. Later that year, he was also diagnosed with granulomatosis with polyangiitis and was treated with prednisolone. Despite complete viral suppression and increasing CD4+ count (162 cells/µL), he was readmitted with PCP in April 2015. Subsequently, he returned to Denmark (CD4+ count: 80 cells/µL, viral suppression). Over the following months, he developed progressive dyspnoea. Lung function tests demonstrated severely reduced lung capacity with an obstructive pattern and a moderately reduced diffusion capacity. High resolution computer tomography revealed minor areas with tree-in-bud pattern and no signs of air trapping on expiratory views. Lung biopsy showed lymphocytic infiltration surrounding the bronchioles with sparing of the alveolar septa. He was diagnosed with follicular bronchiolitis. The patient spontaneously recovered along with an improvement of the immune system.
Treatment of drug resistant protozoa, bacteria, and viruses requires new drugs with alternative chemotypes. Such compounds could be found from Southeast Asian medicinal plants. The present study examines the cytotoxic, antileishmanial, and antiplasmodial effects of 11 ethnopharmacologically important plant species in Malaysia. Chloroform extracts were tested for their toxicity against MRC-5 cells and Leishmania donovani by MTT, and chloroquine-resistant Plasmodium falciparum K1 strain by Histidine-Rich Protein II ELISA assays. None of the extract tested was cytotoxic to MRC-5 cells. Extracts of Uvaria grandiflora, Chilocarpus costatus, Tabernaemontana peduncularis, and Leuconotis eugenifolius had good activities against L. donovani with IC50 Malaysia have potentials as a source of chemotypes for the development of anti-infective leads.
BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.
METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.
FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012).
INTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.
The seeds of Swietenia macrophylla King (SM) (Meliaceae) are used as a folk medicine for the treatment of hypertension in Malaysia. However, the antihypertensive and vasorelaxant effects of SM seeds are still not widely studied. Thus, this study was designed to investigate the in vivo antihypertensive effects and in vitro mechanism of vasorelaxation of a 50% ethanolic SM seed extract (SM50) and the fingerprint of SM50 was developed through tri-step Fourier transform infrared (FTIR) spectroscopy. The vasorelaxant activity and the underlying mechanisms of SM50 were evaluated on thoracic aortic rings isolated from Sprague-Dawley rats in the presence of antagonists. The pharmacological effect of SM50 was investigated by oral administration of spontaneously hypertensive rats (SHRs) with three different doses of SM50 (1000, 500, and 250 mg/kg/day) for 4 weeks and their systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were measured weekly using tail-cuff method. The tri-step FTIR macro-fingerprint of SM50 showed that SM50 contains stachyose, flavonoids, limonoids, and ester, which may contribute to its vasorelaxant effect. The results showed that the vasorelaxant activity of SM50 was mostly attributed to channel-linked receptors pathways through the blockage of voltage-operated calcium channels (VOCC). SM50 also acts as both potassium channels opener and inositol triphosphate receptor (IP3R) inhibitor, followed by β2-adrenergic pathway, and ultimately mediated through the nitric oxide/soluble guanylyl cyclase/cyclic 3',5'-guanosine monophosphate (NO/sGC/cGMP) signaling pathways. The treatment of SM50 also significantly decreased the SBP and DBP in SHRs. In conclusion, the antihypertensive mechanism of SM50 was mediated by VOCC, K+ channels, IP3R, G-protein-coupled β2-adrenergic receptor, and followed by NO/sGC/cGMP signaling mechanism pathways in descending order. The data suggested that SM50 has the potential to be used as a herbal medicament to treat hypertension.
1. Diabetes and hypertension are both associated with an increased risk of renal disease and are associated with neuropathies, which can cause defective autonomic control of major organs including the kidney. This study aimed to examine the alpha(1)-adrenoceptor subtype(s) involved in mediating adrenergically induced renal vasoconstriction in a rat model of diabetes and hypertension. 2. Male spontaneously hypertensive rats (SHR), 220-280 g, were anaesthetized with sodium pentobarbitone 7-day poststreptozotocin (55 mg x kg(-1) i.p.) treatment. The reductions in renal blood flow (RBF) induced by increasing frequencies of electrical renal nerve stimulation (RNS), close intrarenal bolus doses of noradrenaline (NA), phenylephrine (PE) or methoxamine were determined before and after administration of nitrendipine (Nit), 5-methylurapidil (5-MeU), chloroethylclonidine (CEC) and BMY 7378. 3. In the nondiabetic SHR group, mean arterial pressure (MAP) was 146+/-6 mmHg, RBF was 28.0+/-1.4 ml x min(-1) x kg(-1) and blood glucose was 112.3+/-4.7 mg x dl(-1), and in the diabetic SHR Group, MAP was 144+/-3 mmHg, RBF 26.9+/-1.3 ml(-1) min x kg(-1) and blood glucose 316.2+/-10.5 mg x dl(-1). Nit, 5-MeU and BMY 7378 blunted all the adrenergically induced renal vasoconstrictor responses in SHR and diabetic SHR by 25-35% (all P<0.05), but in diabetic rats the responses induced by RNS and NA treated with 5-MeU were not changed. By contrast, during the administration of CEC, vasoconstrictor responses to all agonists were enhanced by 20-25% (all P<0.05) in both the SHR and diabetic SHR. 4. These findings suggest that alpha(1A) and alpha(1D)-adrenoceptor subtypes contribute in mediating the adrenergically induced constriction of the renal vasculature in both the SHR and diabetic SHR. There was also an indication of a greater contribution of presynaptic adrenoceptors, that is, alpha(1B)-, and/or alpha(2)-subtypes.
(R)-(+)-Goniothalamin (GTN), a styryl-lactone isolated from the medicinal plant Goniothalamus macrophyllus, exhibits pharmacological activities including cytotoxic and anti-inflammatory effects. In this study, GTN modulated TNF-α induced NF-κB activation. GTN concentrations up to 20 μM showed low cytotoxic effects in K562 chronic myelogenous leukemia and in Jurkat T cells. Importantly, at these concentrations, no cytotoxicity was observed in healthy peripheral blood mononuclear cells. Our results confirmed that GTN inhibited tumor necrosis factor-α (TNF-α)-induced NF-κB activation in Jurkat and K562 leukemia cells at concentrations as low as 5 μM as shown by reporter gene assays and western blots. Moreover, GTN down-regulated translocation of the p50/p65 heterodimer to the nucleus, prevented binding of NF-κB to its DNA response element and reduced TNF-α-activated interleukin-8 (IL-8) expression. In conclusion, GTN inhibits TNF-α-induced NF-κB activation at non-apoptogenic concentrations in different leukemia cell models without presenting toxicity towards healthy blood cells underlining the anti-leukemic potential of this natural compound.