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Context Various herbal medicines are thought to be useful in the management of cardiometabolic disease and its risk factors. Ganoderma lucidum (Curtis) P. Karst. (Ganodermataceae), also known as Lingzhi, has received considerable attention for various indications, including some related to the prevention and treatment of cardiovascular and metabolic disease by ameliorating major cardiovascular risk factors. Objective This review focuses on the major studies of the whole plant, plant extract, and specific active compounds isolated from G. lucidum in relation to the main risk factors for cardiometabolic disease. Methods References from major databases including PubMed, Web of Science, and Google Scholar were compiled. The search terms used were Ganoderma lucidum, Lingzhi, Reishi, cardiovascular, hypoglycaemic, diabetes, dyslipidaemia, antihypertensive, and anti-inflammatory. Results A number of in vitro studies and in vivo animal models have found that G. lucidum possesses antioxidative, antihypertensive, hypoglycaemic, lipid-lowering, and anti-inflammatory properties, but the health benefits in clinical trials are inconsistent. Among these potential health benefits, the most compelling evidence thus far is its hypoglycaemic effects in patients with type 2 diabetes or hyperglycaemia. Conclusions The inconsistent evidence about the potential health benefits of G. lucidum is possibly because of the use of different Ganoderma formulations and different study populations. Further large controlled clinical studies are therefore needed to clarify the potential benefits of G. lucidum preparations standardised by known active components in the prevention and treatment of cardiometabolic disease.

Purpose: This study was performed to investigate the effects of common polymorphisms in CYP2D6 and CYP3A5 on the plasma concentrations and antihypertensive effects of bisoprolol in hypertensive Chinese patients.Methods: One hundred patients with essential hypertension were treated with open-label bisoprolol 2.5 mg daily for 6 weeks. Clinic blood pressure (BP) and ambulatory BP (ABP) were measured after the placebo run-in and after 6 weeks treatment. Peak plasma concentrations of bisoprolol were measured at 3 h after the first dose and 3 h after the dose after 6 weeks treatment. Trough levels were measured before the dose after 6 weeks treatment. Bisoprolol plasma concentrations were measured with a validated liquid chromatography tandem mass spectrometry method. Six common polymorphisms in CYP2D6 and the CYP3A5*3 polymorphism were genotyped by TaqMan® assay.Results: After 6 weeks of treatment, clinic BP and heart rate were significantly reduced by 14.3 ± 10.9/8.4 ± 6.2 mmHg (P < 0.01) and 6.3 ± 7.6 BPM (P < 0.01), respectively. Similar reductions were seen in ABP values. Bisoprolol plasma concentration at 3 h after the first dose and 3 h post-dose after 6 weeks of treatment were significantly associated with baseline body weight (P < 0.001) but there was no significant effect of the CYP2D6 and CYP3A5 polymorphisms on these or the trough plasma concentrations. There was no significant association of the CYP2D6 and CYP3A5 polymorphisms or plasma bisoprolol concentrations with the clinic BP or ABP responses to bisoprolol.Conclusion: Bisoprolol 2.5 mg daily effectively reduced BP and HR. The common polymorphisms in CYP2D6 that were examined and the CYP3A5*3 polymorphism appear to have no benefit in predicting the hemodynamic response to bisoprolol in these patients.

Background Ambulatory blood pressure monitoring (ABPM) is important in evaluating average 24-hour blood pressure (BP) levels, circadian rhythm, sleeping BP and BP variability but many patients are reluctant to use standard ABPM devices. Methods We compared two validated ABPM devices, the BPro tonometric wrist monitor and the A&D TM-2430 oscillometric upper arm monitor, for agreement of recordings and acceptability in 37 hypertensive patients (aged 55±9 years). Results Successful BP measurements were less frequent with the wrist-type than the arm-type device during the sleeping (66.3% vs. 92.9%, P P P Conclusions Despite the difference in individual BP measurements and the systematic overestimation of DBP values with the BPro device, wrist monitors with good patient acceptability may be useful to facilitate ABPM in some patients to provide additional information about cardiovascular risk and response to antihypertensive therapies.

Bilberry (Vaccinium myrtillus L.) is one of the richest natural sources of anthocyanins which are powerful antioxidants and reported to have antiinflammatory, antidyslipidemic, antihypertensive, and hypoglycemic effects. The objective of this study was to assess the effect of bilberry supplementation on biomarkers of glycemic control, lipid profile, antioxidant, and inflammatory status in patients with type 2 diabetes in a randomized, double-blind, placebo-controlled cross-over study. Twenty patients were randomized to receive either bilberry supplementation (1.4 g/day of extract) daily for 4 weeks followed by 6 weeks of washout and then an additional 4 weeks of matching placebo or vice versa. Blood pressure, metabolic parameters, antioxidant status, and oxidative stress were measured before and after each period. Results showed no effect on body weight, blood pressure, or lipid profile. HbA1c was reduced by 0.31 ± 0.58% during bilberry supplementation, but this change was not significantly different from that with placebo. Antioxidant status, oxidative stress, and inflammatory status showed no significant differences across treatments. This short-term study of bilberry supplementation did not show significant effects on cardiovascular risk factors or antioxidant status, but the tendency for improved glycemic control may suggest a longer treatment period may be effective in diabetic patients.

GLP-1 receptor agonists are used for the treatment of type 2 diabetes but they may reduce appetite and cause nausea and emesis. We investigated if GLP-1 (7–36) amide can modulate glucose homoeostasis, emesis and feeding via an exendin (9–39)-sensitive mechanism in Suncus murinus. The effect of GLP-1 (7–36) amide on glucose homeostasis was examined using an intraperitoneal glucose tolerance test. In conscious fasted animals, food and water consumption and behavior were measured for 1 h following drug administration. c-Fos expression in the brain was measured using immunohistochemistry. GLP-1 (7–36) amide reduced blood glucose levels dose-dependently. Exendin (9–39) did not modify blood glucose levels but suppressed the glucose-lowering effect of GLP-1 (7–36) amide. GLP-1 (7–36) amide inhibited food and water intake, induced emesis and elevated c-Fos expression in the brainstem and hypothalamic nuclei in the brain. Exendin (9–39) antagonised the inhibition of food and water intake and emesis induced by GLP-1 (7–36) amide and the effects on c-Fos expression in the hypothalamus and brainstem, excepting for the bed nucleus of the stria terminalis. These data suggest that the action of GLP-1 (7–36) amide to modulate blood glucose, suppress food and water intake and induce emesis involve GLP-1 receptors in the hypothalamus and brainstem.

Metabolic syndrome is a cluster of interrelated conditions that is associated with an increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Oxidative stress may impair normal physiological functions, leading to various illnesses. T2DM is considered to be associated with increased oxidative stress, inflammation, and dyslipidemia, which may play a significant role in the development of cardiovascular complications, cancer and vision loss through cataracts and retinopathy. While conventional therapies are a cornerstone for the management of the major risk factors of metabolic syndrome, increasing antioxidant defense by increasing intake of antioxidant-rich foods may improve long term prospects in CVD, obesity and T2DM. Bilberry (Vaccinium myrtillus L.) is one of the richest natural sources of anthocyanins which give berries their red/purple/blue coloration. Anthocyanins are powerful antioxidants and are reported to play an important role in the prevention of metabolic disease and CVD as well as cancer and other conditions. This review focuses on the potential effects of bilberry supplementation on metabolic and cardiovascular risk factors. Although there is evidence to support the use of bilberry supplementation as part of a healthy diet, the potential benefits from the use of bilberry supplementation in patients with T2DM or CVD needs to be clarified in large clinical trials.

Background The roles of transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and subfamily A, member 1 (TRPA1) in mechanisms of gastrointestinal motility are complex. This study aimed to clarify the effects of several TRPV1 and TRPA1 ligands on the electrical potentials generated by pacemaker cells in the mouse-isolated ileum. Method The pacemaker potentials of ileal segments of mice were recorded extracellularly using a 60-channel microelectrode array. The dominant frequencies, average waveform periods and propagation velocities were quantified. The effects of TRPV1 and TRPA1 agonist and antagonist were compared with the baseline recordings. Results The electrophysiological recordings showed that capsaicin (30 μM to 3 mM), resiniferatoxin (300 μM), capsazepine (100–300 μM), allyl isothiocyanate (300 μM), isovelleral (300 μM), icilin (300 μM), A-967,079 (10 μM), AP18 (20 μM) and HC-030,031 (50 μM) significantly reduced the pacemaker frequency and increased the waveform period relative to the baseline. Conversely, ruthenium red (300 μM) significantly increased the pacemaker frequency and reduced the waveform period. Capsaicin (3 mM) and AP18 (20 μM) also significantly reduced the propagation velocity. However, all tested antagonists failed to inhibit the effects of agonists. AMG9810 (300 μM), but not A-967,079 (300 μM), significantly inhibited the increases in pacemaker frequency caused by increased temperatures. Conclusion Our findings suggest that TRPV1 and TRPA1 play a minor role in regulating pacemaker potentials and that at non-specific actions at other TRP and ion channels most likely contributed to the overall effects on the electrophysiological recordings that we observed.

The use of glucagon-like peptide-1 (7-36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Previous studies using Suncus murinus revealed that the GLP-1 receptor agonist, exendin-4, induces emesis via the brainstem and/or hypothalamus. The present study investigated the mechanism of exendin-4-induced emesis in more detail. Ondansetron (1 mg/kg, s.c.) and CP-99,994 (10 mg/kg, s.c) failed to reduce emesis induced by exendin-4 (3 nmol, i.c.v.), suggesting that 5-HT3 and NK1 receptors are not involved in the mechanism. In other studies, the GLP-1 receptor antagonist, exendin (9-39), antagonised emesis and c-Fos expression in the brainstem and the paraventricular hypothalamus induced by the chemotherapeutic drug cisplatin (30 mg/kg, i.p.; p 0.05), but not the emesis induced by nicotine (5 mg/kg, s.c.; p 0.05), or copper sulphate pentahydrate (120 mg/kg, p.o.; p 0.05). GLP-1 receptors may therefore represent a potential target for drugs to prevent chemotherapy-induced emesis in situations where 5-HT3 and NK1 receptor antagonists fail.

Bacopa monnieri (BM, family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The present study investigated the potential of BM methanol (BM-MetFr) and BM n-butanol fractions (BM-ButFr) to reduce chemotherapy-induced emesis in Suncus murinus (house musk shrew). Cisplatin (30 mg/kg, i.p.) reliably induced retching and/or vomiting over a 2 day period. BM-MetFr (10–40 mg/kg, s.c.) and BM-ButFr (5–20 mg/kg, s.c.) antagonized the retching and/or vomiting response by ∼59.4% (p 0.05). In conclusion, the n-butanol fractions of BM have anti-emetic activity comparable with palonosetron and MPG. BM may be useful alone or in combination with other anti-emetic drugs for the treatment of chemotherapy-induced emesis in man.

The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol.The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high-performance liquid chromatographic method. Subjects were genotyped for the CYP2C19 2 and 3, UGT1A1 6, 28 and 60, UGT2B7 2 and ABCB1 1236CT, 2677GT/A and 3435CT polymorphisms.Subjects with the CYP2C19 2/ 2 genotype had a higher peak concentration (255.5 ± 80.1 vs. 156.0 ± 66.3 ng/mL; P 0.05) and area under the concentration-time curve (AUC0-∞; 1,473.7 ± 493.6 vs. 502.8 ± 176.1 ng[Symbol: see text]h/mL; P 0.001) than subjects with 60 or 28, and UGT2B7 2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0-∞ and lower total clearance than the wild-types (P 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0-∞.Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects.

β-Blockers have an important therapeutic role throughout the cardiovascular continuum. However, there is considerable variation in response to these drugs, which may be related to genetic influences on their pharmacokinetics and pharmacodynamic effects.This review focuses on genetic variations in the drug metabolizing enzymes which influence the pharmacokinetics and potentially the pharmacodynamics of some β-blockers. It also reviews the polymorphisms in the adrenergic receptors (ARs) and their related pathways which are likely to influence the responses to β-blockers.The CYP2D6 genotypes influence the pharmacokinetics of some β-blockers but the effects on β-blocker responses have been inconsistent and there is currently no general role for CYP2D6 genotyping prior to choosing a particular β-blocker or dose. The common polymorphisms producing changes in the β(1)-ARs, and their signaling pathways, have been associated with clinical outcomes in several studies in hypertension and heart failure. Treatment with β-blockers, especially with higher doses, appears to have greater benefits in patients with the genetic forms of the β(1)-ARs which are more responsive to both agonists and antagonists. However, current data are not sufficiently consistent to support genotyping for these polymorphisms before selecting or initiating β-blocker treatment and further study results are needed to clarify the situation.

In the present studies, a simple rapid ultra performance liquid chromatography (UPLC) method with UV detection for the simultaneous determination of cortisol, cortisone and 6β-hydroxycortisol in human urine was developed. The three analytes and the internal standard dexamethasone were separated on a Waters Acquity UPLC-Tunable UV system with an Acquity UPLC BEH C18 column (50 × 2.1 mm ID, 1.7 μm) using a gradient elution of methanol and water (containing 0.01% formic acid) with a run time of 7 min. The method was accurate and precise, over the ranges of 5–200 ng mL−1 for cortisol, and 10–1,000 ng mL−1 for both cortisone and 6β-hydroxycortisol, and showed good linearity (r 2 > 0.999). This method was applied for the measurement of cortisol, cortisone and 6β-hydroxycortisol in samples collected over different periods as a tool to assess the activity of CYP3A and 11β-hydroxysteroid dehydrogenase type 2 enzymes.

Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut as an incretin hormone to stimulate glucose-stimulated insulin secretion. GLP-1 is also produced in the central nervous system (CNS) as a neurotransmitter that regulates feeding behaviour. By using polyclonal antiserum against GLP-1 and GLP-1 receptors, we identified the distribution of GLP-1 immunoreactive fibres and GLP-1 receptor immunoreactivity in the ventromedial hypothalamus of Suncus murinus (house musk shrew). In functional studies, subcutaneous administration of exendin-4 (1 - 30 nmol/kg) reduced blood glucose levels dose-dependently by up to 49% during an intraperitoneal glucose tolerance test (P

Glucagon-like peptide-1 (GLP-1) receptor agonists have been reported to modulate gastrointestinal motility but the mechanism is essentially unknown. In the present studies, we investigated the potency and mechanism of action of GLP-1 receptor ligands on the isolated ileum of Suncus murinus, an insectivore used in anti-emetic research. Ileal segments were mounted in organ baths containing Kreb's solution. Cumulative concentration-response curves to GLP-1 (7-36) amide (0.1-300 nM) and exendin-4 (0.1-100 nM) were constructed in the absence and presence of exendin (9-39) amide (0.3-3 nM). GLP-1 (7-36) amide and exendin-4 induced concentration-dependent contractions yielding pEC50 values of 8.4+/-0.2 and 8.4+/-0.4, respectively. Exendin (9-39) antagonized the action of both agonists in a non-competitive reversible manner, with apparent pKB values of 9.5 and 9.7, respectively. Tetrodotoxin (1 microM), atropine (1 microM) and hexamethonium (500 microM) were used to determine the contractile mechanism of action of exendin-4. Tetrodotoxin and atropine significantly antagonized (P

BACKGROUND Although flecainide is thought to be meta-bolized predominantly by cytochrome P450 (CYP) 2D6, it shows pharmacokinetic interactions with drugs, such as verapamil and digoxin, which may suggest other CYP pathways or ATP-binding cassette (ABC) transporters might be involved. This study evaluated effects of common polymorphisms in Chinese in CYP2D6, CYP3A5, CYP1A2, and ABCB1 on flecainide pharmacokinetics. METHODS Single oral 100-mg doses of flecainide were given to 15 healthy male Chinese subjects who were genotyped for the CYP2D6*2, *5, *10, CYP3A5*3, CYP1A2*1F and ABCB1 C1236T, G2677T/A, and C3435T polymorphisms. RESULTS There was no significant difference in the pharmacokinetics of flecainide among CYP2D6 (mainly involving *10) genotypes. The CYP3A5*3/*3 subjects (n=8) had a 26% higher systemic exposure (AUC0-∞) and 17% lower apparent oral clearance of flecainide than the combined group of CYP3A5*1/*1 (n=6) and CYP3A5*1/*3 (n=1) subjects (p

Cardiovascular diseases are the major cause of morbidity and mortality worldwide, and there is considerable interest in the role of dietary constituents and supplements in the prevention and treatment of these disorders. We reviewed the major publications related to potential effects on cardiovascular risk factors and outcomes of some common dietary constituents: carotenoids, flavonoid-rich cocoa, tea, red wine and grapes, coffee, omega-3 fatty acids, and garlic. Increased intake of some of these has been associated with reduced all-cause mortality or reduced incidence of myocardial infraction, stroke, and hypertension. However, although the evidence from observational studies is supportive of beneficial effects for most of these foodstuffs taken as part of the diet, potential benefits from the use of supplements derived from these natural products remain largely inconclusive.

An improved and simple reversed-phase high performance liquid chromatography method with electrochemical detection for the simultaneous determination of amino acids in brain tissue of Suncus murinus was developed. Homogenates from 5 different brain areas were derivatized with o-phthalaldehyde in the presence of sodium sulphite. Subsequent separation was achieved using linear gradient elution over 30 min. The derivatives were stable for up to 20 h at 4 °C. The method was accurate, reproducible, and showed good linearity. The recoveries were >88% for aspartate, glutamine, glutamate, glycine and γ-aminobutyric acid, with the limit of quantification varying from 5 to 30 pmol. The method was successfully applied for the measurement of amino acids under fed and fasted conditions.

We investigated the effect of cisplatin on glutamate release in the hypothalamus of Suncus murinus measured by brain microdialysis. Dialysis samples were collected every 20 min for 1 h before and 3 h after the cisplatin (30 mg/kg, i.p.) administration with the animals also being observed for the development of emesis. Cisplatin increased glutamate levels within 1 h and this was closely associated with the occurrence of emesis. Pretreatment with the 5-HT3– receptor antagonist ondansetron (2 mg/kg, i.p.) inhibited both the emesis and the increased glutamate levels. These results suggest that hypothalamic glutamate is involved in cisplatin-induced emesis in Suncus murinus. Keywords:: glutamate, microdialysis, Suncus murinus

Background: Rodents are incapable of emesis and consequently the emetic potential of glucagon-like peptide-1 receptor (GLP-1R) agonists in studies designed to assess a potential blood glucose lowering action of the compound was missed. Therefore, we investigated if the ferret, a carnivore with demonstrated translation capability in emesis research, would identify the emetic potential of the GLP-1R agonist, exendin-4, and any associated effects on gastric motor function, appetite and cardiovascular homeostasis.\ud \ud Methods: The biological activity of the GLP-1R ligands was investigated in vivo using a glucose tolerance test in pentobarbitone-anesthetised ferrets and in vitro using organ bath studies. Radiotelemetry was used to investigate the effect of exendin-4 on gastric myoelectric activity (GMA) and cardiovascular function in conscious ferrets; behaviour was also simultaneously assessed. Western blot was used to characterize GLP-1R distribution in the gastrointestinal and brain tissues.\ud \ud Results: In anesthetised ferrets, exendin-4 (30 nmol/kg, s.c.) reduced experimentally elevated blood glucose levels by 36.3%, whereas the GLP-1R antagonist, exendin (9–39) (300 nmol/kg, s.c.) antagonised the effect and increased AUC0–120 by 31.0% when injected alone (P < 0.05). In animals with radiotelemetry devices, exendin-4 (100 nmol/kg, s.c.) induced emesis in 1/9 ferrets, but inhibited food intake and decreased heart rate variability (HRV) in all animals (P < 0.05). In the animals not exhibiting emesis, there was no effect on GMA, mean arterial blood pressure, heart rate, or core body temperature. In the ferret exhibiting emesis, there was a shift in the GMA towards bradygastria with a decrease in power, and a concomitant decrease in HRV. Western blot revealed GLP-1R throughout the gastrointestinal tract but exendin-4 (up to 300 nM) and exendin (9–39), failed to contract or relax isolated ferret gut tissues. GLP-1R were found in all major brain regions and the levels were comparable those in the vagus nerve.\ud \ud Conclusions: Peripherally administered exendin-4 reduced blood glucose and inhibited feeding with a low emetic potential similar to that in humans (11% vs 12.8%). A disrupted GMA only occurred in the animal exhibiting emesis raising the possibility that disruption of the GMA may influence the probability of emesis occurring in response to treatment with GLP-1R agonists.