An exploratory double-blind,randomized clinical trial with selisistat,a SirT1 inhibitor,in patients with Huntington’s disease

AimsSelisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington''s disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers.MethodsThis was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers.ResultsSelisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC₅₀ for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen.ConclusionsSelisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.     

The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre,randomized, double-blind,placebo-controlled phase I clinical trial

ContextCapsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma.ObjectiveTo observe the clinical safety and tolerability of CALAS.Materials and methodsSubjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects.ResultsSixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%).Discussion and conclusionsCALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.     

Pharmacokinetics of tralokinumab in adolescents with asthma: implications for future dosing

AimsTralokinumab, an investigational human immunoglobulin G4 monoclonal antibody, potently and specifically neutralizes interleukin‐13, a central mediator of asthma. Tralokinumab has shown improvements in clinical endpoints in adults with uncontrolled asthma. The present study explored the pharmacokinetics (PK) and safety of a single tralokinumab dose, and utilized a population PK modelling and simulation approach to evaluate the optimal dosing strategy for adolescents.MethodsAdolescent subjects with asthma, using daily controller medication, received a single subcutaneous dose of tralokinumab 300 mg. Safety, immunogenicity and PK data were collected during a 57‐day follow‐up. A population PK model was developed using data from the present study and prior studies in adults. Simulations were performed to evaluate dose adjustment requirements for adolescents.ResultsTwenty adolescents (12–17 years) were enrolled; all completed the study. No clinically relevant safety findings or antidrug antibodies were detected. PK parameters were similar to those observed in adults. PK modelling showed that body weight was a minor predictor of tralokinumab PK; after incorporating body weight into the PK model, a 15% (nonparametric 95% confidence interval 5%, 26%) lower clearance was found in adolescents compared with adults [173 (151, 209) vs. 204 (191, 229) ml day^–1]. Simulations showed no therapeutically relevant differences in exposures between adolescent and adult populations, and similar PK profiles for weight‐based (4 mg kg^–1) and fixed (300 mg) fortnightly subcutaneous doses of tralokinumab.ConclusionSingle‐dose administration of tralokinumab 300 mg in adolescents was well tolerated, with a PK profile similar to that in adults. Exposure predictions suggest that dose adjustment is not required for adolescents.     

An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib

Aim/MethodsThis was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12).ResultsFor total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration−time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml⁻¹ h [90% CI 158, 316 ng ml⁻¹h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml⁻¹h [90% CI 159, 217 ng ml⁻¹h], in healthy subjects) and maximum concentration (C_max) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (t_max). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs.ConclusionsThe results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.     

Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic,in a first-in-human study

Aims

The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM).

Methods

T2DM subjects (glycosylated haemoglobin: 7.0–10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5–200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride – an early marker of drug activity.

Results

No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5–7.7 h and 66.5– 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups.

Conclusions

Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.     

Effects of boceprevir and telaprevir on the pharmacokinetics of dolutegravir

AimsThe aim was to evaluate the effect of boceprevir and telaprevir on dolutegravir pharmacokinetics (PK); the effect of dolutegravir on boceprevir and telaprevir PK was assessed through comparison with historical data for each hepatitis C virus (HCV) drug''s prescribing information alone.MethodsThis was a single-centre, randomized, open-label, two-cohort, two-period, one-way study in healthy adult subjects. Dolutegravir 50 mg once daily was administered for 5 days in Period 1, and dolutegravir 50 mg once daily was coadministered with either boceprevir 800 mg every 8 h (Cohort 1) or telaprevir 750 mg every 8 h (Cohort 2) for 10 days in Period 2.ResultsNo deaths or serious adverse events were reported during the study. Four subjects were withdrawn from the study because of adverse events (elevated alanine aminotransferase, cellulitis, increased serum creatinine and dizziness). One subject became pregnant during the study. Coadministration of dolutegravir with boceprevir had no effect on dolutegravir area under the plasma concentration–time curve (AUC) and maximal plasma concentration (C_max) and caused a small increase in concentration at the end of the dosing interval (C_τ; 8%). Coadministration of dolutegravir with telaprevir resulted in increased dolutegravir plasma exposures compared with those after administration of dolutegravir alone; AUC_0–τ, C_max and C_τ increased by 25, 19 and 37%, respectively. Coadministration of boceprevir or telaprevir with dolutegravir had no clinically significant effect on dolutegravir PK. Plasma boceprevir and telaprevir PK data for either combined treatment were similar to historical data, indicating no effect of dolutegravir on boceprevir or telaprevir exposure.ConclusionsDolutegravir can be coadministered with boceprevir or telaprevir in patients coinfected with HIV and HCV with no dose adjustment.     

Investigation of mutual pharmacokinetic interactions between macitentan,a novel endothelin receptor antagonist,and sildenafil in healthy subjects

AimTo study the mutual pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects.MethodsIn this open-label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration−time profiles of macitentan and its active metabolite ACT-132577 (treatments A and C) and sildenafil and its N-desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non-compartmentally.ResultsThe pharmacokinetics of macitentan were not affected by sildenafil. In the presence of sildenafil C_max and AUC_τ of the metabolite ACT-132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased C_max and AUC_τ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N-desmethylsildenafil were not affected by macitentan. All treatments were well tolerated.ConclusionA minor, not clinically relevant, pharmacokinetic interaction was observed between macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with macitentan and sildenafil.     

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria

Aims

The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment.

Methods

Exposure–response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100–800 mg and 160–1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing.

Results

A significant relation between plasma concentrations and placebo-corrected change from baseline QT_cF (ΔΔQT_cF) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml⁻¹ (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QT_cF effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml⁻¹) and 1440 mg (281 ng ml⁻¹), respectively, administered in the fasted state.

Conclusions

Piperaquine prolongs the QT_c interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QT_c prolongation.     

Pharmacodynamics,pharmacokinetics and safety of GSK2190915, a novel oral anti‐inflammatory 5‐lipoxygenase‐activating protein inhibitor

Aim

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5‐lipoxygenase‐activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations.

Method

Western European subjects received single (50–1000 mg) or multiple (10–450 mg) oral doses of GSK2190915 or placebo in a dose‐escalating manner. Japanese subjects received three of four GSK2190915 doses (10–200 mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B₄ and leukotriene E₄, respectively, as pharmacodynamic markers of drug activity.

Results

There was no clear difference in adverse events between placebo and active drug‐treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose‐related manner and mean half‐life values ranged from 16–34 h. Dose‐dependent inhibition of blood leukotriene B₄ production was observed and near complete inhibition of urinary leukotriene E₄ excretion was shown at all doses except the lowest dose. The EC₅₀ values for inhibition of LTB₄ were 85 nm and 89 nm in the Western European and Japanese studies, respectively.

Conclusion

GSK2190915 is well‐tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24 h inhibition of leukotrienes. Doses of ≥50 mg show near complete inhibition of urinary leukotriene E₄ at 24 h post‐dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄.     

Efficacy,Safety, and Tolerability of Ansofaxine (LY03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized,Double-Blind,Placebo-Controlled,Dose-Finding,Phase 2 Clinical Trial

BackgroundAnsofaxine (LY03005) extended-release tablet is a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. This study assessed the efficacy, safety, and appropriate dosage of ansofaxine for the treatment of major depressive disorder (MDD).MethodsA multicenter, randomized, double-blind, placebo-controlled, dose-finding, Phase 2 clinical trial was conducted in China. Eligible patients with MDD (18–65 years) were randomly assigned to receive fixed-dose ansofaxine extended-release tablets (40, 80, 120, or 160 mg/d) or placebo for 6 weeks. The primary outcome measure was a change in the total score on the 17-item Hamilton Depression Rating Scale from baseline to week 6.ResultsA total of 260 patients were recruited from October 2015 to September 2017, and 255 patients received the study drug as follows: 40 mg (n = 52), 80 mg (n = 52), 120 mg (n = 51), and 160 mg (n = 51) ansofaxine and placebo (n = 49). Significant differences were found in mean changes in 17-item Hamilton Depression Rating Scale total scores at week 6 in the 4 ansofaxine groups vs placebo (−12.46; χ²=−9.71, P = .0447). All doses of ansofaxine were generally well-tolerated. Treatment-related adverse events occurred in 141 patients (303 cases), yielding incidence rates of 51.92%, 65.38%, 56.86%, and 62.75% in the 40-, 80-, 120-, and 160-mg ansofaxine groups and 38.78% in the placebo group.ConclusionActive doses (40, 80, 120, and 160 mg/d) of ansofaxine in a controlled setting were safe, tolerated, and effective in improving depression symptoms in MDD patients.     

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A,for the treatment of Alzheimer's disease

Aim:

Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects.

Methods:

This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including C_max, AUC_{0–72 h} and AUC_0–∞ were calculated. Tolerance assessments were conducted throughout the study.

Results:

ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean t_max of huperzine A was 0.76–0.82 h; the AUC_{0–72 h} and C_max of huperzine A showed approximately dose-proportional increase over the dose range of 0.5–1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed.

Conclusion:

ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.     

The impact of co-administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers

AimsTwo clinical studies were conducted to determine possible drug−drug interactions between apremilast and a strong CYP3A4 inhibitor, ketoconazole, or a potent CYP3A4 inducer, rifampicin. The main objectives of these two studies were to evaluate the impact of multiple doses of ketoconazole on the pharmacokinetics of apremilast and its metabolites, and the effect of multiple oral doses of rifampicin on the pharmacokinetics of apremilast.MethodsThese single centre, open label, sequential treatment studies in healthy subjects included two treatment periods for ketoconazole and three treatment periods for rifampicin. Apremilast was administered as a 20 mg (ketoconazole study) or 30 mg (rifampicin study) single oral dose.ResultsKetoconazole increases overall exposure (AUC(0,∞)) of apremilast by ≈36% (2827 vs. 2072 ng ml⁻¹ h, 90% CI = 126.2, 147.5) and peak exposure (C_max) by 5% (247 vs. 236 ng ml⁻¹). Multiple doses of rifampicin increase apremilast clearance ≈3.6-fold and decrease apremilast mean AUC(0,∞) by ≈72% (3120 vs. 869 ng ml⁻¹ h, 90% CI = 25.7, 30.4) and C_max (from 290 vs. 166 ng ml⁻¹) relative to that of apremilast given alone. A 30 min intravenous infusion of rifampicin 600 mg had negligible effects on the overall exposure (AUC(0,∞)) of apremilast (2980 vs. 3120 ng ml⁻¹ h, 90% CI = 88.0, 104.1).ConclusionKetoconazole slightly decreased apremilast clearance, resulting in a small increase in AUC which is probably not meaningful clinically. However, the effect of CYP3A4 induction by rifampicin on apremilast clearance is much more pronounced than that of CYP3A4 inhibition by ketoconazole. Strong CYP3A4 inducers may result in a loss of efficacy of apremilast because of decreased drug exposure.     

Safety,tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and C_max increased in an approximately dose-proportional manner in the dose range of 25–800 mg. T_1/2 was within 4.80–6.95 h. In MAD, the accumulation ratio for C_max and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on C_max and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.     

Clinical pharmacology of AMG 181, a gut-specific human anti-α4β7 monoclonal antibody,for treating inflammatory bowel diseases

Aims

AMG 181 pharmacokinetics/pharmacodynamics (PK/PD), safety, tolerability and effects after single subcutaneous (s.c.) or intravenous (i.v.) administration were evaluated in a randomized, double-blind, placebo-controlled study.

Methods

Healthy male subjects (n= 68) received a single dose of AMG 181 or placebo at 0.7, 2.1, 7, 21, 70 mg s.c. (or i.v.), 210 mg s.c. (or i.v.), 420 mg i.v. or placebo. Four ulcerative colitis (UC) subjects (n= 4, male : female 2:2) received 210 mg AMG 181 or placebo s.c. (3:1). AMG 181 concentration, anti-AMG 181-antibody (ADA), α₄β₇ receptor occupancy (RO), target cell counts, serum C-reactive protein, fecal biomarkers and Mayo score were measured. Subjects were followed 3–9 months after dose.

Results

Following s.c. dosing, AMG 181 was absorbed with a median t_max ranging between 2–10 days and a bioavailability between 82% and 99%. C_max and AUC increased dose-proportionally and approximately dose-proportionally, respectively, within the 70–210 mg s.c. and 70–420 mg i.v. ranges. The linear β-phase t_1/2 was 31 (range 20–48) days. Target-mediated disposition occurred at serum AMG 181 concentrations of less than 1 μg ml⁻¹. The PD effect on α₄β₇ RO showed an EC₅₀ of 0.01 μg ml⁻¹. Lymphocytes, eosinophils, CD4+ T cells and subset counts were unchanged. AMG 181-treated UC subjects were in remission with mucosal healing at weeks 6, 12 and/or 28. The placebo-treated UC subject experienced colitis flare at week 6. No ADA or AMG 181 treatment-related serious adverse events were observed.

Conclusions

AMG 181 has PK/PD, safety, and effect profiles suitable for further testing in subjects with inflammatory bowel diseases.     

Clinacanthus nutans attenuates atherosclerosis progression in rats with type 2 diabetes by reducing vascular oxidative stress and inflammation

ContextAtherosclerosis predisposes individuals to adverse cardiovascular events. Clinacanthus nutans L. (Acanthaceae) is a traditional remedy used for diabetes and inflammatory conditions.ObjectivesTo investigate the anti-atherosclerotic activity of a C. nutans leaf methanol extract (CNME) in a type 2 diabetic (T2D) rat model induced by a high-fat diet (HFD) and low-dose streptozotocin.Materials and methodsSixty male Sprague-Dawley rats were divided into five groups: non-diabetic fed a standard diet (C), C + CNME (500 mg/kg, orally), diabetic fed an HFD (DM), DM + CNME (500 mg/kg), and DM + Metformin (DM + Met; 300 mg/kg). Treatment with oral CNME and metformin was administered for 4 weeks. Fasting blood glucose (FBG), serum lipid profile, atherogenic index (AI), aortic tissue superoxide dismutase levels (SOD), malondialdehyde (MDA), and tumour necrosis factor-alpha (TNF-α) were measured. The rats’ aortas were stained for histological analysis and intima-media thickness (IMT), a marker of subclinical atherosclerosis.ResultsThe CNME-treated diabetic rats had reduced serum total cholesterol (43.74%; p = 0.0031), triglycerides (80.91%; p = 0.0003), low-density lipoprotein cholesterol (56.64%; p = 0.0008), AI (51.32%; p < 0.0001), MDA (60.74%; p = 0.0026), TNF-α (61.78%; p = 0.0002), and IMT (39.35%; p < 0.0001) compared to untreated diabetic rats. SOD level, however, increased (53.36%; p = 0.0326). These CNME effects were comparable to those in the metformin-treated diabetic rats.ConclusionsC. nutans possesses anti-atherosclerotic properties, which may be due to reductions in vascular tissue oxidative stress, inflammation, and serum AI. Continued studies on atherosclerotic animal models are suggested.     

Evaluation of the toxicology,anti-lipase,and antioxidant effects of Callistemon citrinus in rats fed with a high fat-fructose diet

ContextCallistemon citrinus Skeels (Myrtaceae) exhibits many biological activities.ObjectiveThis study analyzes for the first time, the toxicity, obesogenic, and antioxidant effects of C. citrinus in rats fed with a high fat-fructose diet (HFFD).Materials and methodsFour studies using male Wistar rats were conducted: (a) 7 groups (n = 3): control (corn oil) and ethanol extract of C. citrinus leaf (single oral dose at 100–4000 mg/kg) for acute toxicity; (b) 2 groups (n = 8): control (corn oil) and C. citrinus (1000 mg/kg/day) for 28 days for subacute toxicity; (c) 3 groups (n = 4) with single oral dose of lipid emulsion: control (lipid emulsion), C. citrinus and orlistat (250 and 50 mg/kg, respectively) for lipid absorption; (d) 4 groups (n = 6): control (normal diet) and 3 groups fed with HFFD: HFFD only, C. citrinus and simvastatin (oral dose 250 and 3 mg/kg, respectively) for 13 weeks. Antioxidant enzymes and biomarkers were evaluated and inhibition of pancreatic lipase was determined in vitro.ResultsToxicological studies of C. citrinus showed no differences in biochemical parameters and lethal dose (LD₅₀) was higher than 4000 mg/kg. C. citrinus inhibited pancreatic lipase activity, with IC₅₀ of 392.00 µg/mL, and decreased lipid absorption by 70%. Additionally, it reduced the body weight 22%, restored the activities of antioxidant enzymes, and reduced the biomarkers of oxidative stress.ConclusionsCallistemon citrinus showed an effect against oxidative stress by reducing biomarkers and induced antioxidant system, without toxic effects.     

Bilastine vs. hydroxyzine: occupation of brain histamine H1-receptors evaluated by positron emission tomography in healthy volunteers

AimA close correlation exists between positron emission tomography (PET)-determined histamine H₁-receptor occupancy (H₁RO) and the incidence of sedation. Antihistamines with H₁RO <20% are classified as non-sedating. The objective was to compare the H₁RO of bilastine, a second generation antihistamine, with that of hydroxyzine.MethodsThis randomized, double-blind, crossover study used PET imaging with [¹¹C]-doxepin to evaluate H₁RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H₁ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated.ResultsThe mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H₁RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine.ConclusionsA single oral dose of bilastine 20 mg had minimal H₁RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.     

Effects of garden cress,fenugreek and black seed on the pharmacodynamics of metoprolol: an herb-drug interaction study in rats with hypertension

ContextGarden cress (GC), fenugreek (FG), and black seed (BS) are traditional herbal medicine for managing hypertension.ObjectiveThe effects of the three herbs on the pharmacodynamics of metoprolol tartrate (MT) in hypertensive rats were investigated.Materials and methodsWistar rats were divided in five groups (n = 6). Group I served as normal control group and Group II (hypertensive control group) had rats treated orally with N-nitro L-arginine methyl ester (L-NAME, 40 mg/kg/day) only. Groups III, IV, and V rats were orally treated with L-NAME (40 mg/kg/day) + GC (300 mg/kg, once daily), L-NAME (40 mg/kg/day) + FG (300 mg/kg, once daily) and L-NAME (40 mg/kg/day) + BS (300 mg/kg, once daily), respectively, for 2 weeks, and on the 14th day, blood pressure and heart rate were recorded using a tail-cuff blood pressure-measuring system. On the 16th day, a single dose of MT (10 mg/kg) was orally administered, and the rats’ blood pressure and heart rate were recorded.ResultsGC, FG, and BS decreased systolic blood pressure (SBP) by 8.7%, 8.5%, and 8.7%, respectively, in hypertensive rats. A greater decrease in SBP by 14.5%, 14.8%, and 16.1% was observed when hypertensive rats were treated with L-NAME + GC + MT, L-NAME + FG + MT, and L-NAME + BS + MT, respectively. Similarly, hypertensive rats treated with the combination of herbs and MT had significantly lower diastolic blood pressure (DBP) than those treated with herbs alone and those treated with L-NAME alone.ConclusionsThe combination of investigated herbs and MT had a beneficial effect on hypertension. However, the concurrent administration of drugs, particularly those predominantly cleared through CYP450 2D6-catalyzed metabolism, with the three investigated herbs should be considered with caution.     

Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist

AIMS

To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist.

METHODS

Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge.

RESULTS

Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and C_max, while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2-to 4-fold shift in capsaicin potency.

CONCLUSIONS

Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluation.