Discover the most talked about and latest scientific content & concepts.

Journal: British journal of clinical pharmacology


To investigate whether acid suppression medicines (ASMs) increase the risk of bacterial gastroenteritis.

Concepts: Foodborne illness, Diarrhea, Cohort study


Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9) -tetrahydrocannabinol is already under clinical evaluation in patients with Huntington’s disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9) -tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.

Concepts: Cannabinoids, Serotonin, Neurology, Cannabis, Cannabinoid, Cannabidiol, Cannabinoid receptor, Receptor


AIM: This study examined the effects of grapefruit juice on the new P2Y(12) inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein. METHODS: In a randomized crossover study, ten healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for four days. On day three, they ingested a single 90-mg dose of ticagrelor. RESULTS: Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (C(max) ) to 165% (95% confidence interval, 147-184%) and area under the concentration-time curve (AUC(0-∞) ) to 221% of control (95% confidence interval, 200-245%). The C(max) and AUC(0-34h) (P < 0.05) but not the AUC(0-∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity. CONCLUSIONS: Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice-ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.

Concepts: Effect, Pharmacokinetics, Grapefruit, Statistical hypothesis testing, Interval finite element, Statistics, Crossover study, Pharmacology


Two randomized, double-blind, placebo-controlled studies were performed to characterize the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the investigational metastin analogue, TAK-683, in healthy men.

Concepts: Pharmacodynamics, Pharmacokinetics


For approximately six years, the only commercially available direct renin inhibitor aliskiren, which inhibits the renin-angiotensin-aldosterone system at the initial rate limiting step, has been marketed for the treatment of hypertension. Concurrently, much attention has been given the possibility that renin inhibition could hold potential for improved treatment in patients with chronic kidney disease, with diabetic nephropathy as an obvious group of patients to investigate, as the activity of the renin-angiotensin-aldosterone system is enhanced in these patients and as there is an unmet need for improved treatment and prognosis in these patients. Several short term studies have been performed in diabetic nephropathy, showing consistent effect on the surrogate endpoint lowering of albuminuria, both as monotherapy and in combination with other blockers of the renin-angiotensin-aldosterone system. In addition, combination treatment seemed safe and effective also in patients with impaired kidney function. These initial findings formed the basis for the design of a large morbidity and mortality trial investigating aliskiren as add-on to standard treatment. The study has just concluded, but was terminated early as a beneficial effect was unlikely and there was an increased frequency of side effects. Also in non-diabetic kidney disease a few intervention studies have been carried out, but there is no ongoing hard outcome study. In this review we provide the current evidence for renin inhibition in chronic kidney disease by reporting of the studies published so far as well as perspective on the future possibilites.

Concepts: Nephrology, Medical terms, Renin-angiotensin system, Renin inhibitor, Renin, Blood pressure, Kidney, Hypertension


WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The microdose administration of novel drug candidates to humans in early development is currently undergoing evaluation as a cost-efficient approach to the early assessment of pharmacokinetics (PK) before the commitment of resources required to support formal phase 1 studies. • The microdose approach assumes that PK can be extrapolated linearly over the full range of exposures achieved with sub-pharmacological doses up to the therapeutic dose range. • Few microdose studies have been undertaken in the context of pharmaceutical drug development and their precise role in the selection of candidates for further clinical evaluation at therapeutic doses has yet to be fully substantiated. WHAT THIS STUDY ADDS • The present study describes the elective application of a human microdose study with a novel EP(1) receptor antagonist, GSK269984A, to address a critical development liability posed by uncertainty with respect to the predicted human PK profile. • Microdose data revealed a favourable PK profile, consistent with a clinically acceptable dosing regimen. These data support the value of undertaking a microdose study early in the drug discovery process to facilitate risk evaluation and to enable decision-making. AIM The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP(1) antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg). METHOD GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography-tandem mass spectrometry method following solid phase extraction. RESULTS Following the i.v. microdose, the geometric mean values for clearance (CL), steady-state volume of distribution (V(ss) ) and terminal elimination half-life (t(½) ) of GSK269984A were 9.8 l h(-1) , 62.8 l and 8.2 h. C(max) and AUC(0,∞) were 3.2 ng ml(-1) and 10.2 ng ml(-1)  h, respectively; the corresponding oral parameters were 1.8 ng ml(-1) and 9.8 ng ml(-1)  h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre-clinical species (rat, dog and monkey). CONCLUSION For drug development programmes characterized by inconsistencies between pre-clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

Concepts: In vivo, Pharmaceutical industry, Receptor, Clinical trial, Drug development, Pharmacokinetics, Drug discovery, Pharmacology


AIMS: Fostamatinib (R788) is an orally-dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406. METHODS: Three clinical studies were conducted in healthy subjects: (A) A single ascending-dose study for R406 with doses ranging from 80-600 mg, (B) A single and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80-400 mg and multiple doses at 160 mg bid, and © A study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states. RESULTS: These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12-21 h was observed. Similar R406 exposure could be achieved with fostamatinib suspension, and steady-state was achieved after 3-4 days following twice-daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon coadministration with food, a delay in peak time and lower peak concentrations of R406 were observed, at the same time the overall exposure did not change. CONCLUSIONS: Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once-daily or twice-daily oral administration of fostamatinib.

Concepts: Rheumatoid arthritis, Protein kinase, Solubility, Syk, Dosage forms, Dose, Pharmacokinetics, Pharmacology


BACKGROUND AND PURPOSE: Preterm infants are deprived of the normal intrauterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. METHODS: Melatonin was administered to eighteen preterm infants in doses ranging from 0.04-0.6 micrograms/kilograms, over 0.5-6 hours. Pharmacokinetic profiles were analysed individually and by population methods. RESULTS: Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 micrograms/kilogram/hour for 2 hours showed a median half-life of 15.82 hours and median maximum plasma concentration of 203.3 picograms/millilitre. On population pharmacokinetics, clearance was 0.045 litre/hour, volume of distribution 1.098 litres and elimination half-life 16.91 hours with gender (p=0.047) and race (p<0.0001) as significant covariates. CONCLUSIONS: A two-hour infusion of 0.1 micrograms/kilogram/hour increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can used to guide therapeutic clinical trials of melatonin in preterm infants.

Concepts: Circadian rhythm sleep disorder, Circadian rhythm, Normal distribution, Biological half-life, Distribution, Pharmacology, Pharmacokinetics


The examination of cough reflex sensitivity through inhalational challenge can be utilised to demonstrate pharmacological end points. Here we compare the effect of butamirate, dextromethorphan and placebo on capsaicin-induced cough in healthy volunteers.

Concepts: Randomized controlled trial, Effects unit, Effect, Pharmacology, Reflexes, Clinical trial, Effectiveness, Cough


LDL-receptor expression is inhibited by the protease PCSK9, which is considered a pharmacological target to reduce LDL-C levels in hypercholesterolemic patients. We performed a first-in-human trial with SPC5001, a locked nucleic acid antisense inhibitor of PCSK9.

Concepts: Hydrogen, Carbon dioxide, DNA, Nitrogen