Keith Tan

Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity

Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da. Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.

Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities.

This study investigated the relationship between plasma voriconazole concentrations (pVC) and risk of visual adverse events (VAEs) or liver function test (LFT) abnormalities using longitudinal logistic regression. Seven‐day mean pVC were calculated from 2925 plasma samples (1053 patients); in each 7‐day period, the presence or absence of VAEs/abnormal LFTs was analyzed as a binary outcome variable. There was a relationship between pVC and risk of VAE (P = .011) and a weaker, but statistically significant, association with risk of aspartate transaminase (AST), alkaline phosphatase (ALP), or bilirubin but not alanine transaminase (ALT) abnormalities. The odds ratios of LFT abnormalities per 1 μg/mL pVC increase ranged from 1.07 to 1.17. Maximum weekly occurrences were 10%, 8%, 5%, and 14% for AST, ALT, ALP, and bilirubin abnormalities, respectively. Receiver‐operating characteristic curve analysis indicates that individual pVC cannot be used to predict subsequent LFT abnormalities.

Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia.

OBJECTIVE Fibromyalgia (FM) represents a complex disorder that is characterized by widespread pain and tenderness and is frequently accompanied by additional somatic and cognitive/affective symptoms. Genetic risk factors are known to contribute to the etiology of the syndrome. The aim of this study was to examine >350 genes for association with FM, using a large-scale candidate gene approach. METHODS The study group comprised 496 patients with FM (cases) and 348 individuals with no chronic pain (controls). Genotyping was performed using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing >350 genes known to be involved in the biologic pathways relevant to nociception, inflammation, and mood. Association testing was performed using logistic regression. RESULTS Significant differences in allele frequencies between cases and controls were observed for 3 genes: GABRB3 (rs4906902; P = 3.65 × 10(-6)), TAAR1 (rs8192619; P = 1.11 × 10(-5)), and GBP1 (rs7911; P = 1.06 × 10(-4)). These 3 genes and 7 other genes with suggestive evidence for association were examined in a second, independent cohort of patients with FM and control subjects who were genotyped using the Perlegen 600K platform. Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4. CONCLUSION Variation in these 4 replicated genes may serve as a basis for development of new diagnostic approaches, and the products of these genes may contribute to the pathophysiology of FM and represent potential targets for therapeutic action.

Pharmacokinetic–Pharmacodynamic Analysis of the Static Allodynia Response to Pregabalin and Sildenafil in a Rat Model of Neuropathic Pain

The objective of this study was to develop a pharmacokinetic–pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mg·kg−1·h−1; 3) a 2-h pregabalin infusion at 10 mg·kg−1·h−1; 4) a 2.2-mg loading dose + 12 mg·kg−1·min−1 infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mg·kg−1·h−1 with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mg·kg−1·h with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration–response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC50 of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3–66.9%) decrease in EC50, whereas the percentage-transformed PD model demonstrated a 53.5% (42.7–64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.

Pharmacokinetics and Safety of Fosfluconazole after Single Intravenous Bolus Injection in Healthy Male Japanese Volunteers

This was a single blind, placebo‐controlled, escalating single‐dose, three‐period crossover study using two subject cohorts to investigate the safety, tolerability, and pharmacokinetics in healthy male Japanese subjects after intravenous bolus injection of fosfluconazole 50 to 2000 mg, a phosphate prodrug of fluconazole (FLCZ). Fosfluconazole was rapidly converted to FLCZ with only minor amounts excreted in the urine (less than 4% of the dose). Fosfluconazole had a volume of distribution at the higher doses, which was similar to the extracellular volume in man (0.2 L/kg) and was eliminated with a terminal half‐life of 1.5 to 2.5 hours. There was apparent dose proportionality in FLCZ pharmacokinetics. Cmax and AUC of FLCZ appeared to increase proportionally with increasing doses of fosfluconazole. There were no apparent dose‐dependent trends in tmax, t1/2, or mean residence time (MRT) of FLCZ. Bolus injection of fosfluconazole was well tolerated at doses of up to 2000 mg in healthy Japanese subjects.

Assessment of Pain and Activity Using an Electronic Pain Diary and Actigraphy Device in a Randomized, Placebo-Controlled Crossover Trial of Celecoxib in Osteoarthritis of the Knee

The primary goal was to determine whether a composite measure of pain and activity is a more responsive assessment of analgesic effect than pain alone or activity alone in patients with osteoarthritis (OA) of the knee.