Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder.

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of ß3-adrenergic receptors (ß3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel ß3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of ß3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full ß3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a ß3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel ß3AR agonist probe, [3H]MRL-037, that selectively labels ß3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of ß3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

Vecuronium pharmacokinetics in patients with major burns.

BACKGROUND: Burn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. METHODS: Twenty adults, aged 23-58 yr, with 27-81% total body surface area (TBSA) burn, were studied at 4-57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg(-1) was given i.v. as a single bolus within 10 s. Blood samples (n=20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration-time profiles for burns and non-burns. RESULTS: A three-compartment model best described vecuronium concentration-time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min(-1), P<0.0001), which yielded shorter elimination half-life for vecuronium (5.5 vs 6.6 h, P<0.001). BURN was the single most significant covariate that explained the altered vecuronium disposition in burns. CONCLUSIONS: The altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

Rods-cones and melanopsin detect light and dark to modulate sleep independent of image formation.

Light detected in the retina modulates several physiological processes including circadian photo-entrainment and pupillary light reflex. Intrinsically photosensitive retinal ganglion cells (ipRGCs) convey rod-cone and melanopsin-driven light input to the brain. Using EEGs and electromyograms, we show that acute light induces sleep in mice during their nocturnal active phase whereas acute dark awakens mice during their diurnal sleep phase. We used retinal mutant mouse lines that lack (i) the ipRGCs, (ii) the photo-transduction pathways of rods and cones, or (iii) the melanopsin protein and showed that the influence of light and dark on sleep requires both rod-cone and melanopsin signaling through ipRGCs and is independent of image formation. We further show that, although acute light pulses overcome circadian and homeostatic drives for sleep, upon repeated light exposures using a 3.5 h/3.5 h light/dark cycle, the circadian and homeostatic drives override the light input. Thus, in addition to their known role in aligning circadian physiology with day and night, ipRGCs also relay light and dark information from both rod-cone and melanopsin-based pathways to modulate sleep and wakefulness.

Improved selectivity for partial oxidation of methane to methanol in the presence of nitrite ions and BiVO4 photocatalyst.

Nitrite ions are shown to have significant influence on the selectivity of the photocatalytic oxidation of methane to methanol. An almost complete inhibition of undesired CO2 has been achieved with BiVO4 in the presence of a low concentration of nitrite, which might act both as a UV filter and as a hydroxyl radical scavenger.

An economic evaluation of a chlorhexidine chip for treating chronic periodontitis: the CHIP (chlorhexidine in periodontitis) study.

BACKGROUND: The authors previously suggested that an adjunctive, controlled-release chlorhexidine, or CHX, chip may reduce periodontal surgical needs at little additional cost. This article presents an economic analysis of the CHX chip in general dental practice. METHODS: In a one-year prospective clinical trial, 484 chronic periodontitis patients in 52 general practices across the United States were treated with either scaling and root planing, or SRP, plus any therapy prescribed by treating, unblinded dentists; or SRP plus other therapy as above but including the CHX chip. Economic data were collected from bills, case report forms and 12-month treatment recommendations from blinded periodontist evaluators. RESULTS: Total dental charges were higher for SRP + CHX chip patients vs. SRP patients when CHX chip costs were included (P = .027) but lower when CHX chip costs were excluded (P = .012). About one-half of the CHX chip acquisition cost was offset by savings in other charges. SRP + CHX chip patients were about 50 percent less likely to undergo surgical procedures than were SRP patients (P = .021). At the end of the trial, periodontist evaluators recommended similar additional procedures for both groups: SRP, about 46 percent; maintenance, about 37 percent; surgery, 56 percent for SRP alone and 63 percent for SRP + CHX chip. CONCLUSIONS: Adjunctive CHX chip use for general-practice patients with periodontitis increased costs but reduced surgeries over one year. At study's end, periodontists recommended similar additional surgical treatment for both groups. CLINICAL IMPLICATIONS: In general practice, routine use of the CHX chip suggests that costs will be partially offset by reduced surgery over at least one year.

Quantitative Systems Pharmacology Model of NO Metabolome and Methemoglobin Following Long-Term Infusion of Sodium Nitrite in Humans.

A long-term sodium nitrite infusion is intended for the treatment of vascular disorders. Phase I data demonstrated a significant nonlinear dose-exposure-toxicity relationship within the therapeutic dosage range. This study aims to develop a quantitative systems pharmacology model characterizing nitric oxide (NO) metabolome and methemoglobin after sodium nitrite infusion. Nitrite, nitrate, and methemoglobin concentration-time profiles in plasma and RBC were used for model development. Following intravenous sodium nitrite administration, nitrite undergoes conversion in RBC and tissue. Nitrite sequestered by RBC interacts more extensively with deoxyhemoglobin, which contributes greatly to methemoglobin formation. Methemoglobin is formed less-than-proportionally at higher nitrite doses as characterized with facilitated methemoglobin removal. Nitrate-to-nitrite reduction occurs in tissue and via entero-salivary recirculation. The less-than-proportional increase in nitrite and nitrate exposure at higher nitrite doses is modeled with a dose-dependent increase in clearance. The model provides direct insight into NO metabolome disposition and is valuable for nitrite dosing selection in clinical trials.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e60; doi:10.1038/psp.2013.35; published online 31 July 2013.

An economic assessment of Apligraf (Graftskin) for the treatment of hard-to-heal venous leg ulcers.

Several recent advances in wound care may offer promise for the treatment of hard-to-heal venous leg ulcers. One such treatment is Apligraf (Graftskin), a bilayered, living human skin construct. To assess the economic impact of Graftskin, a model was constructed to compare the annual medical costs and cost-effectiveness of treating hard-to-heal venous leg ulcers with Graftskin vs. compression therapy using Unna's boot. A semi-Markov model was used to describe the pattern of ulcer treatment, healing, and recurrence among patients with venous leg ulcers. Patients received 1 of 2 treatment regimens, Graftskin or Unna's boot, and were followed in the model for a 12-month period. The analysis was done from the perspective of a commercial health plan; therefore, only direct medical costs were included. Health care resource use included the primary therapeutic intervention, additional compression dressings, physician office visits, home health visits, laboratory tests and procedures, management of adverse events, and hospitalizations. The model estimated the annual medical cost of managing patients with hard-to-heal venous leg ulcers to be $20,041 for those treated with Graftskin and $27,493 for those treated with Unna's boot. In addition, treatment with Graftskin led to approximately 3 more months in the healed state per person per year than did treatment with Unna's boot. Because patients treated with Graftskin experienced improved healing compared with those treated with compression therapy using Unna's boot, they required fewer months of treatment for unhealed ulcers. As a result, the use of Graftskin for treating hard-to-heal venous leg ulcers resulted in lower overall treatment costs.

Birth and first-year costs for mothers and infants attributable to maternal smoking.

Maternal smoking during pregnancy has been linked to high costs. This study estimates the magnitude of excess costs attributable to smoking during pregnancy for mothers and infants. The model estimates smoking-attributable costs for 11 infant and maternal conditions. From a claims database of 7784 mothers and 7901 infants who had deliveries during 1996, we estimated total cost over the infants' first year of life for each mother and infant and identified each complication of interest, based on ICD-9 codes. The average cost for smokers and non-smokers could not be computed directly because smoking status is not available in claims data. Therefore, the population attributable risk percentage (PAR%) due to smoking for each complication was identified from the literature. Multiple linear regression was used to provide estimates of the incremental cost associated with each smoking-related complication. The total cost attributable to smoking was computed as a function of the incremental cost of each complication and the PAR% for each complication. The conditions associated with the largest incremental costs compared to patients without those conditions were abruptio placenta ($23,697) and respiratory distress syndrome ($21,944). Because they were more common, the conditions with the largest smoking-attributable cost were low birth weight ($914) and lower respiratory infection ($428). The sum of the additional costs attributable to smoking for all conditions yielded a total in the first year after birth ranging from $1142 to $1358 per smoking pregnant woman. It was concluded that maternal smoking during pregnancy results in an economic burden to payers and society. These estimates may be useful in formal cost-effectiveness evaluations of individual smoking cessation strategies.

The cost-effectiveness of octreotide acetate in the treatment of carcinoid syndrome and VIPoma.

Markov modeling was used to evaluate the cost-effectiveness of octreotide in treating carcinoid syndrome and VIPoma. For each condition, using octreotide was associated with doubled survival time. Octreotide was cost-effective for treating carcinoid tumor ($752 per additional year of life, two additional years on average), and cost saving for VIPoma.