Trends in prevalent and incident opioid receipt: an observational study in Veterans Health Administration 2004-2012.

BACKGROUND: Improved understanding of temporal and regional trends may support safe and effective prescribing of opioids. OBJECTIVE: We describe national, regional, and facility-level trends and variations in opioid receipt between fiscal years (FY) 2004 and 2012. DESIGN: Observational cohort study using Veterans Health Administration (VHA) administrative databases. PARTICIPANTS: All patients receiving primary care within 137 VHA healthcare systems during a given study year and receiving medications from VHA one year before and during a given study year. MAIN MEASURES: Prevalent and incident opioid receipt during each year of the study period. KEY RESULTS: The overall prevalence of opioid receipt increased from 18.9% of all veteran outpatients in FY2004 to 33.4% in FY2012, a 76.7% relative increase. In FY2012, women had higher rates of prevalent opioid receipt than men (42.4% vs. 32.9%), and the youngest veterans (18-34 years) had higher prevalent opioid receipt compared to the oldest veterans (≥ 80 years) (47.6% vs. 17.9%). All regions in the United States saw increased rates of prevalent opioid receipt during this time period. Prevalence rates varied widely by facility: in FY2012, the lowest-prescribing facility had a rate of 13.5%, and the highest of 50.8%. Annual incident opioid receipt increased from 8.8% in FY2004 to 10.2% in FY2011, with a decline to 9.8% in FY2012. Incident prescribing increased at some facilities and decreased at others. Facilities with high prevalent prescribing tended to have flat or decreasing incident prescribing rates during the study time frame. CONCLUSIONS: Rates of opioid receipt increased throughout the study time frame, with wide variation in prevalent and incident rates across geographical region, sex, and age groups. Prevalence and incidence rates reflect distinct prescribing practices. Areas with the highest prevalence tended to have lower increases in incident opioid receipt over the study period. This likely reflects facility-level variations in prescribing practices as well as baseline rates of prevalent use. Future work assessing opioid prescribing should employ methodologies to account for and interpret both prevalent and incident opioid receipt.

Determination of the absolute configuration of (+)-neopentyl-1-d alcohol by neutron and x-ray diffraction analysis.

The absolute configuration of (+)-neopentyl-1-d alcohol, prepared by the reduction of 2,2-dimethylpropanal-1-d by actively fermenting yeast, has been determined to be S by neutron diffraction. The neutron study was carried out on the phthalate half ester of neopentyl-1-d alcohol, crystallized as its strychnine salt. The absolute configuration of the (-)-strychninium cation was first determined by an x-ray anomalous dispersion study of its iodide salt. The chiral skeleton of strychnine then served as a reference from which the absolute configuration of the -O-CHD-C(CH3)3 group of neopentyl phthalate was determined. Difference Fourier maps calculated from the neutron data showed unambiguously that the -O-CHD-C(CH3)3 groups of both independent molecules in the unit cell had the S configuration. This work proves conclusively that the yeast system reduces aldehydes by delivering hydrogen to the re face of the carbonyl group. Crystallographic details: (-)-strychninium (+)-neopentyl-1-d phthalate, space group P2(1) (monoclinic), a = 18.564(6) A, b = 7.713(2) A, c = 23.361(8) A, beta = 94.18(4) degrees, V = 3336.0(5) A3, Z = 2 (T = 100 K). Final agreement factors are R(F) = 0.073 for 2768 reflections collected at room temperature (x-ray analysis) and R(F) = 0.144 for 960 reflections collected at 100 K (neutron analysis).

The Bushman arrow toxin, Diamphidia toxin: isolation from pupae of Diamphidia nigro-ornata.

The Bushmen of the Kalahari Desert in Botswana use the pupae of the beetle Diamphidia nigro-ornata Ståhl to poison their arrows. Sequential aqueous extraction, ammonium sulfate precipitation, ultrafiltration and chromatofocusing have given an apparently homogeneous active protein from these pupae with an approximate mol. wt of 54,000, an isoelectric point of about 8.0 pH and a lethal potency (minimum lethal dose, MLD) between 5 and 20 micrograms/kg (i.p. mouse). Preliminary pharmacological studies on less purified material show that, after a delay, this Diamphidia toxin causes sustained contraction of isolated intestinal smooth muscle. This contraction is not blocked by atropine or mepyramine and, therefore, is not due to release of acetylcholine or histamine. Results on the phrenic nerve - hemidiaphragm preparation demonstrate that in the presence of the toxin, contraction in response to indirect stimulation gradually fails and is accompanied by contracture. Since direct stimulation of the muscle still elicits a contraction, the toxin apparently does not affect the contractile mechanism itself. We conclude that Diamphidia pupae contain a protein toxin that is responsible for its lethality. Although this toxin appears to differ in some properties from the toxins reported by Mebs et al., de la Harpe et al. and Kündig, these protein preparations undoubtedly correspond to each other. We did not find any evidence of the low molecular weight toxic component reported by Mebs et al.

Current status of asymmetric synthesis.

In the last 30 years the subject of asymmetric synthesis has grown from a little studied academic niche in organic chemistry to an intensely investigated field of commercial importance and heightened general interest. Impressive advances have been made in several areas, notably catalytic asymmetric homogeneous hydrogenation, catalytic asymmetric epoxidation of allyl alcohols and stereochemical control of carbon-carbon bond-forming reactions. Asymmetric synthesis must now be deliberately considered along with other available methods as a practical strategy for the synthesis of any chiral compound.

Chiriquitoxin, a new tool for mapping ionic channels.

Chiriquitoxin is a new natural analog of tetrodotoxin in which the -CH2OH group on C6 has been replaced with a yet unidentified group consisting of 104 mass units. It is unique in being the only known stable analog to be equally potent as tetrodotoxin in blocking the sodium channel. It additionally interferes with the delayed rectifier (potassium) channel. In frog skeletal muscle, it significantly reduced the outward current while abolishing the inward current. It also slows the fast repolarization of the action potential and obliterates the voltage response characteristic of delayed rectification to large outward currents. It completes the tetrodotoxin for the same membrane binding site, thereby suggesting that the same molecule interferes with both the sodium and the potassium channels. A new working hypothesis is proposed in which tetrodotoxin and chiriquitoxin are postulated to bind to a membrane receptor located in the outside surface of the muscle fiber membrane. From the structure of tetrodotoxin and a presumed structure of chiriquitoxin, the Na+ and K+ channels have been estimated to be separated from each other by not less than 5 A nor much more than 15 A.

Isoguanosine: isolation from an animal.

Isoguanosine (oxyadenosine or crotonoside), previously known to occur in nature only in the croton bean, was isolated from an animal, the marine nudibranch mollusk Diaulula sandiegensis.

Doridosine, 1-methylisoguanosine, from Anisodoris nobilis; structure, pharmacological properties and synthesis.

The new N-methylnucleoside named doridosine, isolated from the shell-less marine dorid nudibranch Anisodoris nobilis, has been identified as 1-methylisoguanosine (1) by its spectral properties and by synthesis via methylation of isoguanosine. Doridosine has been shown to be identical to the nucleoside isolated from the Australian sponge Tedania digitata by Quinn, Gregson, Cook and Bartlett. They have also proved their product to be 1-methylisoguanosine. Doridosine was shown to cause prolonged reduced arterial pressure and reduced heart rate in the rat. The action is qualitatively similar to that of adenosine but of much greater duration, possibly because doridosine is resistant to attack by adenosine deaminase.

Doridosine: a new hypotensive N-methylpurine riboside from the nudibranch Anisodoris nobilis.

A new N-methylpurine riboside (doridosine), probably N1-Methylisoguanosine, was isolated from the digestive glands of a nudibranch. Doridosine produces prolonged hypotension and bradycardia in anesthetized rats, decreases the rate and the amplitude of contraction of guinea pig atria in vitro, and causes the heart rate in anesthetized mice to be reduced by 50 percent for many hours after which the animals recover completely.

Toxin from skin of frogs of the genus Atelopus: differentiation from Dendrobatid toxins.

A potent, dialyzable toxin (atelopidtoxin) occurs in the skin of frogs of the genus Atelopus. A concentrate of atelopidtoxin from Atelopus zeteki has an LD(50) in mice of 16 micrograms per kilogram. It differs from batrachotoxin, tetrodotoxin, and saxitoxin, the only known nonprotein substances of greater toxicity, as well as from all toxins previously isolated from amphibia.