The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics

The heritability of nociception and antinociception has been well established in the mouse. The pharmacogenetics of morphine analgesia are fairly well characterized, but far less is known about other analgesics. The purpose of this work was to begin the systematic genetic study of non-mu-opioid analgesics. We tested mice of 12 inbred mouse strains for baseline nociceptive sensitivity (49 degrees C tail-withdrawal assay) and subsequent antinociceptive sensitivity to systemic administration of (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488; 10-150 mg/kg), a kappa-opioid receptor agonist; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; 0.5-480 mg/kg), a synthetic cannabinoid receptor agonist; epibatidine (7.5-150 microg/kg), a nicotinic receptor agonist; clonidine (0.1-5 mg/kg), an alpha(2)-adrenergic receptor agonist; and, for purposes of comparison, the prototypic mu-opioid receptor agonist, morphine (5-200 mg/kg). Robust interstrain variability was observed in nociceptive sensitivity and in the antinociceptive effects of each of the drugs, with extreme-responding strains exhibiting antinociceptive potencies differing up to 37-fold. Unexpectedly, we observed moderate-to-high genetic correlations of strain sensitivities to the five drugs (r = 0.39-0.77). We also found moderate-to-high correlations between baseline nociceptive sensitivity and subsequent analgesic response to each drug (r = 0.33-0.68). The generalizability of these findings was established in follow-up experiments investigating morphine and clonidine inhibition of formalin test nociception. Despite the fact that each drug activates a unique receptor, our results suggest that the potency of each drug is affected by a common set of genes. However, the genes in question may affect antinociception indirectly, via a primary action on baseline nociceptive sensitivity.     

Chemopotentiation of temozolomide,irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor

Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear zinc finger DNA-binding protein that is implicated in the repair of DNA damage. Inhibition of PARP-1 through genetic knockouts causes cells to become hypersensitive to various chemotherapeutic agents. We tested the chemopotentiating ability of the PARP-1 inhibitor, CEP-6800, when used in combination with temozolomide (TMZ), irinotecan (camptothecin or SN38), and cisplatin against U251MG glioblastoma, HT29 colon carcinoma, and Calu-6 non-small cell lung carcinoma xenografts and cell lines, respectively. Exposure of tumor cells to TMZ, camptothecin (or SN38), and cisplatin before, or in the presence of, CEP-6800 significantly increased the onset and the magnitude of DNA damage, the duration for cells to effect repair, and the onset, duration, or fraction of cells arrested at the G(2)/M boundary. In addition, in vivo biochemical efficacy studies with CEP-6800 showed that it was able to attenuate irinotecan- and TMZ-induced poly(ADP-ribose) accumulation in LoVo and HT29 xenografts, respectively. Treatment of CEP 6800 (30 mg/kg) with TMZ (17 and 34 mg/kg) resulted in 100% complete regression of U251MG tumors by day 28 versus 60% complete regression caused by TMZ alone. CEP-6800 (30 mg/kg) in combination with irinotecan (10 mg/kg) resulted in a 60% inhibition of HT29 tumor growth versus irinotecan alone by day 33. The combination therapy of cisplatin (5 mg/kg) with CEP-6800 (30 mg/kg) caused a 35% reduction in Calu-6 tumor growth versus cisplatin alone by day 28. These data suggest that CEP-6800 could be used as a chemopotentiating agent with a variety of clinically effective chemotherapeutic agents.     

Korean Translation and Validity of FACT-BMT Version 4 and the Quality of Life in Allogeneic Bone Marrow Transplantation Patients

We undertook to translate and cross-culturally adapt the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) scale Version 4, an assessment tool for BMT patients’ quality of life (QoL). The translation procedure followed the standard Functional Assessment of Chronic Illness Therapy (FACIT) translation methodology. At baseline, prior to BMT, 70 allogeneic BMT patients were administered the FACT-BMT scale version 4, as well as the Eastern Cooperative Oncology Group Performance Status Rating (ECOG-PSR), Functional Living Index-Cancer (FLIC), and the Shortened Forms of the Profile of Mood States (BPOMS). Forty seven of these patients were also administered these questionnaires 3 months after BMT, thirty eight patients did 6 months after BMT, and finally 35 patients did 1 year after their BMT. Our results indicated that the FACT-BMT scale Version 4 gave convergent and divergent validity, and had a high internal consistency with its Cronbach’s alpha coefficients ranging from 0.64 (EWB at pre-BMT) to 0.94 (the FACT-BMT total). These data support that Korean FACT-BMT is a reliable and valid assessment for measuring the QoL of BMT patients. In the future study, we have to increase the number of cases with larger sample of allogeneic bone marrow transplantation patients, and the duration of long term follow-up should be at least more than 1 year.     

Determining normal variability in a developmental neurotoxicity test: a report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints

With the implementation of the Food Quality Protection Act in 1996, more detailed evaluations of possible health effects of pesticides on developing organisms have been required. As a result, considerable developmental neurotoxicity (DNT) data have been generated on a variety of endpoints, including developmental changes in motor activity, auditory startle habituation, and various learning and memory parameters. One issue in interpreting these data is the level of variability for the measures used in these studies: excessive variability can obscure treatment-related effects, or conversely, small but statistically significant changes could be viewed as treatment related, when they might in fact be within the normal range. To aid laboratories in designing useful DNT studies for regulatory consideration, an operational framework for evaluating observed variability in study data has been developed. Elements of the framework suggest how an investigator might approach characterization of variability in the dataset; identification of appropriate datasets for comparison; evaluation of similarities and differences in variability between these datasets, and of possible sources of the variability, including those related to test conduct and test design. A case study using auditory startle habituation data is then presented, employing the elements of this proposed approach.     

Analgesic activity of metabotropic glutamate receptor 1 antagonists on spontaneous post-operative pain in rats

Activation of metabotropic glutamate (mGlu) receptors has previously been shown to play a role in inflammatory or neuropathic pain states. However, the role of mGlu type 1 receptors in post-operative pain remains to be investigated. In the present study, effects of potent and selective mGlu₁ receptor antagonists A-841720, A-794282, A-794278, and A-850002 were evaluated in a skin incision-induced post-operative pain model in rats. Post-operative pain was examined 2 h following surgery using weight-bearing difference between injured and uninjured paws as a measure of spontaneous pain. In this model, A-841720, A-794282, A-794278, and A-850002 induced significant attenuation of spontaneous post-operative pain behavior, with ED_50s of 10, 50, 50, and 65 μmol/kg i.p., respectively. Depending on the compound, significant motor side effects were also observed at 3 to 10 fold higher doses. These results support the notion that mGlu₁ receptor activation plays a significant role in nociceptive transmission in post-operative pain, though motor impairment may be a limiting factor in developing mGlu₁ receptor antagonists as novel analgesics.     

Terminology Standardization in Chinese Medicine： The Perspective from UCLA Center for East-West Medicine（Ⅰ）

INTRODUCTION by Ka-kit Hui, M.D. Because we recognize the clinical, educational, and cultural importance of translation and terminology in Chinese medicine, we feel that it is imperative to understand the perspectives of all concerned parties. This article thus addresses the issue of terminology standardization in English language Chinese medical publications from the point of view of multiple stakeholders in this field at the UCLA Center for East-West Medicine. A great deal of discussion about the issue has arisen among faculty and staff at the Center, prompted especially by my invitation by the World Health Organization （W.H.O.） Western Pacific Region to review the draft document of English terminology standards in Chinese medicine. As the discussion within the Center reflects the wider debates within the field, we would like to address the topic by inviting seven Center staff and faculty, all of whom have been trained as clinicians and teachers rather than translators or linguistic scholars, to formally provide their insights into the matter. Sonya Pritzker, M.S., M.A., L.Ac. will first offer a brief background derived from her presentation at the original Grand Rounds at the Center upon which the current article is based. Staff and faculty from the Center then offer their contributions to the discussion, after which I discuss participants＇ views and conclude by suggesting that a biomedical interface syste in combination with a system of open standards offers a possible solution to the several divergent views brought up by the terminology debates.     

“I Met Someone Like Me!”: Autistic Adolescents and Their Parents’ Experience of the KONTAKT® Social Skills Group Training

Journal of Autism and Developmental Disorders - This study captured the experiences of 35 autistic adolescents and their parents after completing a 16-session variant of social skills group...