Pharmacokinetics of low doses of colchicine in the leukocytes of Japanese healthy individuals.

The venerable drug colchicine has garnered significant recent attention due to its endorsement by the United States Food and Drug Administration as an anti-inflammatory medication for cardiovascular diseases. However, the administration of this drug at its minimal available dose of 0.5 mg has been associated with certain adverse reactions. Once colchicine is administered, the drug disappears from blood in a short time and distributes in the leukocytes for a certain period of time that elicits anti-inflammatory effect. Consequently, an in-depth comprehension of the pharmacokinetics of lower dosages within leukocytes assumes important for its broader application in routine clinical contexts. In this study, we present a comprehensive analysis of the pharmacological disposition of colchicine in the plasma, polymorphonuclear leukocytes, and mononuclear leukocytes among healthy Japanese male subjects, following both single and multiple oral administrations of 0.5 mg and 0.25 mg doses of colchicine. Our investigation reveals that colchicine persists within leukocyte populations even when administered at reduced dosages. The findings herein hold promise for mitigating the adverse effects associated with its use in the treatment of inflammatory cardiovascular disorders.

Comparison of two screening tests for HIV-Associated Neurocognitive Disorder suspected Japanese patients with respect to cART usage.

In this study, we demonstrated the pervasiveness of HIV-associated neurocognitive disorders (HAND) among a selection of Japanese patients as well as evaluated and compared the Mini Mental State Examination (MMSE) and the International HIV Dementia Scale (IHDS) for use as a screening tool among combination anti-retroviral therapy (cART)-naïve and cART experienced patients. The MMSE and the IHDS have both been used as HAND screening tests around the world with variable success. It has been reported the increased usage of cART the utility of these screening tests may have been diminished due to the decreased severity of impairment and the altered pattern of neurocognitive impairments in cART era HAND patients. It is therefore possible the MMSE and the IHDS may still be useful among cART-naïve patients even in the cART era. However, only one study has investigated and compared the screening results of the IHDS among cART-naïve and cART experienced patients. All HIV positive patients who visited, or were admitted, to the Ryukyu University Hospital between January 2009 and March 2014 were evaluated for inclusion. Selected patients (n = 49) had data without omission for all tests. The overall prevalence of HAND in our cohort was 44%. The area under the curve (AUC), for all subjects using the MMSE and the IHDS, were 0.60 and 0.69, respectively. However, the AUC among cART-naïve patients were 0.58 and 0.76 for the MMSE and the IHDS, respectively. Whereas, cART experienced patients had an AUC of 0.60 and 0.61, respectively. Overall, the MMSE demonstrated a poor screening ability for HAND, regardless of cART usage (the cut-off value of 27 had a Youden's J-Index of 0.1, in all groups). Alternatively, the IHDS was moderately useful for HAND screening among cART-naïve patients (the cut-off value of 11 had a Youden's J-Index of 0.4), but performed poorly as a screening test among cART experienced patients (the cut-off value of 11 had a Youden's J-Index of 0.1).

Evaluation of the Lipid Concentrations after Switching from Antiretroviral Drug Tenofovir Disoproxil Fumarate/Emtricitabine to Abacavir Sulfate/Lamivudine in Virologically-suppressed Human Immunodeficiency Virus-infected Patients.

Objective Recently, tenofovir disoproxil fumatate (TDF)-related side effects, such as renal nephrotoxicity and reduction of bone mineral density, have been reported. Consequently, increased switching from fixed-dose tablet TDF and emtricitabine (TDF/FTC) to abacavir and lamivudine (ABC/3TC) has occurred. Interestingly, while TDF has a lipid-lowering property, one of the ABC-related side effects is hyperlipidemia. Therefore, such switching could cause lipid elevation. To evaluate the change in lipid levels associated with switching from TDF/FTC to ABC/3TC in virologically-suppressed human immunodeficiency virus (HIV)-infected patients. Methods This is a retrospective, single-center study. We included the HIV-infected patients whose therapy included a drug switch from TDF/FTC to ABC/3TC between September 2009 and December 2012 at Ryukyu University Hospital. The exclusion criteria were HIV-RNA >40 copies/mL on the switching day, and a documented therapy change to a lipid-lowering agent or any other antiretroviral agents within 3 months before or after switching. We compared the low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglyceride (TG) levels before switching to three months after. Results A total of 18 patients met the inclusion criteria. The LDL, HDL, and TC levels significantly increased three months following the switch (p<0.05), with median (interquartile range) values of 17 (7, 32), 6 (2, 13), and 27 (10, 45) mg/dL, respectively. The TG values did not markedly change. Conclusion Switching from TDF/FTC to ABC/3TC resulted in significantly increased LDL, HDL, and TC levels.

Autophagy regulation in pancreatic acinar cells is independent of epidermal growth factor receptor signaling.

Autophagy is an intracellular degradation system in eukaryotic cells that occurs at a basal level. It can also be induced in response to environmental signals including nutrients, hormones, microbial pathogens, and growth factors, although the mechanism is not known in detail. We previously demonstrated that excessive autophagy is induced within pancreatic acinar cells deficient in Spink3, which is a trypsin inhibitor. SPINK1, the human homolog of murine Spink3, has structural similarity to epidermal growth factor (EGF), and can bind and stimulate the EGF receptor (EGFR). To analyze the role of the EGFR in pancreatic development, in the regulation of autophagy in pancreatic acinar cells, and in cerulein-induced pancreatitis, we generated and examined acinar cell-specific Egfr-deficient (Egfr(-/-)) mice. Egfr(-/-) mice showed no abnormalities in pancreatic development, induction of autophagy, or cerulein-induced pancreatitis, suggesting that Egfr is dispensable for autophagy regulation in pancreatic acinar cells.

Chronic pancreatitis in mice by treatment with choline-deficient ethionine-supplemented diet.

Although chronic pancreatitis is a risk factor for pancreatic ductal adenocarcinoma (PDA), the relationship between chronic pancreatitis and PDA remains obscure. A critical obstacle to understanding the role of chronic pancreatitis is the lack of animal models. To develop one such model, mice were fed long-term with a choline deficient ethionine-supplemented (CDE) diet. Histological evaluation revealed that chronic pancreatitis, characterized by acinar atrophy, fibrosis and well-developed tubular complexes (TCs), was observed after 24 weeks of CDE diet treatment. Furthermore, expression of epidermal growth factor receptor (EGFR) and its ligands; serine protease inhibitor Kazal type 3 (Spink3) and transforming growth factor alpha (TGF alpha) and activation of K-Ras (GTP-Ras formation), which are frequently observed in human PDA, were indeed observed in parallel with TCs formation. Neoplastic lesions were not found after 54 weeks of treatment, suggesting that a continuation of CDE diet or another insult is required for the development of PDA.