An attempt at administering a transdermal formulation of bisoprolol in patients with acute cardiac symptoms.

BACKGROUND: Bisono® is the world's first transdermal formulation of a bisoprolol, which is approved for the treatment of hypertension in Japan. We aimed to investigate the usefulness of this formulation in patients who were admitted to our hospital with cardiac symptoms suggestive of acute coronary syndrome or an acute exacerbation of heart failure. METHODS: This study involved a retrospective survey of medical records from September 1, 2017 to April 30, 2018 obtained from the Cardiovascular Center of Kyoto Katsura Hospital. The clinical data of patients on admission who had received a transdermal formula of bisoprolol (Bisono® tape) were retrieved; their blood pressure and heart rate data were analyzed in relation to the doses of Bisono® tape administered. RESULTS: Sixty-three patients received the Bisono® tape. Their final diagnoses included acute myocardial infarction, an exacerbation of heart failure, and atrial fibrillation. While there was no significant correlation observed between the administered doses of the drug and reduction in blood pressure achieved within 24 h after admission, there was a significant (p < 0.05) correlation between the doses of Bisono®tnd reduction in the heart rate within 24 h after admission (ΔHR0-24 h). Only one patient who received 8 mg of Bisono® exhibited temporal bradycardia (heart rate < 50 bpm). CONCLUSION: The transdermal formulation of bisoprolol may be useful for the early introduction of ß-blockers in patients admitted with cardiac symptoms associated with myocardial ischemia or heart failure. However, caution should be exercised because of the possible risk of hypotension.

A retrospective analysis of patient-specific factors on voriconazole clearance.

BACKGROUND: Voriconazole concentrations display a large variability, which cannot completely be explained by known factors. We investigated the relationships of voriconazole concentration with patient-specific variables and concomitant medication to identify clinical factors affecting voriconazole clearance. METHODS: A retrospective chart review of voriconazole trough concentration, laboratory data, and concomitant medication in patients was performed. The concentration/dose ratio (C/D-ratio) was assessed as a surrogate marker of total clearance by dividing voriconazole concentration by daily dose per kg of body weight. RESULTS: A total of 77 samples from 63 patients were obtained. In multiple linear regression analysis, increased C-reactive protein (CRP) level (p < 0.05) and decreased albumin (Alb) level (p < 0.05) were associated with significantly increased C/D-ratio of voriconazole, and coadministration with a glucocorticoid was associated with significantly (p < 0.05) decreased C/D-ratio of voriconazole (adjusted r (2) = 0.31). Regarding CRP and Alb, receiver operating characteristic curve analysis indicated that increased CRP level and decreased Alb level were significant predictors of toxic trough concentration of voriconazole. For CRP, area under the curve (AUC) and cutoff value were 0.71 (95 % confidence interval (CI), 0.57-0.86, p < 0.01) and 4.7 mg/dl, respectively. For Alb, AUC and cutoff value were 0.68 (95 % CI, 0.53-0.82, p < 0.05) and 2.7 g/dl, respectively. A significant difference was seen in voriconazole trough concentration between patients with hepatotoxicity and those without (5.69 µg/ml vs 3.0 µg/ml, p < 0.001). CONCLUSION: Coadministration of glucocorticoid and inflammation, reflected by elevated CRP level and hypoalbuminemia, are associated with voriconazole clearance. We propose that early measurement of voriconazole concentration before the plateau phase will lead to avoidance of a toxic voriconazole level in patients with elevated CRP level and hypoalbuminemia, although further studies are needed to confirm our findings.

Molecular mechanisms in dizocilpine-induced attenuation of development of morphine dependence: an association with cortical Ca2+/calmodulin-dependent signal cascade.

We investigated how dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, affects the development of morphine dependence in mice. Co-administration of dizocilpine (0.25 mg/kg) and morphine (10 mg/kg) for 5 days attenuated the development of tolerance to the antinociceptive effects of morphine. The withdrawal manifestation induced by the naloxone-challenge (5 mg/kg) was significantly reduced in mice that were treated with a combination of dizocilpine and morphine, compared to the mice treated with morphine and saline. The present study revealed a significant increase in c-Fos protein expression in the cortex and thalamus of mice showing naloxone-precipitated withdrawal syndrome. The combination of dizocilpine and morphine prevented the increase of c-Fos protein expression in the cortex and thalamus. Interestingly, repeated co-administration of dizocilpine and morphine prevented the withdrawal-induced phosphorylation of Ca2+/calmodulin kinase II (p-CaMK II) in the cortex, but not in the thalamus. Acute dizocilpine treatment prior to the naloxone-challenge and repeated treatment with dizocilpine alone had no effect on analgesia, withdrawal manifestations, p-CaMK II levels or c-Fos protein levels. These results showed that co-administration of dizocilpine and morphine prevented the development of morphine tolerance and dependence and suggested that the preventive effect of dizocilpine results from the regulation of c-Fos protein expression, which is possibly involved in the activation of the Ca2+/calmodulin-dependent signal cascade in the cortex.