Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam

The effects of repeated ingestion of grapefruit juice, an inhibitor of cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics and pharmacodynamics of both single and multiple oral doses of alprazolam, a substrate of CYP3A4, were examined. In study 1, eight healthy volunteers ingesting 600 ml/day water or grapefruit juice for 10 days took a single oral 0.8-mg dose of alprazolam on the eighth day. Plasma drug concentrations were monitored up to 48 h after alprazolam dosing together with evaluation of psychomotor function. Grapefruit juice altered neither the plasma concentrations of alprazolam at any time points, any pharmacokinetic parameters, nor the majority of psychomotor function parameters in subjects. In study 2, 11 patients with anxiety disorders receiving alprazolam (0.8-2.4 mg/day) ingested grapefruit juice (600 ml/day) for 7 days. Blood samples were collected before and during grapefruit juice ingestion and 1 week after its discontinuation together with an assessment of clinical status. Grapefruit juice altered neither the steady-state plasma concentration of alprazolam nor the clinical status in patients. The present study shows that grapefruit juice is unlikely to affect pharmacokinetics or pharmacodynamics of alprazolam due to its high bioavailability.     

New monordens produced by amidepsine-producing fungus Humicola sp. FO-2942

Based on UV spectrum-guided purification, new monordens C, D and E, known monordens A (radicicol) and B and 5-O-methylsclerone were isolated from the fermentation broth of amidepsine-producing Humicola sp. FO-2942 by solvent extraction, silica-gel column chromatography, ODS column chromatography and HPLC. All monordens cause the cell cycle arrest at G1 and G2/M phases in Jurkat cells. But among them, monordens A and E show antifungal activity only against Aspergillus niger.     

Evaluation of image qualities on the international standard video-conferencing

International standard-based video-conferencing systems are widely used in telemedicine activities worldwide. Through our experiences with these systems, it is apparent that the image quality is high enough to conduct educational and conferential sessions. However, because the terminals are intended for common use, we evaluated their qualities. After having an international standard system evaluated by a general practitioner using medical images, we prepared non-medical graphic images to examine the characteristics of the video-conferencing equipment. ROC (Receiver Operation Characteristic) analysis was employed for the evaluation. We concluded that the international standard video-conferencing systems are of sufficient quality for medical presentations, and that their interactivity and the use of proper software will aid the understanding of images in specific medical areas.     

Papillary renal cell carcinoma in a young adult: serial changes in diagnostic images

In renal tumors, we often encounter cases in which accurate diagnosis before surgery is difficult. The serial changes in various diagnostic images were studied in a case of renal cell carcinoma in which definitive diagnosis could not be made by various imaging examinations and biopsies. We report on a case of renal cell carcinoma in a young adult. A 19-year old man complained of left flank pain and pyrexia. Computerized tomography (CT) scan and urography revealed a solid mass in the left kidney. Angiography revealed no abnormality, and CT scan after 3 months showed that the mass was decreasing in size, which suggested an inflammatory mass. CT scan and retorograde pyelography 12 months later showed that the tumor had enlarged and that much of the tumor had extended into the renal pelvis. Left nephrectomy was performed and histological examination revealed that the tumor was papillary renal cell carcinoma. When imaging results and clinical symptoms are atypical, pre-surgery diagnosis of renal cell carcinoma is extremely difficult. In such cases, we found that it was effective to observe the changes in various diagnostic images and to make an overall judgment based on these results.     

Effect of grapefruit juice on the disposition of manidipine enantiomers in healthy subjects

AIM: To examine the effect of grapefruit juice, an inhibitor of CYP3A4 in the small intestine, on the disposition of manidipine enantiomers in healthy subjects. METHODS: A randomized cross-over study with at least a 2-week wash-out period was performed. Seven healthy male volunteers received an oral 40-mg dose of racemic manidipine after an overnight fast with either grapefruit juice (GFJ) or water, as a control study. Plasma concentrations of (S)- and (R)-manidipine were monitored up to 10 h after the dosing. RESULTS: The plasma concentrations of (S)-manidipine were significantly higher (P<0.001) than those of (R)-manidipine in the control phase with an S/R ratio for the AUC0-infinity of 1.62 (95% confidence interval 1.52, 1.73). GFJ significantly increased Cmax and AUC0-infinity of (S)-manidipine by 2.4-fold (P<0.01) and 2.3-fold (P<0.01), respectively, and Cmax and AUC0-infinity of (R)-manidipine were increased by 3.4-fold (P<0.01) and 3.0-fold (P<0.01), respectively. There were significant differences (P<0.01) in GFJ-mediated percentage increases in Cmax and AUC0-infinity of (S)-manidipine compared with those of (R)-manidipine. The S/R ratio for AUC0-infinity was significantly decreased from 1.6 to 1.2 during the GFJ phase (P<0.01). CONCLUSION: These results indicate that the stereoselective disposition of manidipine was altered by GFJ, as an inhibitor of CYP3A4. GFJ appears to affect this metabolic disposal of (R)-manidipine to a greater extent than that of (S)-manidipine.     

Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein

AIMS: Fexofenadine is a substrate of several drug transporters including P-glycoprotein. Our objective was to evaluate the possible effects of two P-glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P-glycoprotein activity in vivo, and compare the inhibitory effect between the two in healthy volunteers. METHODS: In a randomized three-phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing. RESULTS: Itraconazole pretreatment significantly increased mean (+/-SD) peak plasma concentration (Cmax) of fexofenadine from 699 (+/-366) ng ml-1 to 1346 (+/-561) ng ml-1 (95% CI of differences 253, 1040; P<0.005) and the area under the plasma concentration-time curve [AUC0,infinity] from 4133 (+/-1776) ng ml-1 h to 11287 (+/-4552) ng ml-1 h (95% CI 3731, 10575; P<0.0001). Elimination half-life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affect Cmax (704+/-316 ng ml-1, 95% CI -145, 155), AUC0, infinity (4433+/-1565 ng ml-1 h, 95% CI -1353, 754), or other pharmacokinetic parameters of fexofenadine. CONCLUSIONS: Although some drug transporters other than P-glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first-pass effect by inhibiting the P-glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P-glycoprotein activity in vivo.     

Congenital melanocytic nevi and nevus spilus have a tendency to follow the lines of Blaschko: an examination of 200 cases

There have been few reports about the characteristics of the pigmentary arrangement of congenital melanocytic nevi (CMN) and nevus spilus (NS). Though the lines of Blaschko, which don't correspond to other lines such as Langer's lines and skin dermatomes, are well known to be followed by some rare pigmentary disorders, the relationship between these two disorders and the lines of Blaschko has not been discussed. Therefore, through an examination of 200 cases, we investigated whether or not the arrangement of CMN and NS follow the lines of Blaschko. Thirty-nine out of 92 cases (42.4%) of CMN and 67 out of 108 cases (62.0%) of NS were considered to follow the lines of Blaschko. Today, the idea is widely accepted that two functionally different cells proliferate during early embryogenesis of the skin which is caused from mosaicism and, as a result, the lines of Blaschko appear visually. In our results, we found that there were some cases of CMN and NS which showed a relationship with the lines of Blaschko, which is meaningful considering that the lesions and the lines are both related to pigmentary gene anomalies. The result was compared with CMN and NS by the chi(2) test. NS showed a predominant tendency to follow the lines with a significant difference (P = 0.0055). This may indicate that the lines of Blaschko reflect more clearly the proliferation of the epidermal cells than other cells in growth of the skin of the embryo. Further studies are required to elucidate the reason why some cases follow these lines and others do not.     

Diagnostic localization of extra-adrenal pheochromocytoma: comparison of (123)I-MIBG imaging and (131)I-MIBG imaging

The accurate diagnostic localization of extra-adrenal pheochromocytoma is important in the treatment of primary and metastatic tumors. In this study, we report on a case of extra-adrenal pheochromocytoma in which the tumor could not be diagnosed by 131I-metaiodobenzylguanidine (MIBG) scintigraphy but only by 123I-MIBG scintigraphy. Our patient was a 16-year old girl whose chief complaint was headaches. High levels of catecholamines were detected in the blood and urine samples. 131I-MIBG scintigraphy could not detect any abnormal accumulation, but an accumulation of 123I-MIBG was found in the pelvis. Magnetic resonance imaging (MRI) revealed a broad-based bladder tumor at the site of the accumulation. Partial cystectomy was performed, and immunohistochemical staining examination confirmed the diagnosis of extra-adrenal pheochromocytoma in the urinary bladder. In this report, we compare 131I-MIBG scintigraphy with 123I-MIBG scintigraphy and discuss their characteristics.     

Response to Commentary on “The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients”

In a recent review, we have suggested a neuroinvasive potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its possible role in the causation of acute respiratory failure of coronavirus disease 2019 (COVID-19) patients (J Med Viol doi: 10.1002/jmv.25728), based upon the clinical and experimental data available on the past SARS-CoV-1 and the recent SARS-CoV-2 pandemic. In this article, we provide new evidence recently reported regarding the neurotropic potential of SARS-CoV-2 and respond to several comments on our previously published article. In addition, we also discuss the peculiar manifestations of respiratory failure in COVID-19 patients and the possible involvement of nervous system.