Effect of chronic administration of ritonavir on function of cytochrome P450 3A and P-glycoprotein in rats

Ritonavir (RTV) is well known as an inhibitor of many drugs that are metabolized by cytochrome P450 (CYP) 3A or fluxed via P-glycoprotein (Pgp), although it is also reported that RTV is a potent inducer for them. In this study, to elucidate these contradictory phenomena, functional changes of CYP3A or Pgp during chronic administration of RTV were examined in rats. After pretreatment with RTV for indicated days (day 3-day 14), rats were used in the experiments. The area under the plasma drug concentration vs. time curve (AUC(0-infinity)) after oral administration of RTV (20 mg/kg) to these rats showed an RTV-treatment period-dependent decrease, and the mean AUC(0-infinity) of RTV in Day 14 rats decreased significantly by 57% as compared to the control. The AUC(0-infinity) after intravenous (i.v.) administration of RTV to Day 3 and Day 5 rats increased significantly by 28% and 22%, respectively, while there were no significant changes in the AUC(0-infinity) in Day 7 and Day 14 rats as compared to the control. As for i.v. administration of erythromycin (EM) or midazolam (MDZ) to RTV-treated rats, the AUC(0-infinity)in Day 3 and Day 5 rats increased significantly as compared to the control, while in Day 7 rats and rifampicin-treated rats, the AUC(0-infinity) of EM decreased significantly by 82% and 42%, respectively, as compared to the control. For MDZ, there were no significant changes in the AUC(0-infinity) in Day 7 or Day 14 rats. After i.v. administration of rhodamine123 (Rho123), the excretion clearances from blood circulation to the intestinal lumen and the biliary excretion clearances in Day 14 rats increased markedly by 2.2-fold and 2.6-fold as compared to the control. It has been confirmed that RTV is not only a potent inhibitor but also a potent inducer of CYP3A, and that RTV is a potent inducer of intestinal Pgp. This property of RTV is responsible for regulating the oral bioavailability of drugs that are mediated by CYP3A and Pgp.     

Apoptosis-mediated cytotoxicity of prodigiosin-like red pigment produced by gamma-Proteobacterium and its multiple bioactivities

Recently we discovered a bacterial strain (MS-02-063) that produces large amounts of red pigment (PG-L-1). Among the cell lines tested, U937 cells showed the highest susceptibility to PG-L-1 toxicity. PG-L-1 induced typical apoptotic nuclear morphological changes, and single cell gel electrophoresis revealed that PG-L-1 caused DNA fragmentation in U937 cells. In PG-L-1 treated U937 cells, the acidic compartment such as lysosomes disappeared, suggesting that PG-L-1-induced disorder of intracellular pH compartmentalization might trigger apoptotic signal. Since p38 MAP kinase inhibitor specifically prevented the PG-L-1 mediated cell death, p38 MAP kinase may be involved in the cytotoxic mechanism. In fact, immunoblot analysis of p38 MAP kinase revealed that phosphorylation of p38 MAP kinase occurred in PG-L-1-treated U937 cells. In addition to the activity to induce apoptotic cell death as reported in several PG family members, our chemiluminescence analysis suggested that PG-L-1 inhibited superoxide generation by 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated U937 cells in a dose-dependent manner. Since PG-L-1 had no effect on the chemiluminescence response caused by xanthine oxidase/hypoxanthine system, PG-L-1 acts on the enzyme system responsible for O(2)(-) generation rather than direct scavenging toward O(2)(-). Our results suggest that PG-L-1 causes multiple biochemical effects on the target cells such as increase in pH in acidic intracellular compartment, activation of p38 MAP kinase, inhibition of O(2)(-) generation, and eventually induces apoptotic cell death.     

Usefulness of the percentage of plasma lymphocytes as a prognostic marker in patients with congestive heart failure

This prospective study was designed to evaluate the prognostic value of the percentage of plasma lymphocytes in patients with diastolic dysfunction as well as systolic dysfunction of the left ventricle. The subjects were 70 consecutive patients who were hospitalized in our institution from April 2001 to August 2002. Following the improvement of congestive heart failure, leukocyte differentiation and neurohumoral factors (plasma levels of atrial and brain natriuretic peptide, norepinephrine, epinephrine, and dopamine) were measured. During the follow-up period (17 +/- 9 months), 18 patients experienced a cardiac event. In the univariate analysis, the percentage of plasma lymphocytes in the cardiac event group was significantly less than that in the noncardiac event group (24.7 +/- 8.40 vs 33.3 +/- 7.64%, P = 0.0006), and brain natriuretic peptide was significantly larger in the cardiac event group (402 +/- 168 vs 153 +/- 51 pg/mL, P = 0.04). However, in patients with preserved systolic function, there was a significant difference in the percentage of plasma lymphocytes between the cardiac and noncardiac event groups (21.7 +/- 9.42 vs 34.2 +/- 8.21%, P = 0.037), although no difference was observed in brain natriuretic peptide (133 +/- 43 vs 125 +/- 50 pg/mL, P = 0.87). Multivariate analysis showed the percentage of plasma lymphocytes was an independent predictor of a cardiac event. The percentage of plasma lymphocytes may be useful for predicting the course of patients with congestive heart failure based on diastolic dysfunction as well as systolic dysfunction.     

Cell distribution differences of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in patients with kawasaki disease

The interaction of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase-1 has been implicated in the formation of coronary aneurysms in Kawasaki disease. MMP-9 and tissue inhibitor of matrix metalloproteinase-1 were distributed predominantly in the granulocytes and platelets, respectively, in patients with Kawasaki disease. The plasma values of MMP-9 correlated positively with the circulating neutrophil count. Inhibiting the activity of granulocytes and maintaining the platelet activity might prevent coronary aneurysms.     

Pediatric orbital schwannoma originating from the oculomotor nerve

Intraorbital schwannoma is a rare tumor that constitutes approximately 1%-8% of all orbital tumors. The authors report a case of orbital schwannoma in a 5-year-old boy who was admitted to their institute with exophthalmos and ptosis of the right eye. Computed tomography scanning and MR imaging revealed a retroocular mass in the right orbit. The tumor was successfully removed via a transcranial approach. The pathological diagnosis was schwannoma that appeared to originate from the superior branch of the oculomotor nerve. Despite the rarity of these intraorbital extraocular tumors in children, schwannomas should be differentiated from other intraorbital tumors.     

Inertial migration of cancer cells in blood flow in microchannels

The circulating tumor cell test is used to evaluate the condition of breast cancer patients by counting the number of cancer cells in peripheral blood samples. Although microfluidic systems to detect or separate cells using the inertial migration effect may be applied to this test, the hydrodynamic forces acting on cancer cells in high hematocrit blood flow are incompletely understood. In the present study, we investigated the inertial migration of cancer cells in high hematocrit blood flow in microchannels. The maximum hematocrit used in this study was about 40%. By measuring the cell migration probability, we examined the effects of cell–cell interactions, cell deformability, and variations in cell size on the inertial migration of cancer cells in blood. The results clearly illustrate that cancer cells can migrate towards equilibrium positions up to a hematocrit level of 10%. We also performed simple scaling analysis to explain the differences in migration length between rigid particles and cancer cells as well as the effect of hematocrit on cancer cell migration. These results will be important for the design of microfluidic devices for separating cells from blood.     

Dorsally extended digital island flap for repairing soft tissue injury of the fingertip

Background

The digital triangular island flap is one of the most useful types of flap for repairing soft-tissue loss at the fingertip, because it is sensate and has glabrous skin. However, this type of flap has several disadvantages, including limited length of advancement and limited flap size.

Methods

We have developed a new type of dorsally extended digital island flap to extend the reach of the digital triangular island flap. This dorsally extended portion, 15 mm in width and 20 mm in length, is based on the dorsal branch of the digital artery at the distal phalanx level. This island flap has a longer reach than the conventional digital island flap and can transfer larger amounts of soft tissue to the injured fingertip. Sixteen patients with fingertip amputation were treated using this flap.

Results

All of the flaps survived. The dorsally extended digital island flap could repair pulp tissue losses up to 30 mm in length in oblique volar injury. In transverse injury, a new fingertip could be produced with this flap in a single stage. We successfully covered the exposed bone without shortening the digital bone of the fingertip using our extended flap. No claw nail deformity occurred and no flexion contracture remained in any of the cases.

Conclusion

Use of a dorsally extended digital island flap is recommended for repairing fingertip injury in cases with defect sizes ranging from 10 to 30 mm in length and also in both oblique volar and transverse injuries. This flap is more versatile for repair of fingertip injury than the conventional digital island flap.