CYP isoforms involved in the metabolism of clarithromycin in vitro: comparison between the identification from disappearance rate and that from formation rate of metabolites

To clarify whether CYP2C19 is involved in the overall metabolism of clarithromycin (CAM) or not, in vitro studies using human liver microsomes and recombinant CYPs were performed by an approach based on the disappearance rate of parent compound from the incubation mixture. In addition, the results of disappearance rate were compared with those obtained from the formation rates of the major metabolites of CAM, 14-(R)-hydroxy-CAM and N-demethyl-CAM.The intrinsic clearance (CL(int)) values determined from the disappearance of CAM in nine different human liver microsomes were highly correlated with the testosterone 6beta-hydroxylation activity (r=0.957, p<0.001). The CL(int) of CAM was markedly reduced by selective inhibitors of CYP3A4 (ketoconazole and troleandomycin) and by polyclonal antibodies raised against CYP3A4/5 in human liver microsomes. Among the 11 isoforms of recombinant human CYP, only CYP3A4 revealed the metabolic activity for the disappearance of CAM. These results were fairly consistent with those obtained from the conventional approach based on the formation of major metabolites of CAM. Comparison of the kinetic parameters estimated from the disappearance rate of CAM and the formation rates of 14-(R)-hydroxy-CAM and N-demethyl-CAM indicates that N-demethylation and 14-(R)-hydroxylation account for 65% of CL(int) derived from the disappearance of CAM in human liver microsomes.The findings suggest that CYP3A4 plays a predominant role in the overall metabolic clearance of CAM as well as in the formation of 14-(R)-hydroxy-CAM and N-demethyl-CAM. CYP2C19 does not appear to be involved in the overall metabolism of CAM at least in human liver microsomes. A combination of the disappearance rate of a parent compound and the formation rate of metabolites appears to be a useful approach for estimating the percentage contribution of the formation of metabolites to the overall metabolic clearance of a parent compound in vitro.     

Retrospektive Analyse von Frakturen des Viszerokraniums nach Sturztraumen in einem japanischen Patientenkollektiv

Objective. Numerous epidemiological studies concerning fall-related injuries have been performed in the geriatric and orthopedic field to clarify the relation between the type of fall and fracture patterns. Although falls are a common cause of facial fractures, there is no study describing these relations. This study thus investigates the relationship between the type of fall and fracture pattern. Materials and methods. We analyzed 260 patients with fall-related facial fractures treated between 1995 and 2000 at the First Department of Oral and Maxillofacial Surgery, Osaka University Dental Hospital, Japan. These patients were classified into two groups: (1) those who suffered fractures by a fall from a standing position or lower and (2) those who suffered fractures by a fall from a level higher than the standing position. Results. Fractures caused by falling from a standing position or lower was more common in older patients, especially in women beyond 70 years. The localization of mandibular fractures was not significantly different between the two groups. However, a high incidence of midface fractures was observed in the patients who fell from a higher position. These patients tended to suffer from central midface or dislocated fractures. Conclusion. The results were consistent with recent orthopedic studies, which suggest a relation between fractures in old patients and osteoporosis. A strong force caused by falls from a high position tends to act on the high portion of the midface. Our classification based on the height of the falls was able to demonstrate clearly the relation between etiological factors and fracture patterns. Therefore, it seemed reasonable to analyze patients treated in the Department of Oral and Maxillofacial Surgery, Heidelberg University, Germany, according to the same classification in order to compare both collectives.     

Spatial reference and standing posture during high-speed Coriolis stimulation

BACKGROUND: In a previous study, we found that sensation, gaze, and posture during Coriolis stimulation differ considerably between vision and nonvision conditions during rotations at 60 degrees x s(-1). To determine the validity of these findings at higher velocities, we compared standing postures during Coriolis stimulation up to 150 degrees x s(-1) between vision and nonvision conditions. METHODS: The 19 subjects underwent 5-min rotation tests at 50 to 150 degrees x s(-1). While standing on a force platform attached to a rotating device, each subject tilted his or her head and then returned it to upright, first with the eyes covered, then with eyes open. Six subjects were re-examined 5 d later after 4 consecutive days of 20-min rotations with their eyes open. We assessed success and failure to stand and recorded the center of pressure during rotation. RESULTS: Although success rates (number of successes/19) differed between vision and nonvision conditions at 50 degrees x s(-1) (94.7% vs. 57.9%), they steeply decreased as rotation velocity increased and showed no difference at 70 degrees x s(-1) and faster velocities. After the 4-d exposure, however, subjects could stand at higher velocities particularly under the vision condition. A patient with bilateral labyrinthine loss, being examined for reference, could stand at 110 degrees x s(-1) even with the eyes covered. CONCLUSIONS: Untrained subjects frequently fell during high-speed Coriolis stimulation, apparently because vision was insufficient to provide a spatial reference frame from the stationary surroundings. Following rotation training with their eyes open, subjects appeared more able to use the visual reference frame and falls were reduced.     

Replacement of the aortic root and ascending aorta using a freestyle valve and woven Dacron graft

We contrived a surgical technique for the purpose of improving recent results. From April 1998 to June 2001, 24 patients (aged 60 to 81 years, mean age 71.0 +/- 4.8 years; 11 men, 13 women) underwent replacement of the aortic root and the ascending aorta electively using a Freestyle stentless valve with woven Dacron graft at our institution. The aortic root was replaced first, the distal side of the Dacron graft was then anastomosed, and finally, the proximal side was anastomosed with the outflow of the Freestyle valve. Cardiopulmonary bypass time and cardioplegic time were 297 +/- 83 min and 210 +/- 51 min, respectively. The geometry of the ascending aorta and the diameter mismatch between the dilated ascending aorta and the outflow of the Freestyle valve were fully corrected. There were two early deaths and three late deaths; none valve-related. Postoperative aortogram showed an excellent shape. The mortality, morbidity, and clinical events after the procedure were acceptable.     

Islet hyperperfusion during prediabetic phase in OLETF rats,a model of type 2 diabetes

Although it has been hypothesized that initial hyperperfusion followed by late hypoperfusion in islet circulation occurs in rodent models of type 2 diabetes, islet blood flow has not been measured during prediabetic phase. We studied islet blood flow in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of slowly progressive obese type 2 diabetes. Islet blood flow was measured by the two-color microsphere method under anesthesia at different ages. Islet blood flow was significantly higher in young OLETF rats compared with control Long-Evans Tokushima Otsuka (LETO) rats when the former were not obese or diabetic and had normal insulin secretion at 5 weeks of age (LETO 4.6 +/- 1.1, OLETF 8.8 +/- 1.2 ml. min(-1). mg(- 1), P < 0.01). At 6 months of age, islet hyperperfusion was observed in OLETF rats, and >40% of whole pancreatic blood flow was diverted into islets in OLETF rats. Prevention of obesity by food restriction increased basal islet blood flow. On the other hand, long-term hyperglycemia induced by sucrose feeding decreased fractional islet blood flow as well as glucose-stimulated islet blood flow. Our results indicate that hyperperfusion is present during the preobese and prediabetic phase in our type 2 diabetes rats.     

Chronic central infusion of orexin-A increases arterial pressure in rats

We determined the cardiovascular responses as well as food and water intakes to chronic intracerebroventricular administration of orexin-A and orexin-B for 14 days in conscious rats. Chronic intracerebroventricular infusion of orexin-A (50 pmol/h) elicited a significant increase in systolic blood pressure on the third day (+15.6 +/- 2.9 mm Hg), and during the continuous intracerebroventricular infusion of orexin-A the blood pressure returned to the baseline levels at day 14. In contrast, chronic intracerebroventricular infusion of orexin-B (50 pmol/h) failed to change systolic blood pressure during the 14 days of experimental periods. Chronic intracerebroventricular infusions of neither orexin-A nor orexin-B changed urinary catecholamine excretions, food and water intakes, and urine volumes at 7 and 14 days of infusion periods. Mean arterial pressure directly measured at 14 days did not differ among the groups of orexin-A, orexin-B, and artificial cerebrospinal fluid treatments. Both intravenous injections of pentolinium (5 mg/kg), a ganglion blocking agent, and CV-11974 (0.05 mg/kg), an AT(1) receptor antagonist, decreased arterial pressure; however, these responses were not different among the groups. These results suggest that central orexin-A participates in the short-term regulation of blood pressure; however, the contributions of central orexins to the long-term regulations of blood pressure, sympathetic nervous system, and appetite may be little.     

Embolization of the right gastric artery before hepatic arterial infusion chemotherapy to prevent gastric mucosal lesions: approach through the hepatic artery versus the left gastric artery

OBJECTIVE: The purpose of our study was to evaluate whether the hepatic artery or the left gastric artery is the better route of approach for selective embolization of the right gastric artery before hepatic arterial infusion chemotherapy using a port-catheter system. SUBJECTS AND METHODS: Eighty-six patients (56 men, 30 women; mean age, 62.1 years) with unresectable advanced liver cancer underwent percutaneous implantation of a port-catheter system. In the 75 patients who had not undergone gastrectomy, right gastric artery embolization was performed before port-catheter system placement to prevent gastric mucosal lesions. In 43 patients, the approach for embolization was through a microcatheter inserted from the hepatic artery site, and in the remaining 32 patients, the approach was from the left gastric artery. The success rates of these two groups were compared. RESULTS: Embolization was successfully accomplished at the first attempt in 72.1% of the 43 patients in whom the microcatheter was inserted from the hepatic artery site. In contrast, in 93.8% of 32 patients, embolization was successfully performed through the left gastric artery. The success rate of embolization was significantly higher in the latter group (p = 0.0173, chi-square test). A second attempt in which the catheter was redirected to another approach, performed on the same day in a majority of patients, resulted in successful embolization in an additional eight patients, with a final success rate of 92.0%. CONCLUSION: Embolization of the right gastric artery using microcoils through a microcatheter advanced through the left gastric artery may be the preferred method for the preparation of repeated hepatic artery infusion.     

A patient with two thyroid papillary carcinomas demonstrating hot and cold lesions on 113I thyroid scintigraphy

A 44-year-old euthyroid woman had two palpable nodules in the thyroid gland. 123I thyroid scintigraphy showed a hot nodule in the right lobe and a cold one in the left lobe. Total thyroidectomy was performed, and histopathologic examination revealed that both tumors contained papillary carcinoma. Thus, hot nodules on a thyroid scintigram with 123I do not necessarily preclude malignancy.     

Evaluation of radioiodinated 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine as a ligand for SPECT investigations of brain nicotinic acetylcholine receptors

5-Iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), an A-85380 analog iodinated at the 5-position of the pyridine ring, was evaluated as a radiopharmaceutical for investigating brain nicotinic acethylcholine receptors (nAChRs) by single photon emission computed tomography (SPECT). [123/125I]5IA was synthesized by the iododestannylation reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC) with high radiochemical yield (50%), high radiochemical purity (> 98%), and high specific radioactivity (> 55 GBq/micromol). The binding affinity of 5IA for brain nAChRs was measured in terms of displacement of [3H]cytisine and [125I]5IA from binding sites in rat cortical membranes. The binding data revealed that the affinity of 5IA was the same as that of A-85380 and more than seven fold higher than that of (-)-nicotine, and that 5IA bound selectively to the alpha4beta2 nAChR subtype. Biodistribution studies in rats indicated that the brain uptake of [125I]51A was rapid and profound. Regional cerebral distribution studies in rats demonstrated that the accumulation of [125I]5IA was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus, moderate uptake in the cortex and lowest uptake in the cerebellum. Administration of the nAChR agonists (-)-cytisine and (-)-nicotine reduced the uptake of [125I]5IA in all regions studied with most pronounced reduction in the thalamus, and resulted in similar levels of radioactivity throughout the brain. [125I]5IA binding sites were shown to be saturable with unlabeled 5IA. Behavioral studies in mice demonstrated that 5IA did not show signs of behavioral toxicity. Furthermore, SPECT studies with [123I]5IA in the common marmoset demonstrated appropriate brain uptake and regional localization for a high-affinity nAChR imaging radiopharmaceutical. These results suggested that [123I]5IA is a promising radiopharmaceutical for SPECT studies of central nAChRs in human subjects.     

Changes in levels of serum erythropoietin, serum iron and unsaturated iron binding capacity during chemotherapy for lung cancer

BACKGROUND: The serum erythropoietin level increases markedly during chemotherapy for leukemia. A number of hypotheses have been built for the mechanism, none of them satisfactory. Difficulty in evaluating bone marrow activity hampers the elucidation. Therefore, we focused on patients who had non-hematological cancer and no evidence of bone marrow suppression. METHODS: Twelve patients, who had lung cancer (four with small cell cancer and eight with non-small cell cancer) and who had not undergone any chemotherapy, were studied. During chemotherapy, we measured serum erythropoietin, serum iron, unsaturated iron binding capacity and hemoglobin concentration in these patients. RESULTS: The serum erythropoietin level before chemotherapy (10.8 +/- 7.4 mU/ml) was within the normal range but the peak values after the first treatment (73.4 +/- 90.4 mU/ml) increased in all patients. In the patients with small cell cancer, a transient but marked increase in erythropoietin value (204.6 +/- 167.3 mU/ml) was observed after each session of chemotherapy while hemoglobin concentration decreased gradually. Throughout treatments, elevation of the serum iron concentration and concomitant reduction of unsaturated iron binding capacity were observed after each session of chemotherapy. They regained their original values whilst the serum erythropoietin level decreased after each chemotherapy session was completed. CONCLUSIONS: It is suggested that the suppression of erythroid marrow by chemotherapeutic agents causes the changes in serum erythropoietin level during chemotherapy in patients with lung cancer.