Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 µg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 µg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · µg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

Pharmacokinetics and bioequivalence evaluation of leflunomide tablets in Korean healthy volunteers.

Leflunomide is a disease-modifying antirheumatic drug. The purpose of this study was to evaluate the bioequivalence of a test drug (CJ leflunomide) and a commercially available reference drug (Arava®) at 2 doses (10 and 20 mg) in healthy Korean volunteers. This was a single-dose (28 individuals enrolled at each dose group), randomized, open-label, 2-way crossover study. The 2 treatment periods were separated by a 56-day wash-out interval. Blood sampling was conducted until 672 h after drug administration. Plasma teriflunomide (active metabolite of leflunomide) concentrations were determined, and pharmacokinetic parameters were calculated. Bioequivalence was evaluated using an ANOVA model, based on the AUCt and the Cmax after administration of leflunomide tablets. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUCt and Cmax for the test and reference drugs being within the range of 0.80-1.25. The GMRs (90% CI) for AUCt and Cmax were 0.9506 (0.9091-0.9941) and 0.9861 (0.9360-1.0389), respectively, in the 10 mg study, and 0.9524 (0.9101-0.9968) and 0.9740 (0.9314-1.0186), respectively, in the 20 mg study. The 90% CIs of AUCt and Cmax at each dose were within the accepted range for bioequivalence. Based on the results, the test drug (CJ leflunomide) was bioequivalent to the commercially available reference drug (Arava®) at both doses.

Histopathological and immunohistochemical comparison of the brain of human patients with Alzheimer's disease and the brain of aged dogs with cognitive dysfunction.

Alzheimer's disease (AD) is the most common progressive form of dementia in aged people. Microscopical changes in the brains of AD patients include the formation of senile plaques (SPs), neurofibrillary tangles (NFTs) and granulovacuolar degeneration and the deposition of amyloid-beta (Aß). Aged dogs are known to suffer from cognitive dysfunction and this state is associated with deposition of Aß in the brain. The aim of the present study was to investigate tau phosphorylation of neurons and astrocytes in the brain of aged dogs with progressive cognitive impairment. Changes in the brain of aged dogs with cognitive dysfunction were compared with those in the brain of patients with AD of Braak stage V. Immunohistochemically, Aß deposition, phosphorylated tau Ser396 (p-tau Ser396) and ubiquitin were observed in the parietal cortex and hippocampus of aged dogs with cognitive dysfunction. Astrocytes with expression of p-tau Ser396 and neurons with co-localization of p-tau Ser396 and ubiquitin were observed. Expression of p-tau Ser396 and accumulation of ubiquitin were significantly increased in the parietal cortex and dorsal part of the hippocampus of the brain of aged dogs when compared with expression of these molecules in human AD.

Relationship between ambient temperature and heat flux in the scrotal skin.

Excessive scrotal heating or cooling may lead to the cessation of spermatogenesis. Data regarding heat exchange rates in scrotal skin can be used to control testicular temperature within the appropriate range. Heat flux (HF) in the scrotal skin surface is generated based on the surrounding environment. This study aims to elucidate the HF of scrotal skin by varying ambient temperature. Twenty college students including seven varicoceles volunteered as the subjects (mean age: 22.95 +/- SD 1.96 years; height: 175.00 +/- 5.17 cm; weight: 68.40 +/- 8.65 kg; body mass index: 22.28 +/- 2.15), and participated in the experiments from September 11 to October 4, 2006. The environmental temperature was controlled at 20 degrees C and 25 degrees C in the first and second experiment respectively. The HF and skin temperature on both sides of the scrotal surface were measured for 60 min in the environmental chamber. The results revealed that the HF was 87.64 +/- 12.69 W/m(2) and 78.91 +/- 12.09 W/m(2) in the left and right side of the scrotum respectively. The scrotal skin temperature (SST) was 30.28 +/- 0.75 degrees C and 30.24 +/- 0.62 degrees C on the left and right side of the scrotum in the 20 degrees C environment respectively. In the 25 degrees C environment the HF was 53.54 +/- 8.86 W/m(2) and 45.25 +/- 8.32 W/m(2), and the SST was 32.29 +/- 0.61 degrees C and 32.07 +/- 0.36 degrees C on the left and right side of the scrotum respectively. The cooling source power to decrease testicular temperature is suggested at 290 W/m(2). This suggested value could be adopted a cooling device as clinical therapy for a heat stress patient to decrease testicular temperature affecting spermatogenesis.

Effect of floor surface temperature on blood flow and skin temperature in the foot.

UNLABELLED: A total of 16 healthy college students participated as subjects to elucidate the hypothesis that blood flow and skin temperature in foot are affected by the floor surface temperature. The floor surface temperature was controlled by varying the temperature of water (tw) flowing underneath the floor, and it ranged from tw 15 to 40 degrees C at 5 degrees C intervals. The blood flow rate was measured in the dorsal right toe, and skin temperatures were measured for 60 min at 8 points: the neck, right scapular, left hand, right shin, left bottom of the toe, right instep, left finger, and rectum. The blood flow rate in the foot tissue was increased until the foot skin temperature warmed up to 34 degrees C (P = 0.000). The final skin temperatures on the bottom of the toe were 19.4 +/- 2.44 degrees C for tw 15 degrees C, 22.4 +/- 2.45 degrees C for tw 20 degrees C, 24.8 +/- 2.80 degrees C for tw 25 degrees C, 27.7 +/- 2.13 degrees C for tw 30 degrees C, 30.6 +/- 2.06 degrees C for tw 35 degrees C, 33.2 +/- 1.45 degrees C for tw 40 degrees C, 34.2 +/- 1.55 degrees C for tw 45 degrees C, and 35.2 +/- 1.65 degrees C for tw 50 degrees C. Considering blood flow and comfort, the partial floor heating system is suggested and the recommended floor surface temperature range is 27-33 degrees C. PRACTICAL IMPLICATIONS: A warm floor surface can serve to satisfy occupants when the ambient temperature maintained at 20 degrees C which represents an energy conscious temperature. A warm floor can induce high blood perfusion in the feet and consequently improve an occupant's health by treating many vascular-related disorders. Even in a well-insulated residential building, a partially heated floor system could prevent overheating while providing surface warmth.

Pulmonary lymphomatoid granulomatosis in a dog: evidence of immunophenotypic diversity and relationship to human pulmonary lymphomatoid granulomatosis and pulmonary Hodgkin's disease.

We describe a 10-month-old, intact female American Cocker Spaniel with pulmonary lymphomatoid granulomatosis (PLG). On clinical examination, this dog presented with nonproductive dry cough, serous nasal discharge, dyspnea, and lack of appetite. Radiography showed a consolidated lesion in the left cranial lung lobe. Histopathologic examination showed a mixed population of atypical lymphoid cells that had infiltrated into the pulmonary blood vessels angiocentrically. The lymphocytes were CD3 positive, consistent with a pan-T-cell phenotype. The lymphoid cells in the lesion were also positive for CD20cy and CD79a, indicative of the presence of B cells. We also observed large Reed-Sternberg-like cells that were positive for CD15 and CD30, similar to observations in human pulmonary Hodgkin's disease (PHD). In conclusion, canine PLG in this Cocker Spaniel was associated with B and T cells, which is first identified in a case of canine PLG. It was histopathologically similar to human lymphomatoid granulomatosis and immunophenotypically similar to human PHD.

Cellular characterization of multidrug resistance P-glycoprotein, alpha fetoprotein, and neovascular endothelium-associated antigens in canine hepatocellular carcinoma and cirrhotic liver.

P-glycoprotein (P-gp), which is encoded by the multidrug resistance gene (MDR-1); alpha fetoprotein (AFP); and vascular endothelium-associated antigens are well-known markers for human and canine hepatic diseases. We obtained liver tissues from 5 dogs with hepatocellular carcinoma (HCC) and 12 dogs with cirrhosis, and we performed histopathologic and immunohistochemical evaluations using anti-P-gp, anti-AFP, anti-CD31, and anti-CD34 antibodies. P-gp was expressed at higher levels in HCC than in cirrhotic livers ( P < .01), and was most commonly localized in biliary canaliculi and small ductuli. AFP was localized mainly in the cytoplasm in HCC ( P < .01) and in a few cases of cirrhosis. In both HCC and cirrhosis, the AFP-positive cells were morphologically similar to normal hepatocytes and showed an even cytoplasmic distribution of AFP. The endothelial markers CD31 and CD34 were used to investigate vascular distribution. CD31 was expressed strongly in the portal area and parenchyma in HCC, but it was rarely observed in the parenchyma in cirrhosis. CD34 expression could not be detected in both HCC and cirrhosis. This study constitutes the first comprehensive study of P-gp, AFP, and endothelial markers in canine HCC and cirrhosis. The importance of these markers in HCC and cirrhosis in dogs was demonstrated and provides a more accurate basis for a definitive diagnosis of HCC and cirrhosis in dogs.

Adenocarcinoma arising from an ectopic pancreas in the stomach.

Ectopic pancreas is rare, being found in between 0.6 % and 15 % at autopsy. Heterotopic pancreas is usually an asymptomatic condition which is found incidentally at surgery or at autopsy. Occasionally, significant symptoms arise from complications, such as recurrent upper gastrointestinal bleeding, biliary or intestinal obstruction, or malignant degeneration. Malignant change is very rare. We report a case of malignant change (adenocarcinoma) in an ectopic pancreas in the stomach. In the literature, there are eight reported cases of malignant change in ectopic gastric pancreas. The prognosis in the other reported cases is unknown, but in our patient, the tumor was confined to the muscle of the stomach and there was no lymph node invasion.

Biomechanical comparison of C1-C2 posterior fixations. Cable, graft, and screw combinations.

STUDY DESIGN: Four combinations of cable-graft-screw fixation at C1-C2 were compared biomechanically in vitro using nondestructive flexibility testing. Each specimen was instrumented successively using each fixation combination. OBJECTIVES: To determine the relative amounts of movement at C1-C2 after instrumentation with various combinations of one or two transarticular screws and a posterior cable-secured graft. Also to determine the role of each component of the construct in resisting different types of loading. SUMMARY OF BACKGROUND DATA: Spinal stiffness increases after instrumentation with two transarticular screws plus a posterior wire-graft compared with a wire-graft alone. Other C1-C2 cable-graft-screw combinations have not been tested. METHODS: Eight human cadaveric occiput-C3 specimens were loaded nondestructively with pure moments, and nonconstrained motion at C1-C2 was measured. The instrumented states tested were a C1-C2 interposition graft attached with multistranded cable; a cable-graft plus one transarticular screw; two transarticular screws alone; and a cable-graft plus two transarticular screws. RESULTS: The transarticular screws prevented lateral bending and axial rotation better than the posterior cable-graft. The cable-graft prevented flexion and extension better than the screws. Increasing the number of fixation points often significantly decreased the rotation and translation (paired t test; P < 0.05). Axes of rotation shifted from their normal location toward the hardware. CONCLUSIONS: It is mechanically advantageous to include as many fixation points as possible when atlantoaxial instability is treated surgically.

Unilateral posterior atlantoaxial transarticular screw fixation.

Bilateral posterior C 1-2 transfacet screw placement with associated posterior bone graft wiring is the accepted treatment for patients with atlantoaxial instability. This technique was modified to treat 19 patients with atlantoaxial instability and unilateral anomalies that prevented placement of a screw across the C1-2 facet. In these cases, a single contralateral transarticular screw was placed in conjunction with interspinous bone graft wiring to avoid neural or vertebral artery injury and to provide C1-2 stability. Postoperatively, all 19 patients were placed in Philadelphia collars (mean immobilization 8 weeks, range 6-12 weeks). Unilateral C1-2 facet screw fixation was needed for the following reasons: a high-riding transverse foramen of the C-2 vertebra present in 13 patients (left side in eight, right side in five), poor screw purchase in two (left side in both), screw malposition in one (left side), severe degenerative arthritis in one (right side), neurofibroma in one (right side), and fracture of the C-1 lateral mass in one (left side). Six weeks postsurgery, one patient presented with a broken screw and required occipitocervical fusion with a Steinmann pin and wire cable from the occiput to C-3 to achieve solid fusion. Solid fusions were achieved in the other 18 patients (mean follow-up period 31 months, range 14-54 months); there was no delayed screw breakage, wire breakage, or spinal instability. There were no operative or postoperative neurological or vascular complications. The authors' experience demonstrates that unilateral C1-2 facet screw fixation with interspinous bone graft wiring is an excellent alternative in the treatment of atlantoaxial instability when bilateral screw fixation is contraindicated.