Interaction between phenytoin and enteral nutrients and its influence on gastrointestinal absorption.

The gastrointestinal absorption of phenytoin (PHT), an antiepileptic drug, is often affected by its interaction with co-administered enteral nutrients through a nasogastric (NG) tube, resulting in decreased plasma PHT concentration. In this study, we measured the recovery rate (%) of PHT (Aleviatin® powder) passed through an NG tube when co-administered with distilled water or enteral nutrients (F2α®, Racol® NF, Ensure Liquid® and Renalen® LP). We also measured plasma PHT levels in rats, after oral co-administration of PHT with enteral nutrients. We demonstrate that PHT recovery rate was close to 100 % in all cases after passage through the NG tube. In the rat study, the AUC0→∞ of PHT concentration after oral administration significantly decreased when it was co-administered with F2α® and Racol® NF compared to distilled water. However, the AUC0→∞ of PHT was unchanged when co-administered with F2α® 2 h after initial PHT administration. We therefore conclude that the co-administration of PHT with F2α® and Racol® NF caused a reduction in the absorption of PHT from the gastrointestinal tract to the blood, without adsorption to the NG tube. The administration of enteral nutrients 2 h after PHT is one clear way to prevent a decrease in plasma PHT concentration.

Carotid intima-media thickness and cerebral white matter lesions are more advanced in acute ischemic stroke patients with renal dysfunction.

BACKGROUND: It has been shown that chronic kidney disease (CKD) is a risk factor for stroke, but there have been few studies on the relationship between CKD and stroke. The objective of this study was to investigate the relationship between renal dysfunction and cerebral white matter lesions or carotid plaque in patients with acute ischemic stroke. METHODS: Subjects were 202 consecutive patients with ischemic stroke who were admitted to the Stroke Center of Nippon Medical School Hospital from January 2007 to July 2008. The estimated glomerular filtration (eGFR) was calculated and the relationship of renal dysfunction to the subtype of ischemic stroke, cardiovascular risk factors, cerebral white matter lesions on brain magnetic resonance imaging (MRI), and maximum intima-media thickness (IMT) of the carotid artery was analyzed statistically. RESULTS: Among the 202 patients with ischemic stroke, 27.9% had an eGFR < 60 ml/min/1.73 m2 (eGFR < 60 ml group). Age was significantly higher and a history of hypertension, diabetes, and ischemic heart disease was significantly more frequent in this group than in the group with eGFR ≥ 60 ml/min/1.73 m2 (eGFR ≥ 60 ml group). Among the subtypes of ischemic stroke, atherothrombotic cerebral infarction was predominant and accounted for 41.1%, followed by cardiogenic cerebral infarction at 31.1%, lacunar infarction at 18.8%, and unclassified infarction at 8.9%. There was no significant difference in the distribution of ischemic stroke subtype between both groups. Deep and subcortical white matter hypertensity (DSWMH) and periventricular hyperintensity (PVH) were detected by brain MRI in 91.5% of the eGFR < 60 ml group. In the eGFR < 60 ml group, PVH was significantly more frequent than in the eGFR ≥ 60 ml group (p = 0.032) and DSWMH was also more frequent (p = 0.0519). The maximum IMT measured by carotid ultrasound was significantly larger in the eGFR < 60 ml group. CONCLUSION: In patients with acute ischemic stroke, the incidence of renal dysfunction was high like that of heart disease. In the eGFR < 60 ml group, carotid IMT was larger and the incidence of PVH was higher, so these patients presumably had more advanced atherosclerotic changes of the cerebral vessels.

[Planned sedation with dexmedetomidine hydrochloride after pediatric cardiac surgery; an institutional experience].

Dexmedetomidine hydrochloride (DEX) is a newly developed alpha-2 adrenergic agonist sedative and has been shown to be effective in post-surgical patients, providing not only unique sedation but also stabilization of hemodynamic and respiratory function. We investigated the hemodynamic and respiratory effects and efficacy of DEX in 84 consecutive patients (age <6 months: 18, 6-12 months: 13, 1-3 years: 29, 4-9 years: 18, >10 years: 5, male:female = 44:40) who were sedated by DEX in combination with a small dose of midazolam and morphine. DEX was commenced at an initial dose of 0.7 microg/kg/hr during surgery, approximately 1 hour prior to transfer to the intensive care unit (ICU). DEX infusion was maintained at a rate of 0.2-0.7 microg/kg/hr after ICU admission throughout weaning from mechanical ventilation and extubation. The dose of the sedatives was optimized by scoring on Ramsay's sedative scale. There were no undesirable hemodynamic changes throughout the DEX infusion. Respiration was maintained and all patients were extubated uneventfully. Optimal level of sedation was achieved in all patients. There were no adverse events related to DEX administration. Moreover, junctional ectopic tachycardia (JET) and severe pulmonary hypertension (PH) leading to clinical deterioration, which are the major causes of postoperative morbidity in pediatric cardiac surgery, occurred at a low incidence in this series. Our DEX protocol provided 1) satisfactory postoperative sedation without compromising hemodynamics and respiration, and 2) prevention and amelioration of postoperative morbidity caused by sympathomimetic stimulation, in pediatric cardiac surgery.

[Successful administration of nifekalant hydrochloride for postoperative junctional ectopic tachycardia in congenital cardiac surgery].

Two episode of junctional ectopic tachycardia (JET) caused hemodynamic deterioration early after tetralogy of Fallot repair in an 8-month-old infant. Sinus rhythm resumed in each of the episodes immediately after intravenous administration of nifekalant hydrochloride (NIF), a newly developed Vaughan-Williams class III antiarrhythmic drug in Japan. Although QT interval was modestly prolonged with NIF, no life-threatening ventricular arrhythmia (i.e., torsades de pointes) occurred. NIF might be an effective alternative in the treatment of postoperative JET in congenital cardiac surgery.

Extracranial carotid plaque is increasing in Japanese ischemic stroke patients.

OBJECTIVE: The objectives of this study were to investigate the prevalence of extracranial carotid plaque and the association between risk factors and carotid plaque in Japanese patients with ischemic stroke. METHODS: We consecutively recruited patients with ischemic stroke admitted to our hospital from January 2000 to September 2002. Neurologic signs and a brain magnetic resonance imaging diagnosed ischemic stroke. All subjects underwent a carotid ultrasonography. Multiple logistic regression analysis was used to determine the risk factors that independently contributed to the presence of carotid plaques. RESULTS: Carotid plaques were identified in 76.2% of the patients and bilateral plaques were found in 58.2%. These lesions were more frequent in comparison with previous Japanese reports. The risk factors that independently contributed to the presence of extracranial carotid plaques were hypertension, age, smoking and past history of ischemic stroke. CONCLUSIONS: This study demonstrates that extracranial carotid plaque is increasing in Japanese patients with ischemic stroke.

Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity.

Aspirin prevents the production of thromboxane A2 (TXA2) by irreversibly inhibiting platelet cyclooxygenase, exhibiting antiplatelet actions. This agent has been reported to prevent relapse in patients with ischemic heart disease or cerebral infarction via this action mechanism. However, there are individual differences in this action, and aspirin is not effective in some patients, which is referred to as 'aspirin resistance'. In this study, we analyzed laboratory aspirin resistance by platelet aggregation in 110 healthy adult Japanese males using 24 single-nucleotide polymorphisms (SNPs) of nine genes involved in platelet aggregation/hemorrhage. Among SNPs involved in platelet aggregation, aspirin was less effective for 924T homozygote of a TXA2 receptor, 924T>C, and 1018C homozygote of a platelet membrane glycoprotein GPIbalpha, 1018C>T, suggesting that 924T and 1018C alleles are involved in aspirin resistance.

Effects of bisphosphonates on joint damage and bone loss in rat adjuvant-induced arthritis.

OBJECTIVE AND DESIGN: Examination of the effects of bisphosphonates on joint damage and generalized bone loss. MATERIALS: Adjuvant-arthritis was induced by injection of Mycobacterium butyricum into the footpad of the right hind paw of Lewis rats (8 animals/group) on day 0. TREATMENT: Arthritic rats were treated with the vehicle (saline), etidronate or alendronate (subcutaneously, daily 5 times a week for 3 weeks from day 1 to day 21). Experiment-1: Etidronate (0.1, 0.5, 2.5, 12.5 mg/kg) or alendronate (0.02, 0.1, 0.5, 2.5 mg/kg), Experiment-2: Etidronate (2.5, 5, 10mg/ kg) or alendronate (0.001, 0.01, 0.1 mg/kg). METHODS: In the adjuvant-injected side of the hind limbs, paw swelling was evaluated at 1-week intervals, and bone mineral density (BMD) in the proximal tibia, histopathology and radiographical findings in the tibio-tarsal region were evaluated at the time of sacrifice (on day 21). RESULTS: In all treatment schedules, both bisphosphonates significantly prevented paw swelling and bone loss. Alendronate reduced paw swelling at higher doses (over 0.1 mg/ kg) compared with its effect on BMD decrease (over 0.001 mg/kg). In contrast, etidronate reduced paw swelling and joint damage at doses similar to those (over 2.5 mg/kg) prevented BMD decrease. CONCLUSIONS: Both etidronate and alendronate are effective in reducing arthritic damage, but their effective dose ranges for inflammatory responses and BMD decrease clearly differ; i.e., the etidronate dose ranges for anti-inflammatory and anti-resorptive effects are similar, whereas the dose range for anti-inflammatory effects of alendronate is 100-fold higher than that for its anti-resorptive effects.

Effect of etidronate on bone in orchidectomized and sciatic neurectomized adult rats.

The purpose of the present study was to determine whether etidronate treatment could prevent bone loss caused by orchidectomy (ORX) and unilateral sciatic neurectomy (NX) in adult male rats. Seventy-four male Wistar rats, aged 10 months, were randomly divided into eight groups: baseline controls (n = 10); age-matched sham-operated controls (AMC; n = 9); ORX (n = 9); NX (n = 10); ORX + NX (n = 9); ORX + etidronate treatment (ORX + E; n = 7); NX + E (n = 10); and ORX + NX + E (n = 10). Etidronate treatment (10 mg/kg per day subcutaneously) was initiated 2 weeks after surgery and was continued for 2 weeks. Four weeks after surgery, bone mineral density (BMD) of the proximal and middle tibia (PT and MT, respectively), distal and middle femur (DF and MF, respectively), and fourth lumbar vertebral body (LVB) was measured by dual-energy X-ray absorptiometry (Model DCS-600, Aloka, Tokyo, Japan). The mechanical properties of the MF and third LVB were measured by three-point bending and compression tests, respectively. Levels of urinary deoxypyridinoline (Dpd) and serum osteocalcin (Oc) were also measured by enzyme-linked immunosorbent assay. Four weeks of aging had no significant effects on BMD, bone mechanical properties, or bone markers. ORX significantly increased the levels of urinary Dpd and serum Oc, which resulted in significant decreases in BMD of the PT, MT, DF, MF, and fourth LVB, as well as the mechanical strength (maximum load) of the MF and third LVB. NX significantly increased levels of urinary Dpd and decreased levels of serum Oc, resulting in a significant decrease in BMD of the PT, DF, and fourth LVB. The ORX-induced decrease in BMD of the PT was more pronounced when combined with NX. Etidronate treatment for NX, ORX, and ORX + NX rats significantly decreased levels of urinary Dpd and serum Oc, resulting in complete prevention of loss of BMD and/or bone mechanical strength. The present study demonstrates the efficacy of etidronate treatment for prevention of bone loss caused by testosterone deficiency and immobilization in adult male rats.

Essential role of the nonreducing terminal alpha-mannosyl residues of the N-linked carbohydrate chain of bovine zona pellucida glycoproteins in sperm-egg binding.

It has been proposed that mammalian sperm bind species-specifically to carbohydrate chains of zona pellucida glycoproteins at fertilization. Although the sperm ligand carbohydrate chains have been characterized in mice and pigs, the existence of the ligands of other mammals remains unclear. In order to explore the bovine sperm ligand, two in vitro competition assay methods were applied. As a result, a high-mannose-type carbohydrate chain, Manalpha1-6(Manalpha1-3)Manalpha1-6(Manalpha1-3)Manbeta1-4GlcNAcbeta1-4GlcNAc, which is the major neutral chain in bovine egg zona glycoproteins, was shown to possess bovine sperm ligand activity. When nonreducing terminal alpha-mannosyl residues were eliminated from the zona glycoproteins by alpha-mannosidase digestion, the ligand activity was reduced, indicating that the alpha-mannosyl residues play an essential role in bovine sperm-egg binding. The number of sperm binding to eggs was reduced to about one-half after fertilization. The ligand-active high-mannose-type chain may be buried after fertilization, since its amount remains unchanged. Pretreatment of bovine sperm with the sperm ligand-carbohydrate chain significantly inhibited penetration of the sperm into oocyte and the male pronucleus formation. Thus, a correlation between the sperm ligand activity and in vitro fertilization rate was observed.

Development status of Terumo implantable left ventricular assist system.

We have been developing an implantable left ventricular assist system (T-ILVAS) featuring a magnetically suspended centrifugal pump (MSCP) since 1995. In vitro and in vivo studies using a prototype MSCP composed of a polycarbonate housing and impeller (196 ml) have demonstrated long-term durability and excellent blood compatibility for up to 864 days, and excellent stability of the magnetic bearing of the MSCP. These preliminary results strongly suggested that the magnetic bearing of the MSCP is reliable and is a most feasible mechanism for a long-term circulatory assist device. We have recently devised a clinical version pump made of titanium (180 ml) with a new position sensor mechanism and a wearable controller with batteries. Cadaver fit study confirmed that the Type IV pump could be implanted in a small patient with a body surface area as small as 1.3. The in vitro performance tests of the Type IV pump demonstrated excellent hydrodynamic performances with an acceptable hemolysis rate. New position sensors for the titanium housing showed more uniform sensor outputs of a magnetic bearing than in the prototype polycarbonate pump. The Type IV pump then was evaluated in vivo in 6 sheep at the Oxford Heart Centre. Four sheep were electively sacrificed at 3 months and were allowed to survive for more than 6 months for long-term evaluation. In this particular series of experiments, no anticoagulant/antiplatelet regimen was utilized except for a bolus dose of heparin during surgery. There was a left ventricular mural thrombi around the inflow cannula in 1 sheep. Otherwise, there was no mechanical failure nor sign of thromboembolism throughout the study.

Reliable long-term non-pulsatile circulatory support without anticoagulation.

OBJECTIVE: The Terumo implantable left ventricular assist system (T-ILVAS) consists of a titanium centrifugal pump with a unique magnetically suspended impeller producing continuous (non-pulsatile) flow up to 10 l/min. The interior surface is heparin-coated and there is no purge system. We implanted the device into six sheep to ascertain in-vivo haemodynamic function, mechanical reliability and biocompatibility. METHODS: The T-ILVAS was implanted via left thoracotomy without cardiopulmonary bypass. The inflow cannula was placed in the left ventricular apex and a Dacron outflow graft anastomosed to the descending aorta. All animals recovered well. No anticoagulation (heparin or warfarin) was given after the surgery. Suspension position, motor current, impeller speed and pump flow were continuously monitored and stored by on-line computer. Serial blood samples were collected to determine haematological and biochemical indices of renal function, liver function and haemolysis. All animals were electively euthanized between 3 and 7 months postoperatively. The explanted pumps were examined for mechanical reliability and thrombus formation. Major organs were examined macroscopically and histologically for thromboembolism. RESULTS: All animals appeared completely normal for up to 210 days. At speeds between 1500 and 2000 rev./min the device pumped up to 8 l/min capturing all mitral flow. There were no major complications (pump failure, thromboembolism, haemorrhage, or driveline infection). Indices of haemolysis, liver and renal function remained within normal limits. All pumps were mechanically sound and free from thrombus. One embolus was found in a sectioned kidney. CONCLUSION: The T-ILVAS successfully supported the systemic circulation without anticoagulation for up to 210 days. Mechanical reliability and biocompatibility were demonstrated. Organ function remained within normal limits during continuous non-pulsatile flow.

Effect of long-term administration of JTP-2942, a novel thyrotropin-releasing hormone analogue, on neurological outcome, local cerebral blood flow and glucose utilization in a rat focal cerebral ischemia.

The effect of JTP-2942, a novel thyrotropin-releasing hormone analogue on neurological examination, local cerebral blood flow (l-CBF) and local cerebral glucose utilization (l-CGU) were examined when JTP-2942 was administered for 4 weeks after 1 week reperfusion following ischemia in a rat middle cerebral artery (MCA) occlusion. Left middle cerebral artery ischemia was induced for 90 min followed by reperfusion. JTP-2942 (0.03 or 0.003 mg/kg) or saline (vehicle) were administered for 4 weeks after 1 week ischemia, and then the drug was withdrawn. Neurological symptoms and motor disturbance based on inclined plane test were measured once a week after 1 week ischemia. l-CBF and l-CGU were measured by quantitative autoradiographic technique after 6 weeks ischemia. The adjacent sections subjected to l-CBF or l-CGU measurement were stained with Hematoxylin-Eosin, and the infarction volume was measured. JTP-2942 (0.03 mg/kg) significantly ameliorated neurological symptoms and motor disturbance at 5 weeks after ischemia as compared with vehicle, and then after completion of drug administration, amelioration effect continued. JTP-2942 (0.03 mg/kg) also significantly ameliorated the reduced l-CBF and l-CGU in the peri-infarcted areas such as the frontal cortex, motor cortex and medial caudate-putamen. No significant differences were noted in the infarction volume among MCA occlusion rats. This indicates that activating reduced metabolic turnover associated with synaptic connection changes or the activation of compensation mechanisms may result in improvement of neurological symptoms and motor disturbances. It is therefore expected that JTP-2942 may be a possible therapeutic agent for motor disturbance during the subacute or chronic cerebral infarction.

Obliterative arteritis with nitric oxide synthase and HLA-DR expression in Crohn's colitis.

BACKGROUND/AIMS: To cast light on whether inflammatory vascular injury is a possible pathogenic mechanism in Crohn's disease, the histological characteristics of vascular lesions were investigated. METHODOLOGY: Affected vessels in surgically resected colons from 23 patients with Crohn's disease, 20 with ulcerative colitis, 7 with ischemic colitis, and 9 normal controls were analyzed by Victoria blue and hematoxylin and eosin staining as well as immunohistochemistry for HLA-DR, nitric oxid synthase, vascular endothelial growth factor and E-cadherin. RESULTS: Inflammatory-cell infiltrates affecting arteries, accompanied by obliterative intimal thickening, were more frequent in Crohn's disease cases than in the other groups (P < 0.05-0.0001). Crohn's disease activity was positively correlated with the degree of obliterative arteritis. Granulomatous vasculitis was found exclusively in Crohn's disease (10 cases; 43.5%). In addition, focally enhanced endothelial staining of HLA-DR, with expression in granulomas adjacent to vessels was occasionally observed. In the endothelium of affected vessels, strong expression of HLA-DR was more prevalent in Crohn's disease and/or ulcerative colitis as compared with the ischemic colitis and controls (P < 0.05-0.01). In the involved arteries, enhanced endothelial nitric oxide synthase expression was most common in Crohn's disease among the groups (P < 0.05). A few cases of Crohn's disease, ulcerative colitis and ischemic colitis were positive for inducible nitric oxide synthase, vascular endothelial growth factor or E-cadherin in the vessel walls. CONCLUSIONS: The presence of characteristic obliterative arteritis and granulomatous vasculitis, a possible cause of ischemic injury, supports, in part, a vascular hypothesis for the pathogenesis of Crohn's disease. Enhanced expression of endothelial nitric oxide synthase and HLA-DR possibly reflects compensatory endothelium-mediated vasodilation and amplification of the immune response, respectively.

Dioctophymatid nematode larva found from human skin with creeping eruption.

A female dioctophymatid nematode larva, presumably belonging to the genus Dioctophyme, was found in a dermal granuloma accompanied by creeping eruption in the left inner thigh of a 26-yr-old Chinese woman who had stayed in Japan for 4 yr. Morphology of the sectioned worm is described in detail. This is the fourth case of dermal infection with dioctophymatid larva in humans.

Is there a relationship between cognitive dysfunction and systemic inflammatory response after cardiopulmonary bypass?

BACKGROUND: The systemic inflammatory reaction (SIR) is assumed to be one of the factors that causes cerebral dysfunction after cardiopulmonary bypass (CPB). The aim of the present study was to evaluate the relationship between the SIR and postoperative cognitive performance at 5 days and 3 months. METHODS: One hundred patients undergoing coronary artery bypass grafting were studied. Inflammatory markers and markers of coagulation and fibrinolysis were determined at several time points during and after the operation. Correlation analysis between maximum levels of the different markers and early and late performance was performed. RESULTS: No overall association was found between the maximum levels of the inflammatory markers and early and late function. CONCLUSIONS: Notwithstanding limitations of statistical power established markers of systemic inflammatory reaction showed no relationship with outcome at 5-day or 3-month follow-up in this subset of patients.

Infant partial left ventriculectomy for failure to wean from cardiopulmonary bypass.

Following aortic reimplantation of anomalous left coronary artery from the pulmonary artery in a 6-month-old infant, the heart failed to wean after prolonged supportive cardiopulmonary bypass and maximal inotropic support. We performed partial left ventriculectomy (Batista procedure) that halved left atrial pressure and enabled discontinuation of bypass. Postoperative recovery was then uneventful.