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Electrical injury is damage caused by an electrical current passing through the body. We have previously reported that irregular stripes crossing skeletal muscle fibers (python pattern) and multiple small nuclei arranged in the longitudinal direction of the muscle fibers (chained nuclear change) are uniquely observed by histopathological analysis in the skeletal muscle tissues of patients with electrical injury. However, it remains unclear whether these phenomena are caused by the electrical current itself or by the joule heat generated by the electric current passing through the body. To clarify the causes underlying these changes, we applied electric and heat injury to the exteriorized rat soleus muscle in situ. Although both the python pattern and chained nuclear change were induced by electric injury, only the python pattern was induced by heat injury. Furthermore, a chained nuclear change was induced in the soleus muscle cells by electric current flow in physiological saline at 40 °C ex vivo, but a python pattern was not observed. When the skeletal muscle was exposed to electrical injury in cardiac-arrested rats, a python pattern was induced within 5 h after cardiac arrest, but no chained nuclear change was observed. Therefore, a chained nuclear change is induced by an electrical current alone in tissues in vital condition, whereas a python pattern is caused by joule heat, which may occur shortly after death. The degree and distribution of these skeletal muscle changes may be useful histological markers for analyzing cases of electrical injury in forensic medicine., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Biodegradable magnesium (Mg) alloys are the most promising candidates for osteosynthesis devices. However, their in vivo corrosion behaviour has not been fully elucidated. The aim of this study was to clarify the influence of the physiological environment surrounding Mg alloys on their corrosion behaviour. A Mg-1.0Al alloy with a fine-grained structure was formed into plates using titanium (Ti) as a control. These plates were implanted into the subperiosteum in the head, subcutaneous tissue of the back, and in the muscle of the femur of rats for 1, 2 and 4 weeks. The volumes of the remaining Mg alloy and of the insoluble salt deposition and gas cavities around the Mg alloy were determined by microtomography, and the volume losses were calculated. Then, the tissue response around the plates in each implantation site was examined histopathologically, and its relation to the respective volume loss was analyzed. These analyses determined that the Mg alloy was corroded fastest in the head, at an intermediate level in the back, and slowest in the femur. The insoluble salt deposition at the Mg alloy surface had no influence on the volume loss. Gas cavities formed around the Mg alloy at all implantation sites and decreased after 4 weeks. Histopathological examination revealed that the Mg alloy exhibited good biocompatibility, as was seen with Ti. In addition, vascularized fibrous capsules formed around the plates and became mature with time. Notably, the volume loss in the different anatomical locations correlated with capsule thickness. Together, our results suggest that, to facilitate the successful clinical application of Mg alloys, it will be necessary to further comprehend their interactions with specific in vivo environments.

Blood and tissue samples from a forensic autopsy of a man in his late 60s, who developed dementia and died of multiple head traumas due to a fall from a moving vehicle, contained certain amounts of n-butane and i-butane. The concentration of n-butane was in the range of 0.48-70.5 μL/g, which would be considered as toxic or lethal levels. We had to distinguish whether the cause of his unexplained behavior was due to his pre-existing condition (dementia), or from a confused state induced by butane abuse. No traces of butane use were found at the scene. Police investigation revealed that a propellant used in an anticontagious plugging spray had been administered to him during a postmortem treatment in the emergency hospital. In order to prove the postmortem butane diffusion had resulted from the spray administration and to estimate the diffused concentration, experimental simulation was conducted by using rats. As a result of postmortem treatment with the spray, n-butane at concentrations of 0.54-15.5 μL/mL or g were found in the rat blood and tissues. In this case, we provided further evidence that the postmortem butane diffusion, caused by using the anticontagious plugging spray containing butane gas as a propellant administered to a cadaver during a postmortem procedure prior to forensic autopsy, should be distinguished from cases of actual butane poisoning., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The oxidative metabolism of cinnarizine [(E)-1-(diphenylmethyl)-4-(3-phenyl-2-propyl)piperazine, CZ] and flunarizine [(E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propyl)piperazine, FZ] was examined in microsomes from lymphoblastoid cells that expressed human cytochrome P450 (CYP) enzymes. Among 10 kinds of CYP enzymes examined, only CYP2D6 catalyzed p-hydroxylation of the cinnamyl phenyl ring of CZ (C-2 formation) and FZ (F-2 formation), and only CYP2B6 exhibited activity for p-hydroxylation (C-4 formation) of the diphenylmethyl group of CZ at a substrate concentration of 50 microM. On the other hand, CYP2C9 together with CYP1A1, -1A2 and/or -2A6 mediated N-desalkylation at the 1- and 4-positions of the piperazine ring of the two drugs that formed C-1 and C-3 from CZ and F-1 and F-3 from FZ, respectively, whereas CYP2C8, -2C19, -2E1 or -3A4 did not show detectable activity for these reactions under the conditions used. We then examined kinetics for the oxidative metabolism of CZ and FZ using CYP2B6 and -2D6 that have considerable activities. CYP2D6 with Km values of 2 to 4 microM had intrinsic clearance values (Vmax/Km) of 0.31 and 0.14 ml/min/nmol CYP for C-2 and F-2 formation, respectively, while CYP2B6 with a Km value of 17 microM exhibited the clearance value of 0.10 ml/min/nmol CYP for C-4 formation. These results suggest that CYP2D6 mainly mediates p-hydroxylation of the cinnamyl phenyl rings of CZ and FZ, and CYP2B6 mediates that of the diphenylmethyl group of CZ.

A new silicone microballoon was developed for the percutaneous transluminal angioplasty of smaller intracranial vessels, such as A1, A2 and M2. This balloon was 0.5 x 2.0 mm in the deflated condition and became 2.2 x 6.5 mm inflated with 0.02 mL of fluid, and its bursting pressure was 2 atm. Two illustrative cases are presented. The first case was not treated in the M2 distribution. The second case of vasospasm of the left M2 portion was successfully treated with this new balloon, with prompt improvement of the neurological condition and cerebral circulation. The usefulness of our microballoon in treating a patient with vasospasm of small intracranial arteries is discussed.

The oxidative metabolism of flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to 1-[bis-(4-fluorophenyl)methyl]piperazine (M-1), 1-[bis(4-fluorophenyl)methyl]-4-[3-(4'-hydroxyphenyl)-2- propenyl]piperazine (M-2) and 4,4'-difluorobenzophenone (M-3) has been studied in liver microsomes of Wistar and Dark Agouti (DA) rats. Kinetic analysis demonstrated a sex difference (male > female) in the formation of M-1 and M-3, but not in that of M-2 in Wistar rats. Comparison of the kinetic data of FZ with those of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ], a prototypic and unfluorinated drug (Kariya et al., Biochem. Pharmacol., in press) revealed that the formation clearances (Clfs) estimated by Vmax/km for the ring hydroxylated metabolites of FZ and CZ are higher than those for the N-dealkylated metabolites of these drugs in female rats. Furthermore, the introduction of two fluorine atoms to CZ (forming FZ) decreased the Clfs for most of metabolites, especially for the N-dealkylated product, M-3. The formation of the metabolites from FZ was suppressed by carbon monoxide and SKF 525-A, and only the ring hydroxylation forming M-2 was significantly lower in female DA than in female Wistar rats. These results suggest that the microsomal oxidation of FZ is mediated by cytochrome P450, and that a cytochrome P450 isozyme(s) belonging to the CYP2D subfamily is involved in the ring hydroxylation of FZ forming M-2.

The mean hepatic extraction ratio (ER) of propranolol was estimated directly by simultaneous measurements of arterial and hepatic venous blood concentrations of the drug following systemic venous and portal venous administration in the rat. The ER was greater than 0.9 in the dose range of 2.5 to 12.5 mg/kg following rapid infusion of propranolol into the femoral vein and was not dependent on infusion rate. On the other hand, the ER following intraportal constant-rate infusion decreased progressively with increasing dose, although the ER at an intraportal dose of 2.5 mg/kg was as high as that found after administration into the femoral vein. In addition, it was found that the ER at an intraportal dose of 12.5 mg/kg of propranolol was significantly influenced by infusion rate. The unusual AUC-dose relationship of propranolol previously reported in the rat could be explained on the basis of the present nonlinear hepatic extraction depending on the route and rate of administration which was clarified in vivo. The nonlinear hepatic extraction was further confirmed by determining the remarkably decreased ER of (14)C-propranolol given intravenously after pretreatment or during portal venous administration of unlabelled propranolol.

Batter's syndrome characteristically exhibits the constellation of hypokalemic alkalosis, normotensive hyperreninism, hyperalodosteronism, hyporesponsiveness to pressor agent and juxtaglomerular cell hyperplasia. Recently, metabolic mimicry of Batter's syndrome by vomiting, diarrhea, laxatives and diuretics abuse has been reported. We had a 30 year-old female patient who developed so-called pseudo-Bartter's syndrome as the result of surreptitious self-administration of furosemide for about six years. In this case, calcification of bilateral renal medulla was demonstrated. Such adverse reaction has not been reported to date. Moreover, a total 14 cases of pseudo-Bartter's syndrome reported in Japanese literature is reviewed.

The mean hepatic extraction ratio (ER) of propranolol depending on the inflowing blood concentration to the liver was estimated directly by simultaneous measurements of arterial, hepatoportal, and hepatic venous blood concentrations of the drug following intravenous, intraportal, and intraduodenal administration in the rat. It was shown that the inflowing blood concentration to the liver caused considerable variation depending on the route of administration. The mean hepatic extraction ratio of propranolol in the first pass through the liver (ER)fipv and that of the drug after escaping the hepatic first-pass metabolism (ER)ripv were assessed by simultaneous administration of intraportal unlabelled propranolol and intravenous 14C-propranolol over a 50-min period. Consequently, a relation of (ER)fipv less than (ER)ipv less than (ER)ripv was observed in higher propranolol doses, if (ER)ipv refers to the overall mean hepatic extraction ratio following intraportal administration of propranolol. The fraction of orally administered dose reaching the systemic circulation for a drug exhibiting nonlinear hepatic first-pass metabolism was discussed. The unusual AUC-dose relationship of propranolol reported previously in the rat could be explained on the basis of both the nonlinear hepatic first-pass metabolism and the nonlinear hepatic metabolism of drug surviving the hepatic first-pass metabolism.

A high-performance liquid chromatographic method using spectrofluorometric detection is described for the determination of furosemide in plasma, plasma water, urine and ascites fluid. The extraction procedure decreases interference from endogenous substances. The detection limit of furosemide is 10 ng in 0.5 ml of biological sample. The method is sufficiently sensitive for pharmacokinetic study of furosemide with normal subjects and patients with liver cirrhosis and/or renal disease after oral administration of furosemide in a retard capsule, and for study of protein binding of furosemide in patients with various diseases.

Studies on the electrolyte metabolism and the renin-angiotensin-aldosterone system were made in a 47-year-old female patient with factitious Bartter's syndrome induced by surreptitious use of furosemide. The diagnosis was confirmed later by detection of the diuretic in the urine. In metabolic studies patient exhibited abnormalities similar to those reported in Bartter's syndrome; viz, hypokalemic alkalosis, blunted response to exogenous angiotensin II, which reverted to normal by volume expansion with an albumin solution, and diminished fractional free water clearance per fractional distal sodium delivery. The above data, along with the known pharmacological effects of furosemide, suggest that the abnormality in Na+ or Cl- reabsorption in the ascending limb of Henle's loop is a primary cause of Bartter's syndrome.

The extent and rate of absorption of phenytoin (PHT) from tablet and powder were studied in four healthy adult volunteers. It was demonstrated by urinary and fecal excretion that the almost all quantity of PHT in tablet was absorbed through the gastrointestinal tract, and the observed values of the estimated free concentration (Cest.f) estimated from mixed saliva concentration of PHT in the multiple dose were in fair agreement with the calculated values of that by using computer simulation in case of tablet. On the contrary, the variations were observed in Cest.f using therapeutic dose of PHT powder. The values of Cest.f at steady-state in tablet administration were higher than those in powder administration. The absorption ratio of PHT powder was low and variable, and decreased upon increase of dose. The ratio calculated from the Cest.f values of both dosage forms at steady-state were in good correspondence to the observed values of PHT excreted in feces.

A precise and sensitive high-performance liquid chromatographic method using a column packed with porous polystyrene gel is described for the determination of propranolol in plasma and plasma water from normal subjects and patients with angina pectoris. Propranolol in the samples was extracted with an n-heptane-isoamylalcohol (98.5:1.5) mixture after addition of penbutolol used as an internal standard. The extracts were chromatographed and detected with a spectrofluorophotometer. The quantitative limit of propranolol was 1 ng using 1 ml of plasma or 0.5 ml of plasma water. The present method should be useful for monitoring propranolol concentrations in plasma and plasma water during drug therapy and for pharmacokinetic study of propranolol.

The dissolution profiles of furosemide in various solutions were studied with plain tablet and retard capsule of furosemide. The rate constant and percent dissolution in retard capsule were lower than that in plain tablet. Clinical pharmacokinetics and diuretic effect of furosemide after oral administration of two dosage forms were also studied with 3 normal subjects and 3 cirrhotic patients. In normal subjects, the extent of furosemide absorption from retard capsule was 45% of plain tablet. The daily urine volume after oral administration of two dosage forms was comparable, however, quite different profiles were observed between these dosage forms. In patients, the extent of furosemide absorption in retard capsule was one half that of plain tablet. The dose of retard capsule was increased without adverse reactions, thus decreasing of ascites, which was not observed with plain tablet, was achieved with increasing urine volume.