Influence of rotational speed on torque/force generation and shaping ability during root canal instrumentation of extracted teeth with continuous rotation and optimum torque reverse motion.

AIM: To evaluate how different rotational speeds affect the torque/force generation and shaping ability of rotary root canal instrumentation using JIZAI (MANI, Utsunomiya, Japan) nickel-titanium instruments in continuous rotation and optimum torque reverse (OTR) motion. METHODOLOGY: Mesial root canals of extracted mandibular molars were instrumented up to size 25, 0.04 taper using JIZAI instruments, and anatomically matched canals were selected based on geometric features of the canal [canal volume (mm3 ), surface area (mm2 ), length, 15°-20° curvature and radius of curvature (4-8 mm)] after micro-computed tomographic scanning. An automated root canal instrumentation and torque/force analysing device was programmed to permit a simulated pecking motion (2 s downward and 1 s upward at 50 mm min-1 ). The selected canals were prepared with size 25, 0.06 taper JIZAI instruments using continuous rotation or OTR motion and further subdivided according to the rotational speed (300 or 500 rpm, n = 10 each). Real-time clockwise/counterclockwise torque and downward/upward force were recorded using a custom-made torque/force analysing device. Then, the registered pre- and post-operative micro-computed tomographic datasets were examined to evaluate the canal volume changes and centring ratios at 1, 3, 5 and 7 mm from the apical foramen. Data were analysed using two-way analysis of variance or the Kruskal-Wallis test and Mann-Whitney U test with Bonferroni correction (α = 5%). RESULTS: Maximum upward force and clockwise torque were significantly smaller in 500 rpm groups than in 300 rpm groups (P < .05); however, no significant difference was found between continuous rotation and OTR motion (P > .05). OTR motion developed higher maximum counterclockwise torque than continuous rotation (P < .05). Maximum downward force, canal volume changes and centring ratios were not significantly different among all groups (P > .05). There was no file fracture in any of the groups. CONCLUSIONS: Under laboratory conditions using JIZAI instruments, a rotational speed of 500 rpm generated significantly lower maximum screw-in forces and torque values than rotational speed of 300 rpm. Continuous rotation and OTR motion performed similarly in shaping the canals.

Root surface strain during canal shaping and its influence on apical microcrack development: a preliminary investigation.

AIM: To determine the root surface strain (RSS) generated during root canal shaping and its effects on apical microcrack development. METHODOLOGY: Twenty-five extracted human mandibular premolars were selected and decoronated. The teeth were instrumented with either the ProTaper (PT) or WaveOne (WO) (Dentsply Maillefer) NiTi rotary systems (n = 10 per group) or used as controls (n = 5). Instrumented root canals were enlarged to ProTaper F4 (size 40, 0.06 taper) or using WaveOne LARGE (size 40, 0.08 taper) instruments according to the manufacturer's instructions. An electrical strain gage (KFG02-120-C1-16, Kyowa Dengyo, Tokyo, Japan) was fixed on the proximal root surface and connected to a strain amplifier via a bridge box in order to measure RSS. During canal shaping, the strain output of the amplifier was recorded. The instantaneous RSS induced by each instrument and the maximum RSSs were determined. All teeth were then stained with contrast media and imaged with micro-computed tomography (micro-CT) at an isotropic resolution of 10 µm to detect microcracks. The mean maximum RSS values (microstrain) and mean number of microcracks recorded for both groups were tested for statistical significance using Mann-Whitney U-test. Presence/absence of microcracks in both groups was compared by chi-square tests. RESULTS: Increased baseline RSS from strain accumulation during canal shaping was observed, with similar maximum RSS (mean ± SD) for PT (416.6 ± 185.1 µstrain) and WO (398.2 ± 163.8 µstrain) (P = 0.94). The interevaluator reliability for microcrack detection using micro-CT had a kappa value of 0.998. Compared to the PT group, there was a trend for fewer samples with microcracks in the WO group (P = 0.051). On the micro-CT images, apical microcracks were detected in 20 PT and 11 WO samples (P = 0.10). The microcracks were observed in the buccolingual direction in all WO and 81% of PT samples. No vertical root fractures were found. The maximum RSS obtained during canal shaping was poorly correlated with the number of microcracks found (R(2)  = 0.093). CONCLUSIONS: Based on these preliminary data, canal shaping appears to cause apical microcracks regardless of the type of rotary instrument motion. Contrast-enhanced micro-CT was able to identify microcracks in roots.

Nano-indentation testing of new and fractured nickel-titanium endodontic instruments.

AIM: To investigate the effect of cyclic fatigue on nickel-titanium (NiTi) endodontic instruments using a nano-indentation test. METHODOLOGY: Eight ProFile NiTi rotary instruments (size 30, taper 0.06; Dentsply Maillefer, Ballaigues, Switzerland) were tested using a cyclic fatigue set-up until fracture. The fractured instruments and eight new NiTi instruments of the same size and taper were used for a nano-indentation test on the internal surfaces of a NiTi instruments in the region just adjacent to their fractured edge (group I) and in the same region of the new group (group II), and the cutting part beside the shaft for both instruments [group III (fractured) and group IV (new)]. Data were statistically analyzed using one-way analysis of variance and Games-Howell post hoc test. The alpha-type error was set at 0.05. RESULTS: Significant differences in terms of hardness and elastic modulus for each group (P < 0.05) were found, with group I having the lowest mean values followed by group III. Additionally, standard deviations increased remarkably after failure, as represented by groups I and III. CONCLUSION: The nano-indentation technique can be applied to determine the performance and the failure mechanism of NiTi instruments. The fatigue process revealed a significant decrease in the hardness and elastic modulus of the NiTi instrument. As indicated by the low hardness, the fatigue process did not result in work hardening but rather work softening.

Heat treatment of nickel-titanium rotary endodontic instruments: effects on bending properties and shaping abilities.

AIM: To evaluate the bending properties and shaping abilities of nickel-titanium endodontic instruments processed by heat treatment. METHODOLOGY: K3 files were heated for 30 min at 400 °C (group 400), 450 °C (group 450) and 500 °C (group 500). Files that were not heat treated served as controls. A cantilever-bending test was used to evaluate changes in specimen flexibility caused by heat treatment. Curved root canal models were prepared. The times required for preparation, deformation and fracture were recorded. Pre- and postoperative images were superimposed. The amounts of resin removed from both the inner and the outer sides of the curvature in the apical 6 mm were determined. RESULTS: In the cantilever-bending test, load values of the control group and group 500 were higher than those of groups 400 and 450 at the elastic range (P<0.05). At the superelastic range, the bending load of the control group was the highest amongst all groups (P<0.05). Regarding shaping ability, in the control group, root canals at the apex were transported more to the outer side of the curvature compared with those of all heat-treated groups (P<0.05). Root canals of group 400 at 3 mm from the apex were transported less compared with those of other groups (P<0.05). No significant difference was found in working time amongst the groups. In group 450, there was no plastic deformation or fracture of the file. CONCLUSIONS: Heat treatment of files might improve their flexibility, making them more effective for preparation of curved canals.

Phase transformation behaviour and bending property of twisted nickel-titanium endodontic instruments.

AIM: To investigate the relationship between phase transformation behaviour and bending property of nickel-titanium endodontic instruments manufactured by a twisting process. METHODOLOGY: The phase transformation behaviour and bending property of Twisted Files (TF; SybronEndo, Orange, CA, USA) and K3 (SybronEndo) with.06 taper and size 30 tip were investigated. K3 was used as control group. Phase transformation behaviour was estimated by differential scanning calorimetry (DSC). Transformation temperatures were calculated from the DSC curve. Bending load of the instruments was measured by cantilever-bending test at 37°C. Data were analysed by Student's t-test and Mann-Whitney U-test. RESULTS: The phase transformation temperatures of TF were significantly higher (P<0.05) than those of K3. The bending load values were significantly lower for TF than that of K3 (P<0.05), both in the elastic and super-elastic ranges. CONCLUSIONS: The new method of manufacturing NiTi instruments by twisting coupled with heat treatment might contribute to the increased phase transformation temperatures and superior flexibility.

Initial fibroblast attachment to Erbium:YAG laser-irradiated dentine.

AIMS: To evaluate the effects of Erbium (Er):YAG laser irradiation on the morphology of resected dentine surfaces, and to investigate fibroblast attachment to laser-irradiated dentine surfaces. METHODOLOGY: Dentine blocks obtained from single-rooted human teeth were divided into the following groups after sterilization in an autoclave: (i) Laser group treated with Er:YAG laser irradiation (30 mJ per pulse, 10 pps, 60 s); (ii) L-MTAD group treated with laser irradiation as in (i) plus a mixture of doxycycline, tetracycline isomer and citric acid; (iii) RC-Prep group treated with EDTA gel or cream (RC-Prep) and (iv) Control group left untreated. After each treatment, the dentine blocks were incubated with NIH/3T3 fibroblasts cultured to subconfluency in Dulbecco's modified Eagle's medium supplemented with 10% foetal bovine serum and antibiotics. The number of attached cells amongst the groups was analysed statistically at the 5% significance level. The dentine surface morphologies and cell attachments were evaluated by counting assays, histological observations and scanning electron microscopy (SEM). RESULTS: The number of attached cells was significantly higher (P < 0.05) in the Laser group than in the RC-Prep and Control groups at 16 h. Dendritic cell extension of the fibroblasts was only observed in the Laser group at 8 h by SEM. In the histological analyses, significantly more attached cells were found on the dentine surfaces treated with laser irradiation. CONCLUSIONS: Er:YAG laser irradiation induced morphological alterations in dentine surfaces, which may improve the attachment of fibroblasts to dentine.

Effect of heat treatment on transformation temperatures and bending properties of nickel-titanium endodontic instruments.

AIM: To investigate the effect of heat treatment on the bending properties of nickel-titanium endodontic instruments in relation to their transformation behaviour. METHODOLOGY: Nickel-titanium super-elastic alloy wire (1.00 mm Ø) was processed into a conical shape with a 0.30 mm diameter tip and 0.06 taper. The heat treatment temperature was set at 440 or 500 degrees C for a period of 10 or 30 min. Nonheat-treated specimens were used as controls. The phase transformation behaviour was examined using differential scanning calorimetry. A cantilever-bending test was used to evaluate the bending properties of the specimens. Data were analyzed by ANOVA and the Tukey-Kramer test (P = 0.05). RESULTS: The transformation temperature was higher for each heat treatment condition compared with the control. Two clear thermal peaks were observed for the heat treatment at 440 degrees C. The specimen heated at 440 degrees C for 30 min exhibited the highest temperatures for M(s) and A(f), with subsequently lower temperatures observed for specimens heated at 440 degrees C for 10 min, 500 degrees C for 30 min, 500 degrees C for 10 min, and control specimens. The sample heated at 440 degrees C for 30 min had the lowest bending load values (P < 0.05), both in the elastic range (0.5 mm deflection) and in the super-elastic range (2.0 mm deflection). The influence of heat treatment time was less than that of heat treatment temperature. CONCLUSIONS: Change in the transformation behaviour by heat treatment may be effective in increasing the flexibility of nickel-titanium endodontic instruments.

Changes of optical properties of retroreflector installed in LHD.

This article describes changes of optical properties of retroreflectors installed on the inner wall of the vacuum vessel of the Large Helical Device. They were made of stainless steel and were used for a CO(2) laser polarimeter. The reflectivity for a CO(2) laser beam dropped up to 40% after the start of glow discharge cleanings and main plasma experiments. Then it decreased gradually. The reflectivity in a wavelength range shorter than 10 mum decreased significantly through one experimental campaign (about 4 months). On the other hand the reflectivity in a wavelength range longer than 50 mum was larger than 70%. Decrease in the reflectivity in the central region of mirrors was more significant (the reflectivity for visible beams became almost zero) than that in the edge. The distribution of the reflectivity along the radial direction is expected to be related to the shape of the retroreflector. The parallelism of the reflected beam to an incident one also deteriorated. The changes in the polarization angle and in the ellipticity of reflected light polarization were not observed from the visible to the far infrared range.

Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on nitric oxide-induced hydroxyl radical generation in the rat heart.

We examined the effect of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the production of hydroxyl radical (*OH) generation via nitric oxide synthase (NOS) activation by an in vivo microdialysis technique. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and tissue was perfused with Ringer's solution through the microdialysis probe at a rate of 1 microl/min. Sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused directly through a microdialysis probe to detect the generation of *OH. Induction of [K(+)](o) (70 mM) or tyramine (1 mM), significantly increased the formation of *OH trapped as 2,3-dihydroxybenzoic acid (DHBA). The application of N(G)-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, significantly decreased the K(+) depolarization-induced *OH formation, but the effect of tyramine significantly increased the level of 2,3-DHBA. When fluvastatin (100 microM), an inhibitor of low-density lipoprotein (LDL) oxidation, was administered to L-NAME-pretreated animals, both KCl and tyramine failed to increase the level of 2,3-DHBA formation. The effect of fluvastatin may be unrelated to K(+) depolarization-induced *OH generation. To examine the effect of fluvastatin on ischemic/reperfused rat myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, a marked elevation of the level of 2,3-DHBA was observed. However, in the presence of fluvastatin (100 microM), the elevation of 2,3-DHBA was not observed in ischemia/reperfused rat heart. Fluvastatin, orally at a dose of 3 mg/kg/day for 4 weeks, significantly blunted the rise of serum creatine phosphokinase and improved the electrocardiogram 2 h after coronary occlusion. These results suggest that fluvastatin is associated with a cardioprotective effect due to the suppression of noradrenaline-induced *OH generation by inhibiting LDL oxidation in the heart.

Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene.

BACKGROUND: Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. METHODS AND RESULTS: Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. CONCLUSIONS: AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.

Clinical pharmacology and clinical trials in Japan.

Clinical pharmacology is the pursuit of rational therapeutics by following the scientific principles of medicine and pharmacology. In Japan the roles for clinical pharmacology and clinical pharmacologists have been evolving since the discipline appeared in the 1950s. Clinical pharmacology and clinical trials for drug development depend on each other, and clinical pharmacologists play an important role in drug development in Japan. As the discipline becomes more important and complicated, many issues regarding drug therapeutics and clinical trials in Japan have been raised, and several points of view have been expressed. The following suggestions have been made to improve clinical pharmacology in Japan: (a) Medical education in the field of clinical pharmacology must be improved by creating or improving clinical pharmacology programs in medical schools. (b) The appropriate infrastructure for clinical trials must be established so that the physicians' workload is reduced, and patients' participation in clinical trials becomes much easier. (c) Scientific and ethical standards of the pharmaceutical industry must be improved, and the effort should be made to produce drugs with new mechanisms of action or with significant expected benefits. (d) The regulatory agency must provide stronger support, encompassing all the various points of view of academic institutes and the pharmaceutical industry. In light of the enthusiasm demonstrated by the government, physicians, and pharmaceutical industry in Japan for continued progress in clinical pharmacology, it seems likely that all its challenges will be overcome in the near future. Hence, despite the various problems discussed here the future seems promising for the continued development of clinical pharmacology.

Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1.

The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.

Comparative clinical pharmacology of human insulin (Novo) and porcine insulin in normal subjects.

The pharmacokinetics and pharmacologic effects of human insulin (Novo) derived from porcine insulin were studied by a double-blind crossover comparison with porcine monocomponent insulin in healthy volunteers. Both insulins were given by subcutaneous (s.c.) and intravenous (i.v.) injection to healthy male volunteers. The doses of injected insulin were 0.05 U/kg and 0.1 U/kg for the s.c. study, and 0.025 U/kg and 0.05 U/kg for the i.v. study. The plasma immunoreactive insulin (IRI) increased rapidly, plasma C-peptide and glucose decreased gradually, and plasma glucagon increased transiently after injection of the insulins. The pharmacokinetics and pharmacologic actions of human insulin were essentially similar to those of porcine insulin. The area under the time-concentration curve (AUC) of IRI was slightly greater after s.c. injection of human insulin than after that of porcine insulin at the 0.05-U/kg dose level. Because no significant difference was observed in the plasma C-peptide level and no such difference was noticed in the AUC of IRI between the two insulins after i.v. injection, the bioavailability of human insulin seemed to be greater than that of porcine insulin after s.c. injection. The plasma glucose-reducing effect was slightly greater after s.c. injection of 0.05 U/kg of human insulin than after s.c. injection of the same dose of porcine insulin. Apart from symptoms of hypoglycemia (sweating, palpitations, and hot flushes), no other unwanted reactions were observed after administration of either insulin. These results suggest that human insulin has a usefulness similar to that of porcine insulin in clinical practice. The clinical relevance of the slight difference in bioavailability observed in the s.c. study remains to be investigated.

Clinical pharmacology of human insulin of recombinant DNA origin in healthy volunteers.

The serum insulin, fractional absorption, serum human C-peptide, and plasma glucose responses of normal fasting subjects were compared after the subcutaneous and intravenous administration of human insulin (recombinant DNA) and Novo Actrapid insulin. While no statistical difference at each time point was observed between the two insulins, for each time point after 0.05 and 0.1 U/kg s.c., the 0-6 h area under curve (AUC) after the 0.05 U/kg dose was greater for human insulin than for pork insulin. There was no difference in the 0-6 h AUC after the 0.1 U/kg s.c. dose. The serum human C-peptide responses to the two insulins were virtually identical. With the 0.05 U/kg s.c. dose, hypoglycemic effect of human insulin was greater than for Actrapid. This difference did not occur after 0.1 U/kg s.c. Following intravenous administration using 0.05 U/kg, the serum IRI, serum C-peptide, and glucose responses were the same. These data indicate only slight differences between human insulin and Actrapid insulin.

Role of angiotensin II in renal prostaglandin E2 production after furosemide administration.

The role of plasma angiotensin II (Ang II) in furosemide-stimulated renal prostaglandin E2 (PGE2) production was evaluated in eight healthy subjects. Urine was collected for 60 minutes after furosemide administration (20 mg i.v.) with or without captopril pretreatment, and urinary excretion of PGE2, sodium, and furosemide was determined. Plasma renin activity (PRA) and Ang II were also measured before and 60 minutes after furosemide administration. Urinary PGE2 excretion, PRA, and Ang II increased after furosemide administration without captopril pretreatment, and there was a significant correlation between the increment in Ang II and that in urinary PGE2 excretion. Urinary PGE2 excretion and Ang II did not increase after furosemide administration with captopril pretreatment. Urine volume and urinary excretion of sodium and furosemide were not influenced by captopril pretreatment. These results suggest that Ang II may play an important role in furosemide-stimulated PGE2 production.

Acetylation polymorphism of caffeine in a Japanese population.

The frequency distribution of N-acetylation of caffeine was determined in 140 unrelated healthy Japanese subjects by measuring the amount of two main metabolites of caffeine, 5-acetylamino-6-formyl-amino-3-methyluracil (AFMU) and 1-methylxanthine (1X), in urine after an oral dose of caffeine. N-Acetylation capacity for caffeine appeared to be polymorphic: 15 subjects (10.7%) were phenotyped as slow acetylators, whereas 125 subjects (89.3%) were phenotyped as rapid ones. The urinary molar excretion ratio of AFMU (AFMU/1X) in 2 hours-urine samples ranged from 0.03 (slow acetylators) to 2.66 (rapid acetylators). The frequency of slow acetylators in this study was similar to that reported previously for the isoniazid and dapsone polymorphism in Japanese populations.

The effects of age and gender on the stereoselective pharmacokinetics of verapamil.

The effects of age and gender on the pharmacokinetics of verapamil stereoisomers were examined. Eighty milligrams of racemic verapamil was given orally to 12 young and 12 elderly healthy subjects, half of whom were women. The area under the plasma concentration-time curves (AUC) of (S)- and (R)-verapamil were greater in the elderly group than in the young group [(S)-/(R)-verapamil (mean +/- SD), 214.4 +/- 123.0/1582.2 +/- 763.0 and 50.4 +/- 36.5/584.9 +/- 252.4 ng.hr/ml for the elderly and young groups, respectively (p < 0.001/p < 0.001)]. Conversely, the apparent oral clearance values of (S)- and (R)-verapamil were significantly smaller in the elderly group than in the young group [(S)-/(R)-verapamil (mean +/- SD), 4.8 +/- 3.0/0.53 +/- 0.21 and 22.5 +/- 21.3/1.30 +/- 0.67 L/hr/kg for the elderly and young groups, respectively (p < 0.01/p < 0.001)]. The ratio of apparent oral clearance of (S)- to (R)-verapamil was significantly smaller in the elderly group than in the young group. As a consequence, the negative chronotropic and dromotropic effect of verapamil was observed in the elderly group. This study suggests that the effect of age on metabolism was greater for (S)-verapamil than for (R)-verapamil.

Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases.

Paraoxonase 1 (PON1) is proposed to have an anti-atherogenic action. Two polymorphisms at the PON1 (M/L55 and Q/R192) have been shown to be associated with coronary artery disease (CAD). This conclusion is not drawn universally, however, and specific ethnic characteristics may be important determinants in this association. Recently two homologues of PON1 - PON2 and PON3 - were identified and Sanghera et al. demonstrated C/S311 polymorphism at PON2 was associated with the risk of CAD. Within that context, we investigated the association between the aforementioned three polymorphisms and CAD and ischemic stroke in a Japanese population. The study population included 431 control subjects, 210 CAD patients, and 235 ischemic stroke patients. Genotype distributions and allele frequencies of M/L55 and C/S311 were similar among the control and patient groups, whereas the R192 allele frequency was significantly higher (P<0.001) in CAD (75%) and ischemic stroke (76%) patients than in control subjects (65%). When confounding influences of other risk factors were controlled for by multivariate analysis, R192 remained an independent risk determinant (additive model: OR (95% CI), P value CAD: 2.01 (1.45-2.79), 0.0001; ischemic stroke: 1.84 (1.34-2.52), 0.0002 (three genotypes into calculation)). Taken together, our data indicate that the Q/R192 is principally associated with both CAD and ischemic stroke in Japanese.

Metabolites of antihypertensive drugs. An updated review of their clinical pharmacokinetic and therapeutic implications.

Many antihypertensive drugs are extensively metabolised in humans. Since some metabolites are active and may therefore contribute to the pharmacological activity of the parent drugs, knowledge of the pharmacokinetic properties of active metabolites is important for understanding the overall effects of drugs. Four categories of antihypertensive drugs with active metabolites are dealt with, with selected examples described in some detail. First, drugs with effects relying totally on active metabolites include agents such as methyldopa, cadralazine and many angiotensin converting enzyme (ACE) inhibitors. Secondly, those with effects primarily due to active metabolites include drugs such as triamterene and spironolactone. Thirdly, agents with effects primarily due to the parent drug, but with active metabolites providing significant contributions to the overall pharmacological effect, include drugs such as indoramin, alprenolol, acebutolol, diltiazem and verapamil. Lastly, agents with pharmacological effects with only minor (if any) contributions from active metabolites include drugs such as propranolol, metoprolol, carteolol and others.

The influence of delivery mode on biological inactive renin level in umbilical cord blood.

In order to investigate the influence of delivery mode on biological inactive renin levels in fetal circulation, plasma inactive renin (PIR), plasma renin activity (PRA) and plasma total renin (PTR) were measured in umbilical venous blood samples of 21 infants delivered vaginally after spontaneous labor and of 9 infants delivered by elective cesarean section after the onset of labor. Biological renin activities were measured by bioassay. The PIR levels in infants delivered vaginally were significantly lower than those in infants delivered by cesarean section, while the PRA levels were the opposite. However, the PTR levels were not significantly different between the two groups. These results suggest that the plasma levels of biological inactive renin in infants delivered vaginally may decrease, probably due to its conversion to active renin in the second stage of labor.