Effects of dietary alpha-linolenic acid-enriched diacylglycerol oil on embryo/fetal development in rats.

Recent studies suggest that diets supplemented with alpha-linolenic acid (ALA)-enriched diacylglycerol (DAG) oil provide potential health benefits in preventing or managing obesity. However, available safety information about reproductive and developmental toxicities of ALA-DAG oil is limited. This study was conducted to clarify the effect, if any, of ALA-DAG oil on embryo-fetal development, following maternal exposure during the critical period of major organogenesis. ALA-DAG oil was administered via gavage to pre-mated female Sprague Dawley rats from gestation day 6 through 19, at dose levels of 0, 1.25, 2.5, and 5.0 mL/kg/day (equivalent to 0, 1149, 2325, and 4715 mg/kg/day, respectively), with total volume adjusted to 5 mL/kg/day with rapeseed oil. All females survived to the scheduled necropsy. There were no treatment-related changes in clinical or internal findings, maternal body weights, feed consumption, intrauterine growth, survival, and number of implantations. No ALA-DAG oil-related fetal malformations or developmental variations were noted. A maternal maximum tolerated dose for ALA-DAG oil could not be achieved in this study. Based on these results, a dose level of 5.0 mL/kg (4715 mg/kg/day), the highest dose tested, was considered as the no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity.

[Survey of difference in appearance between multiple-specifications press-through-package drug products and an attempt to evaluate their effectiveness based on dispensing incidents].

To survey the difference in appearance between multiple-specification press-through-package (PTP) drug products and to attempt to evaluate their effectiveness as discriminating factors based on dispensing incidents. Front and back sides of, respectively, 153 and 134 PTP drug products of multiple specifications stockpiled in the author's pharmacy were surveyed for differences in wording and appearance between specifications of the same type of drug. Fifty six dispensing incidents with 40 sets occurred over a year and they were analyzed for the appearance similarity of the front side. The difference factors detected in the 40 sets of "mix-ups" were also reviewed after similarity-omitted counting. We identified six factors with difference in appearance: color-related (letter front or patterns, sheet, medicine) and shape- or pattern-related details (sheet and medicine sizes, patterns). Multiple differences on the front packaging of the same type of drug were identified in 93% of the sets, while only one difference was found in about half of the sets on the back, indicating that pharmaceutical companies placed more emphasis on the front side to discriminate their features. When reviewed by similarity-omitted counting, the ratio of sets with only one difference in the 40 mix-ups was higher than those to 128 sets of non-mix-ups, the total sets except the mix-ups, while the ratio of sets with two differences was lower. In addition, the ratio of sets in which only color-related factors differed in the 40 mix-ups was higher than that in the corresponding category to the 128 sets of non-mix-ups. Various discriminating factors were used in combination on the front side of multiple-specification PTP drug products. A combined use of shape- or pattern-related and color-related factors probably reduces dispensing incidents among products with multiple specifications. However, further accumulation of incident data and multifactor analysis of those data seem necessary to clarify the function of difference in appearance in dispensing incidents.

Assessment of suitable antihypertensive therapies: Combination with high-dose amlodipine/irbesartan vs triple combination with amlodipine/irbesartan/indapamide (ASAHI-AI study).

Angiotensin receptor blockers (ARBs) plus calcium channel blockers (CCBs) are a widely used combination therapy for hypertensive patients. In order to determine which combination was better as the next-step therapy for standard-dose combination of ARBs and CCBs, a combination with high-dose CCBs or a triple combination with diuretics, the authors conducted a prospective, randomized, open-label trial to determine which of the following combination is better as the next-step treatment: a combination with high-dose CCBs or a triple combination with diuretics. Hypertensive outpatients who did not achieve their target blood pressure (BP) with usual dosages of ARBs and amlodipine 5 mg were randomly assigned to treatment with irbesartan 100 mg/amlodipine 10 mg (Group 1: n = 48) or indapamide 1 mg in addition to ARBs plus amlodipine 5 mg (Group 2: n = 46). The primary end point was changes in the systolic BP (SBP) and diastolic BP (DBP) after the 12-week treatment period, while secondary end points were changes in BP after the 24-week treatment period and laboratory values. At 12 weeks, the SBP/DBP significantly decreased from 152.1/83.4 mm Hg to 131.5/76.1 mm Hg in Group 1 and 153.9/82.1 mm Hg to 132.7/75.9 mm Hg in Group 2. Although both groups produced a similar efficacy in reducing the SBP/DBP (-19.2/-9.2 mm Hg in Group 1 and -21.6/-8.8 mm Hg in Group 2; SBP P = .378, DBP P = .825), high-dose CCBs combined with ARBs controlled hypertension without elevation of serum uric acid. These results will provide new evidence for selecting optimal combination therapies for uncontrolled hypertensive patients.

[Measurement of amount of fentanyl remaining in used patches: investigation of clinical factors affecting the remaining amounts in 4 patients].

Although fentanyl patches (FP) designed to sustain plasma fentanyl concentrations for 3 days are used in many patients for continuous relief of moderate to severe cancer pain, there are some cases in which effective pain relief is sustained less than for 3 days, and in which plasma fentanyl concentrations rapidly decrease at the third day after the application. In this study, we measured the amount of fentanyl remaining in FP after continuous 3-days use to clarify some clinical factors that can influence the remaining amounts in 4 patients. Average estimated fentanyl-dermal transfer rates of the collected 41 patches calculated from their remaining amounts were less than nominal rates (21.2+/-3.4 cf. 25 microg/h (2.5 mg FP); 44.9+/-5.1 cf. 50 microg/h (5 mg FP)). Intra-individual variability was also observed (CV: 6.6-14.3% (2.5 mg FP), 3.9-13.3% (5 mg FP)). The present study suggests that the estimated fentanyl-dermal transfer rates are affected by fever, patients' body mass index and application sites. Although further study is necessary to elucidate factors that can influence the variability in transdermal fentanyl absorption, the approach in this study would contribute to improving appropriate usage of FP.

[Possibility of interactions between prescription drugs and OTC drugs (2nd report)--interaction between levodopa preparation and OTC Kampo medicines for upset stomach].

Our series of studies aimed to examine the possibility of interactions between prescription drugs and over-the-counter (OTC) drugs by monitoring plasma drug concentrations in rats. When a levodopa preparation indicated for patients with Parkinson's disease was administered in combination with Takeda Kampo Ichoyaku K-matsu (A), Taisho Kampo Ichoyaku (B), or Kanebo Kampo Ichoyaku H(C), which are OTC kampo medicines for upset stomach, the plasma levodopa concentration-time curves were shifted downward and the AUC for levodopa was significantly lowered. These results indicate that there may be some interactions between the levodopa preparation and these OTC kampo medicines when ingested together, which leads to a reduction in the bioavailability of levodopa. On the other hand, concomitant administration of the levodopa preparation with Takeda Kampo Ichoyaku A-matsu (D) did not alter any of the pharmacokinetic parameters for levodopa. According to the package inserts for the OTC kampo medicines, A, B and C, but not D, contain metallic additives, such as aluminum silicate and magnesium stearate. In addition, combination with a kampo basis of D (Koshaheiisan-ka-shakuyaku) showed no detectable change in levodopa bioavailability. From these results, it was concluded that metallic additives may play an essential role in generating the drug-interaction between levodopa preparation and OTC kampo medicine for upset stomach.

Banana juice reduces bioavailability of levodopa preparation.

This study aimed to examine the effects of banana juice on levodopa bioavailability in rats. When a levodopa preparation (EC-Doparl tablets) was orally administered with banana juice made by mixing with a fresh banana and water, there were significant decreases in C(max) (17.4+/-2.5 vs. 8.6+/-3.1 microg/ml; alpha=0.05) and AUC (1882.8+/-49.2 vs. 933.5+/-286.6 microg.min/ml; alpha=0.05) for levodopa. On the other hand, administration of the levodopa preparation with a commercial beverage containing 10% banana juice resulted in no significant change in C(max) or AUC. These results indicate that concomitant intake of levodopa preparations with banana juice, but not with a commercial banana beverage, may cause a drug-food interaction reducing levodopa bioavailability, and we should pay attention to such interactions during levodopa therapy for patients with Parkinson's disease.

OECD validation of the Hershberger assay in Japan: phase 2 dose response of methyltestosterone, vinclozolin, and p,p'-DDE.

The Organisation for Economic Co-operation and Development has initiated the development of new guidelines for the screening and testing of potential endocrine disruptors. The Hershberger assay is one of the assays selected for validation based on the need for in vivo screening to detect androgen agonists or antagonists by measuring the response of five sex accessory organs and tissues of castrated juvenile male rats: the ventral prostate, the seminal vesicles with coagulating glands, the levator ani and bulbocavernosus muscle complex, the Cowper's glands, and the glans penis. The phase 1 feasibility demonstration stage of the Hershberger validation program has been successfully completed with a single androgen agonist and a single antagonist as reference substances. The phase 2 validation program employs a range of additional androgen agonists and antagonists as well as 5alpha-reductase inhibitors. Seven Japanese laboratories have contributed phase 2 validation studies of the Hershberger assay using methyltestosterone, vinclozolin, and 2,2-bis (4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE). The methyltestosterone doses were 0, 0.05, 0.5, 5, and 50 mg/kg/day, and the vinclozolin and p,p'-DDE doses were 0, 3, 10, 30, and 100 mg/kg/day. All chemicals were orally administered by gavage for 10 consecutive days. In the antagonist version of the assay using vinclozolin and p,p'-DDE, 0.2 mg/kg/day of testosterone propionate was coadministered by subcutaneous injection. All five accessory sex preproductive organs and tissues consistently responded with statistically significant changes in weight within a narrow window. Therefore, the Japanese studies support the Hershberger assay as a reliable and reproducible screening assay for the detection of androgen agonistic and antagonistic effects.

Comparison of myocardial fatty acid metabolism with left ventricular function and perfusion in cardiomyopathies: by 123I-BMIPP SPECT and 99mTc-tetrofosmin electrocardiographically gated SPECT.

OBJECTIVE: To investigate myocardial fatty acid metabolism and its relationship with left ventricular (LV) function and perfusion in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). METHODS: Thirty-nine patients with cardiomyopathies (58 +/- 14 y), comprising 15 DCM and 24 HCM, and 9 age-matched healthy controls were studied with 123I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) and 99mTc-tetrofosmin (TF) electrocardiographically gated SPECT. As parameters of myocardial fatty acid metabolism, the heart-to-mediastinum ratio (H/M) and global washout of BMIPP were calculated from early and delayed planar images, while regional BMIPP uptake and washout were calculated from SPECT. In TF study, the H/M (H/M-TF) and LV ejection fraction (LVEF) were calculated as global parameters of perfusion and function, while regional TF uptake and wall thickening index were calculated as regional parameters of perfusion and function using the Quantitative Gated SPECT software. The differences in the parameters and the correlations between the parameters from the 2 studies were investigated by one-way ANOVA and multiple linear regression analysis. RESULTS: BMIPP uptake was decreased (p < 0.05), and its washout was increased (p < 0.05) in DCM and HCM. In multiple linear regression analysis, global BMIPP parameters showed no significant correlation with LVEF (p > 0.05), but showed a significant correlation with H/M-TF (p < 0.05) in DCM and HCM. According to the partial correlation coefficient, early H/M was the only significant factor (p < 0.05) for predicting H/M-TF in DCM and HCM. Multiple linear regression analysis on regional parameters showed regional BMIPP parameters had no correlation with regional function (p > 0.05) but had a significant correlation with regional perfusion (p < 0.0001) in DCM. In HCM, regional BMIPP parameters showed significant multiple linear correlations with both regional function (p < 0.005) and perfusion (p < 0.0001). According to the partial correlation coefficients, delayed regional BMIPP uptake was the most significant factor for predicting regional function in HCM, while early regional BMIPP uptake was the only or the most significant factor for predicting regional perfusion in DCM and HCM, respectively. CONCLUSION: In DCM, BMIPP uptake and washout could not reflect LV function. In HCM, regional delayed BMIPP uptake might be useful for evaluating regional function. In DCM and HCM, early BMIPP uptake might be largely determined by myocardial perfusion.

Historical control data on developmental toxicity studies in rodents.

Historical control data on rodent developmental toxicity studies, performed between 1994 and 2010, were obtained from 19 laboratories in Japan, including 10 pharmaceutical and chemical companies and nine contract research organizations. Rats, mice, and hamsters were used for developmental toxicity studies. Data included maternal reproductive findings at terminal cesarean sections and fetal findings including the spontaneous incidences of external, visceral, and skeletal anomalies. No noticeable differences were observed in maternal reproductive data between laboratories. Inter-laboratory variations in the incidences of fetuses with anomalies appeared to be due to differences in the selection of observation parameters, observation criteria, classification of the findings, and terminology of fetal alterations. Historical control data are useful for the appropriate interpretation of experimental results and evaluation of the effects of chemical on reproductive and developmental toxicities.

[A research of letter color visibility in package insert information using simulator].

Package insert of pharmaceutical drug is one of the most prioritized information for pharmacists to secure safety of patients. However, the color of character, size, font and so on are various company by company product to product from a viewpoint of visibility. It may be cause a serious accident in case visibility is unclear, although it is the most important information. Moreover, package insert with high visibility is required for color vision defectives from a viewpoint of a universal design. Then, the authors selected the package insert which has the boxed warning in the ethical pharmaceutical currently stored mostly in the present health insurance pharmacy and quantified the red color using the color meter. We advocate the state of a suitable package insert from a viewpoint of a universal design, whether the red color is high visible or not for color vision defectives using simulator.

Historical control data on prenatal developmental toxicity studies in rabbits.

Historical control data on rabbit prenatal developmental toxicity studies, performed between 1994-2010, were obtained from 20 laboratories, including 11 pharmaceutical and chemical companies and nine contract laboratories, in Japan. In this paper, data were incorporated from a laboratory if the information was based on 10 studies or more. Japanese White rabbits and New Zealand White rabbits were used for prenatal developmental toxicity studies. The data included maternal reproductive findings at terminal cesarean sections and fetal findings including spontaneous incidences of morphological alterations. No noticeable differences between strains or laboratories were observed in the maternal reproductive and fetal developmental data. The inter-laboratory variations in the incidences of fetal external, visceral, and skeletal alterations seem to be due to differences in the selection of observation parameters, observation criteria, and classification of the findings, and terminology of fetal alterations.

[Furanocoumarins contents and cytochrome P450 3A (CYP3A) inhibitory activities of various processed fruit peel products: outflow of 6',7'-Dihydroxybergamottin during processing treatment of peel].

Furanocoumarins (FCs) such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHBG) contained in grapefruits are known to be cytochrome P450 3A4 (CYP3A4) inhibitors. These are contained in larger quantity in peel than in pulp, and therefore, processed peel products possibly have strong CYP3A4 inhibitory activity. The CYP3A4 inhibitory potency of these processed peel products, however, remains to be elucidated. The FC content and CYP3A inhibitory activities of various processed fruit peel products were investigated. CYP3A inhibitory activities of crystallized grapefruit peel, grapefruit marmalade, lemon peel and bitter orange slice were close to that of 100% grapefruit juice, while the activities of yuzu slice, pomelo (buntan) marmalade and crystallized iyokan peel were very weak, 1/8-1/20 of 100% grapefruit juice. The maximum BG content was 5.6 µg/g in lemon peel. The maximum DHBG content was 7.2 µg/g in crystallized grapefruit peel, about 1/30 that of raw peel. Grapefruit marmalade and crystallized grapefruit peel contained similar amounts of FCs to 100% grapefruit juice, but FCs were not detected in pomelo (buntan) marmalade or crystallized iyokan peel. Good correlation (r=0.78) was observed between the FC contents of these peel products and those CYP3A inhibitory activities. Preparation of homemade grapefruit marmalade and crystallized peel revealed that considerably lower DHBG content in these products and lower CYP3A inhibitory activity than anticipated were attributable to outflow of DHBG to broth during boiling of the raw peel.

Magnesium attenuates isoproterenol-induced acute cardiac dysfunction and beta-adrenergic desensitization.

Sympathetic nervous activation is a crucial compensatory mechanism in heart failure. However, excess catecholamine may induce cardiac dysfunction and beta-adrenergic desensitization. Although magnesium is known to be a cardioprotective agent, its beneficial effects on acute cardiac dysfunction remain to be elucidated. We examined the effects of magnesium on left ventricular (LV) dysfunction induced by a large dose of isoproterenol in dogs. Sixteen anesthetized dogs underwent a continuous infusion of isoproterenol (1 micro g.kg(-1).min(-1)) with or without a magnesium infusion (1 mg.kg(-1).min(-1)). The dose response to small doses of isoproterenol (0.025-0.2 micro g.kg(-1).min(-1)) was tested hourly. A large dose of isoproterenol decreased LV systolic function, increased the time constant of LV isovolumic relaxation, and suppressed the dose response to small doses of isoproterenol in a time-dependent manner. Magnesium significantly attenuated isoproterenol-induced LV systolic and diastolic dysfunction and preserved the dose response to isoproterenol. Serum-ionized calcium significantly decreased with a large dose of isoproterenol but was fully maintained at baseline level with magnesium. A large dose of isoproterenol increased serum lipid peroxide levels and serological markers of myocardial damage, which were significantly suppressed by magnesium. In conclusion, magnesium significantly attenuated excess isoproterenol-induced acute cardiac dysfunction and beta-adrenergic desensitization.

Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol.

Several clinical trials have demonstrated that angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor blocker (ARB) are equally effective in the treatment of chronic heart failure. However, this has not been confirmed for acute cardiac dysfunction. We examined whether ACEI or ARB prevents isoproterenol-induced acute left ventricular (LV) dysfunction in dogs. LV dysfunction induced by a large dose of isoproterenol (1 microg.kg(-1).min(-1), 3-h infusion) was compared in dogs treated with ACEI (temocaprilat) or ARB (olmesartan). Atrial pacing induced a constant heart rate and use of adjustable aortic banding provided a nearly constant afterload. LV systolic function (LV dP/dt, fractional shortening, and ejection fraction) and diastolic function (tau and LV end-diastolic pressure) were significantly deteriorated after isoproterenol infusion. The LV dysfunction was almost totally prevented by ARB but was only partially prevented by ACEI. The partial effect of ACEI was complemented by cotreatment with HOE-140, a bradykinin B2 receptor antagonist. At baseline, the response to low doses of isoproterenol was significantly attenuated by ACEI but not by ARB, and the ACEI-induced attenuation was totally abolished by cotreatment with HOE-140. The response to isoproterenol was significantly attenuated after 3 h of excess isoproterenol loading, and it was almost completely preserved by ARB but not by ACEI. In conclusion, acute LV dysfunction and beta-adrenergic desensitization induced by excess isoproterenol administration were almost totally prevented by ARB but only partially prevented by ACEI. These differences were attributable at least in part to bradykinin pathways activated by ACEI administration in acute LV dysfunction.