Swallowability of Minitablets among Children Aged 6-23 Months: An Exploratory, Randomized Crossover Study.

Minitablets have garnered interest as a new paediatric formulation that is easier to swallow than liquid formulations. In Japan, besides the latter, fine granules are frequently used for children. We examined the swallowability of multiple drug-free minitablets and compared it with that of fine granules and liquid formulations in 40 children of two age groups (n = 20 each, aged 6-11 and 12-23 months). We compared the percentage of children who could swallow minitablets without chewing with that of children who could swallow fine granules or liquid formulations without leftover. The children who visited the paediatric department of Showa University Hospital were enrolled. Their caregivers were allowed to choose the administration method. In total, 37 out of 40 caregivers dispersed the fine granules in water. Significantly more children (80%, 95% CI: 56-94%) aged 6-11 months could swallow the minitablets than those who could swallow all the dispersed fine granules and liquid formulations (22%, 95% CI: 6-47% and 35%, 95% CI: 15-59%, respectively). No significant differences were observed in children aged 12-23 months. Hence, minitablets may be easier to swallow than dispersed fine granules and liquid formulations in children aged 6-11 months.

Post-repair coaptation length and durability of mitral valve repair for posterior mitral valve prolapse.

OBJECTIVE: Chordal placement with no or minimal leaflet resection has been suggested as the preferred technique for mitral valve repair for posterior leaflet prolapse, because it creates a longer coaptation zone. However, whether or not a long coaptation zone improves the durability of mitral valve repairs remains unclear. METHODS: We reviewed 119 patients with chronic degenerative mitral regurgitation including posterior middle scallop prolapse who underwent mitral valve repair between June 2004 and July 2008. We divided them into two groups according to post-repair coaptation length ≥8 mm (group A) or <8 mm (group B). We assessed whether coaptation length is associated with recurrent mitral regurgitation at 1 year after surgery and increase in the regurgitant jet area over 1 year. RESULTS: The group A had a lower incidence of recurrent mitral regurgitation (4.7 vs 9.2%, p = 0.30), smaller increase in mitral regurgitant jet area over 1 year (0.29 vs 0.40 cm(2), p = 0.43), and higher 5-year freedom from recurrent mitral regurgitation (85.6 vs 76.1%, p = 0.76), although the differences were not statistically significant. The multivariate analysis showed that large coaptation length tends to be associated with decreased recurrent mitral regurgitation at 1 year (odds ratio 0.02, 95% confidence interval 0.00-3.67, p = 0.14). CONCLUSIONS: This study did not confirm the association between coaptation length and durability of mitral valve repair for posterior middle scallop prolapse. However, there was a trend towards decreased recurrent mitral regurgitation with larger coaptation length.

Potentiated macrophage activation by acid sensing under low adiponectin levels.

Adiponectin can protect against inflammation; one of the mechanisms involves direct, inhibition of macrophages (MΦ). We postulated that adiponectin anti-sense transgenic (AsTg) mice raised in our laboratory are prone to inflammation because of systemic low adiponectin levels. The writhing response to acetic acid was utilized as an in vivo inflammatory model, and using Ca(2)(+), response to the acid was exploited in vitro to evaluate the function of resident peritoneal MΦ. The in vivo response to the acid was increased and the Ca(2)(+) response of MΦ was enhanced in AsTg mice, compared with those in wild type (WT) mice. In parallel with these enhanced responses, MΦ from AsTg mice augmented TNF-α and IL-6 mRNA expression. We further analyzed the enhancement in activity of MΦ from AsTg mice by acid sensing using specific inhibitors, amiloride for acid-sensing ion channels (ASICs) and KB-R7943 for Na(+)/Ca(2)(+) exchangers (NCXs). Our results indicated that in AsTg mice, the Ca(2)(+) response to the acid was facilitated in MΦ by a low threshold of ASIC1 and NCX1 molecules and the activity of these channel was possibly regulated by adiponectin.

Adiponectin enhances calcium dependency of mouse bladder contraction mediated by protein kinase Cα expression.

Adiponectin is an adipose tissue-secreted protein and is a multifunctional adipocytokine. However, the association of adiponectin with bladder contraction has not been investigated. In this study, the adiponectin-sense transgenic mouse (Adip-Sen mouse; age, 16-24 weeks; male) and age-matched controls (C57Bl mouse) were studied. The Adip-Sen mouse showed a significant increase in plasma adiponectin levels (56.2%; P < 0.01), compared with those in the C57Bl mouse, without affecting other lipid parameters. Isometric force development in bladder smooth muscle tissues were detected using an organ-bath system. Although carbachol (CCh)-induced (0.1-100 µM) time- and dose-dependent contractions in Adip-Sen mouse bladder were slightly enhanced, compared with those in the C57Bl mouse during a low range (0.3-1.0 µM) of CCh, differences could not be detected with other CCh concentrations. However, the reduction in contraction under Ca(2+)-replaced conditions was significantly different between Adip-Sen and C57Bl mice (94.1 and 66.3% of normal contraction, respectively; n = 5). A parameter of Ca(2+) sensitivity, the relation between intracellular Ca(2+) concentration and contraction, was increased in the Adip-Sen mouse, compared with that in the C57B1 mouse. This Ca(2+) dependency in the Adip-Sen mouse was reduced by a protein kinase C (PKC) inhibitor, but not by a Rho kinase inhibitor. Expression of the calcium-dependent isoform of PKC, PKCα, was increased in the Adip-Sen mouse bladder, and CCh-induced phosphorylation of PKCα was also enhanced, compared with those in the C57Bl mouse. In conclusion, adiponectin is associated with bladder smooth muscle contraction, which involves an increase in Ca(2+) dependency of contraction mediated by PKCα expression.

Effect of adiponectin on cardiac allograft vasculopathy.

BACKGROUND: The role of adiponectin (APN), an adipose tissue-specific secretory protein, on chronic rejection after cardiac transplantation in APN-sense transgenic mice (APN-SE) was evaluated. METHODS AND RESULTS: Heterotopic cardiac transplantation in major histocompatibility complex class II-mismatched mice was performed. B6.C-H-2(bm12)KhEg (Bm12) hearts were transplanted into APN-SE, and allografts were harvested at 8 weeks after transplantation. Quantitative polymerase chain reaction (PCR) and immunohistochemical staining showed that the expression of both AdipoR1 and AdipoR2 was induced in APN-SE recipients. Neointimal hyperplasia was significantly decreased in allografts transplanted into APN-SE (luminal occlusion, 8.9 ± 2.2%) compared to those transplanted into controls (49.4 ± 10.5%; P=0.011). APN-SE showed significantly reduced mRNA levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, and monocyte chemoattractant protein-1 (MCP-1) by quantitative PCR. Western blot analysis revealed that the protein levels of IFN-γ and MCP-1 were reduced in APN-SE recipients. Proliferation of smooth muscle cells stimulated with activated T cells was suppressed by APN addition, and this effect was canceled by treatment with an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. CONCLUSIONS: APN plays a critical role in the attenuation of chronic rejection by suppressing inflammatory cytokine and chemokine expression and enhancing APN receptor expression. APN plays a beneficial role in reducing the progression of cardiac allograft vasculopathy through the AMPK pathway.

Adiponectin protects against doxorubicin-induced cardiomyopathy by anti-apoptotic effects through AMPK up-regulation.

AIMS: Adiponectin (APN) has been reported to protect against ischaemia-reperfusion injury and hypertrophy. However, few reports have investigated the cardioprotective effects of APN in doxorubicin (DOX)-induced cardiomyopathy; therefore, we studied the cardioprotective mechanisms of APN in this model. METHODS AND RESULTS: In an in vivo study, we quantified the cardiac pathohistology of C57BL/6 mice [wild-type (WT) mice], APN transgenic mice with high APN concentrations [APN transgenic sense (SE) mice], and those with reduced APN concentrations [APN transgenic antisense (AS) mice] after intraperitoneal injections of DOX (4 mg/kg) weekly for 6 weeks. The survival rate after 14 days was significantly increased in APN-SE mice (WT vs. APN-AS vs. APN-SE: 40 vs. 17 vs. 73%, P < 0.05). We assessed myocardial pathohistological changes and observed that fibrosis and apoptosis were significantly decreased in APN-SE mice compared with those of the other groups. We also assessed DOX-induced apoptotic mechanisms in vitro using cultured cardiomyocytes isolated from neonatal WT mice. The expression of adenosine monophosphate-activated protein kinase (AMPK) and anti-apoptotic factor Bcl-2 increased, but that of pro-apoptotic factor Bax decreased in cardiomyocytes treated with highly concentrated APN. The protective effects of APN were reversed by the addition of an AMPK inhibitor (dorsomorphin) to the culture medium. CONCLUSION: These data suggest that APN improved cardiac function through anti-apoptotic effects by up-regulation of AMPK in DOX-induced cardiomyopathy in mice.

Estimating pediatric doses of drugs metabolized by cytochrome P450 (CYP) isozymes, based on physiological liver development and serum protein levels.

We established a method for estimating pediatric doses of drugs metabolized by cytochrome P450 (CYP) isozymes, using the free fraction of drug in plasma (fu), serum protein level (P), liver volume (LV), and CYP activity (Vmax/Km) as indices of physiological and biochemical development in children up to 15 years old. This method allows the child/adult dose ratio (D(C)/D(A))=child/adult oral clearance ratio (CL((PO)(C))/CL((PO)(A))) of drugs mainly metabolized in the liver to be estimated by the following equation: [formula: see text]. Major metabolism of drugs was ascribed to CYP1A2 for theophylline and caffeine, and CYP1A2 and CYP2D6 for propranolol and mexiletine. For theophylline and caffeine, CL((PO)(C))/CL((PO)(A)) calculated from the child/adult body surface area ratio (BSA ratio) and the value calculated by our method were compared, using CL((PO)(C))/CL((PO)(A)) calculated from the clearance ratio based on population pharmacokinetics (PPK ratio) as a reference. For all drugs, pediatric doses calculated from the Crawford equation and our equation were compared, with predetermined doses as the reference. For theophylline and caffeine, the relative accuracy of our method was significantly higher than that of BSA-based estimation when the PPK ratio was used for reference. For theophylline, caffeine, and propranolol, the relative accuracy of our method was significantly higher than that of BSA-based estimation when predetermined doses were used for reference. These findings indicate the validity of our method which considers the physiological and biochemical development (i.e., fu, P, LV, and CYP activity) for pediatric dose estimation.

Cardioprotective effects of short-term caloric restriction are mediated by adiponectin via activation of AMP-activated protein kinase.

BACKGROUND: Overeating and obesity are major health problems in developed countries. Caloric restriction (CR) can counteract the deleterious aspects of obesity-related diseases and prolong lifespan. We have demonstrated that short-term CR improves myocardial ischemic tolerance and increases adiponectin levels. Here, we investigated the specific role of adiponectin in CR-induced cardioprotection. METHODS AND RESULTS: Adiponectin antisense transgenic (Ad-AS) mice and wild-type (WT) mice were randomly assigned to a group fed ad libitum and a CR group (90% of caloric intake of ad libitum for 3 weeks, then 65% for 2 weeks). Isolated perfused mouse hearts were subjected to 25 minutes of ischemia, followed by 60 minutes of reperfusion. CR increased serum adiponectin levels by 84% in WT mice. Gel filtration analysis of the oligomeric complex distribution showed that CR produced a marked increase in the high-molecular-weight complex of adiponectin in WT mice; in contrast, CR did not change serum adiponectin levels or their oligomeric pattern in Ad-AS mice. CR improved the recovery of left ventricular function after ischemia/reperfusion and limited infarct size in WT mice; these effects were completely abrogated in Ad-AS mice. CR also increased the phosphorylated form of AMP-activated protein kinase and acetyl-CoA carboxylase in WT but not in Ad-AS mice. Recombinant adiponectin restored CR-induced cardioprotection in Ad-AS mice, and inhibition of AMP-activated protein kinase phosphorylation completely abrogated CR-induced cardioprotection in WT mice. CONCLUSIONS: The cardioprotective effects of short-term CR are mediated by increased production of adiponectin and the associated activation of AMP-activated protein kinase.

Adiponectin plays an important role in efficient energy usage under energy shortage.

Adiponectin is an adipose tissue-specific secretory protein known to be an insulin-sensitizing protein. In this study, we generated adiponectin sense and antisense transgenic (Tg) mice to investigate whether adiponectin plays a role in the regulation of energy homeostasis during the growth stage. Spontaneous motor activity of antisense Tg mice were markedly reduced during fasting, particularly in young female mice, compared with wild type (Wt) and sense Tg mice. Furthermore, both body weight and adipose tissue mass of the antisense female Tg mice drastically reduced during fasting. To examine the relationship between the collapse of abdominal white adipose tissue (WAT) and serum adiponectin level, we measured the expression of genes related to energy expenditure, such as uncoupling protein (UCP). Notably, the mRNA of UCP1 in the WAT of antisense Tg female mice was markedly less than that of Wt mice and the UCP1 mRNA was strongly increased during fasting. These findings suggest that the serum adiponectin is important to maintaining energy homeostasis under energy shortage conditions, such as over female pubertal development.

Angiotensin II infusion decreases plasma adiponectin level via its type 1 receptor in rats: an implication for hypertension-related insulin resistance.

We explored the mechanisms underlying the close association between hypertension and insulin resistance by measuring the changes in the plasma levels of adiponectin, a novel insulin sensitizer secreted by adipose tissue, in rats infused with angiotensin II (AII). Angiotensin II (100 ng/kg per minute) was subcutaneously infused with osmotic minipumps for 2 weeks in rats fed with either standard chow or a high-fructose diet. Insulin sensitivity index (SI) was assessed by the minimal model of Bergman [Diabetes 1989;38:1512-27]. Angiotensin II infusion significantly increased blood pressure and decreased SI. Angiotensin II decreased plasma adiponectin levels from 3.7 to 2.9 microg/mL (P < .01) without affecting the expression of adiponectin messenger RNA in adipose tissue. Angiotensin II infusion did not affect plasma leptin and tumor necrosis factor alpha levels. An AII type 1 receptor blocker, olmesartan, restored the low adiponectinemia induced by the AII infusion (50 ng/kg per minute). Plasma adiponectin levels were significantly lower in fructose-fed rats (2.3 microg/mL) than in chow-fed rats. Angiotensin II induced no further decrease of adiponectin, whereas olmesartan increased adiponectin remarkably both with and without AII infusion. The AII type 2 receptor blocker PD123319 left the AII-induced hypoadiponectinemia unchanged in both chow- and fructose-fed rats. The AII type 2 receptor agonist CGP42112A also left the adiponectin unchanged. Plasma adiponectin levels were substantially correlated with SI (r = 0.61, P < .0001). These results suggest that AII suppresses adiponectin production via AII type 1 receptor, resulting in impaired insulin sensitivity.