Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended‐Release Isosorbide‐5‐Mononitrate in Healthy Subjects

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended‐release formulation of isosorbide‐5‐mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18–45 years) received either ISMN 40 mg or furosemide 20 mg once‐daily for 3 days followed by a 3‐day washout. Subjects then received aliskiren 300 mg once‐daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC_τ was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C_max by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC_τ by 28% (0.72 [0.64, 0.81]) and C_max by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC_τ 1.03 [0.90, 1.18]; C_max 0.94 [0.69, 1.29]) and ISMN (AUC_τ 0.88 [0.71, 1.10]; C_max 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP <90 and/or DBP <50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.     

Presence of interferon in acute- and convalescent-phase sera of humans with influenza or influenza-like illness of undetermined etiology

Interferon (IFN;titer, greater than 10 units) was present in the acute-phase sera of 30 of 40 subjects with culture and/or serologically documented, naturally acquired influenza A/Brazil/78 (H1N1) and in the acute-phase sera of five of 27 subjects with an influenza-like illness of undetermined etiology. No statistical correlation existed between the quantity of IFN in acute-phase serum and the course of the clinical illness. Antiviral activity in all of nine acute-phase sera and three of four sera obtained on the fifth to seventh days of illness was neutralized to greater than 50% by antibody to virus-induced human leukocyte IFN (HuIFN-alpha). In contrast, none of five sera collected between 21 and 23 days after the onset of illness contained IFN sensitive to neutralization by antibody to HuIFN-alpha. Resistance of IFN in convalescent-phase sera to neutralization by antibody to HuIFN-alpha suggests that multiple IFN species may evolve during viral infections.     

Epidermal growth factor receptor inhibition by tyrphostin 51 induces apoptosis in luteinized granulosa cells

Growth factors may be involved in the control of ovarian cell fate and could contribute to regulation of ovarian cell apoptosis. Our objective is to test the hypothesis that, in human luteinized granulosa cells, epidermal growth factor (EGF) works through the MAPK signaling pathway and inhibition of EGF receptor by a specific tyrosine kinase inhibitor, tyrphostin 51, will inhibit the activation of MAPK and induce apoptosis. Luteinized granulosa cells from human in vitro fertilization aspirates were treated as follows: 1) vehicle (dimethylsulfoxide:ethanol), 2) EGF, 3) tyrphostin 51, and 4) tyrphostin 51 plus EGF. Blockage of EGF receptor by tyrphostin 51 reduced the MAPK activity and inhibited phosphorylation and nuclear translocation of activated MAPK. Blockage of EGF receptor also induced apoptosis as demonstrated by the activation of caspase-3, an executioner protease of the apoptotic pathway, and by an increased percentage of subdiploid apoptotic nuclei. These results support the hypothesis that in human luteinized granulosa cells, EGF works through the MAPK signaling pathway and that its inhibition by tyrphostin 51 inhibits MAPK phosphorylation and induces apoptotic nuclear changes. Our data thus provide additional information regarding regulation of apoptosis in luteinized granulosa cells.     

Induction of oviposition in the domestic hen by prostaglandins

Single intrauterine injection of prostaglandins E₁, E₂, and F₂α in this order of potency induce premature oviposition in the hen within a few minutes. Similarly, arachidonic acid, a prostaglandin precursor, was also effective in initiating egglaying. PGE₁ and PGE₂ are about 10–20 times more potent than oxytocin, suggesting a possible physiological role in the regulation of oviposition.     

Influence of blood glucose levels on rat liquid gastric emptying

The glycemic influence on liquid gastric emptying in rats was studied. Diabetic hyperglycemia was induced by streptozotocin intravenous injection seven days before the motility experiment. Some streptozotocin-treated rats further received a daily insulin injection (2.5 or 10 IU/kg). Immediate hyperglycemia was induced in a separate group of rats by continuous intravenous glucose infusion (44 or 88 mg/kg/min) 10 min before the experiment. Rats were killed 15 min after radiochromium feeding; then the radioactivity of stomach and small intestine were counted to obtain the gastric emptying value. Emptying in diabetic rats was delayed compared with controls (mean±se: 40.9±2.6% vs. 54.2±2.8%,P<0.01). Low-dose insulin treatment reversed the impairment, while high-dose treatment even enhanced emptying. Immediate hyperglycemia induced with two glucose infusions also inhibited gastric emptying. Present results indicate that hyperglycemia elicited with any hyperglycemic model is at least one of the important mechanisms to delay liquid gastric emptying.This study was supported by the National Science Council, Republic of China, grant NSC 84-2331-B-075-68.     

Effects of glutamine supplementation on splenocyte cytokine mRNA expression in rats with septic peritonitis

AIM: To investigate the effects of glutamine (GLN)-enriched diets before and GLN-containing total parenteral nutrition (TPN) after sepsis or both on the secretion of cytokines and their mRNA expression levels in splenocytes of rats with septic peritonitis. METHODS: Rats were assigned to a control group and 4 experimental groups. The control group and experimental groups 1 and 2 were fed a semipurified diet, while experimental groups 3 and 4 had part of the casein replaced by GLN which provided 25% of the total nitrogen. After rats were fed with these diets for 10 d, sepsis was induced by cecal ligation and puncture (CLP), whereas the control group underwent a sham operation, at the same time, an internal jugular vein was cannulated. All rats were maintained on TPN for 3 d. The control group and experimental groups 1 and 3 were infused with conventional TPN, while the TPN in experimental groups 2 and 4 was supplemented with GLN, providing 25% of the total nitrogen in the TPN solution. All rats were kiued 3 d after sham operation or CLP to examine their splenocyte subpopulation distribution and cytokine expression levels. RESULTS: Most cytokines could not be detected in plasma except for IL-10. No difference in plasma IL-10 was observed among the 5 groups. The IL-2, IL-4, IL-10, and TNF-α mRNA expression levels in splenocytes were significantly higher in experimental groups 2 and 4 than in the control group and group 1. The mRNA expression of IFN-γ was significantly higher in the GLN-supplemented groups than in the control group and experimental group 1. The proportion of CD45Ra+ was increased, while those of CD3+ and CD4+ were decreased in experimental group 1 after CLP was performed. There were no differences in spleen CD3+ lymphocyte distributions between the control and GLN-supplemented groups. CONCLUSION: GLN supplementation can maintain T-lymphocyte populations in the spleen and significantly enhance the mRNA expression levels of Th1 and Th2 cytokines and TNF-αin the spleen of rats with septic peritonitis.     

Urgent/Emergent percutaneous transvenous mitral commissurotomy

Urgent/emergent percutaneous transvenous mitral commissurotomy (PTMC) was performed in 10 patients (two men and eight women, aged 21 to 60 yr). All patients had arterial hypoxemia and four required mechanical respirators. PTMC was performed in the semi-recumbent position in four patients. The seven patients with pliable valves (group 1) achieved good hemodynamic and echocardiographic results after PTMC, but one died 2 wk later because of sepsis complicating preexisting pneumonitis. The two pregnant patients uneventfully delivered normal babies at term. There was continued clinical improvement in the six surviving patients at last follow-up at 11 to 39 mon (median 26). Of the three patients with calcified valves and severe subvalvular lesions (group 2), the premoribund patient in whom last-resort PTMC created severe mitral regurgitation died 3 days later of multiple organ failure. The other two patients underwent mitral valve replacement 1–6 days later because of lack of clinical improvement due to creation of severe mitral regurgitation and ineffective mitral valve dilation, respectively. In conclusion, urgent/emergent PTMC is feasible and safe. However, its outcomes are dictated by the status of diseased mitral valve and coexisting illness.