Weight-adjusted dosing of TNK-tissue plasminogen activator and its relation to angiographic outcomes in the thrombolysis in myocardial infarction 10B trial. TIMI 10B Investigators

Fixed doses of thrombolytic agents are generally administered to patients of varying body weights, and the dose-response relation may be confounded by the variability in patient weight. We hypothesized that higher doses of TNK-tissue plasminogen activator (tPA) per unit body weight would be related to improved flow at 90 minutes after thrombolytic administration. A total of 886 patients with acute myocardial infarction were randomized to receive either a single bolus of 30, 40, or 50 mg of TNK-tPA or front-loaded tPA in the Thrombolysis In Myocardial Infarction (TIMI) 10B trial. The dose of TNK-tPA administered was divided by the patient's weight to arrive at the TNK-tPA dose (mg) per unit body weight (kg), and patients were stratified into tertiles based on mg/kg of TNK-tPA: low dose, 0.2 to 0.39 mg/kg; mid-dose, 0.40 to 0.51 mg/kg; high dose, 0.52 to 1.24 mg/kg. Flow in the culprit and nonculprit arteries was analyzed using the TIMI flow grades and the corrected TIMI frame count (CTFC). The median CTFC in culprit arteries differed between the tertiles (3-way p = 0.007), with the CTFC being 7.2 frames faster in high-dose than in low-dose patients (43.1 +/- 30.1, median 31.2, n = 171 vs 54.6 +/- 34.8, median 38.4, n = 166, 2-way p = 0.002). Patients in the mid- and high-dose tertiles achieved patency more frequently (TIMI grade 2 or 3 flow) by 60 minutes (p = 0.02), and the 90-minute percent diameter stenosis was less severe in patients in the high- versus low-dose tertile (p = 0.03). In nonculprit arteries, the CTFC was faster in high- than in low-dose tertiles (29.6 +/- 13.4, median 26.9, n = 130 vs 34.7 +/- 16.3, median 32.8, n = 108, 3-way p = 0.03, 2-way p = 0.008). In patients who underwent percutaneous transluminal coronary angioplasty (PTCA), the CTFC in culprit arteries after PTCA was fastest in the high- and mid-dose tertiles than in those receiving low doses (2-way p = 0.05). Thus, higher doses per unit body weight of TNK-tPA result in not only faster culprit artery flow, but also faster nonculprit, global, and post-PTCA flow, which may reflect earlier opening, reduced stunning, or improved microvascular function. The greater effectiveness of thrombolysis must be weighed against any increase in risk.     

The effects of esmolol on the hemodynamics of acute theophylline toxicity

The effects of esmolol, a beta 1-selective adrenergic receptor antagonist with a short duration of action, were studied in a canine model of the hemodynamics of theophylline toxicity. Animals were anesthetized, then given 50 mg/kg aminophylline IV over 20 minutes followed by a continuous infusion of 1.75 mg/kg/hr. Hemodynamic parameters, including heart rate, cardiac output, systemic blood pressure, pulmonary arterial pressure, and pulmonary artery wedge pressure, were measured every 30 minutes along with plasma catecholamines and theophylline levels. Marked tachycardia was seen in the intoxicated state, with heart rate rising from a baseline of 128.0 +/- 8.3 beats per minute (BPM) to 179.0 +/- 7.4 BPM (P = .012). This was associated with increases in catecholamines (baseline norepinephrine .04 +/- .04 ng/mL plasma rose to .42 +/- .21 ng/mL plasma after intoxication, P = .048). The average serum theophylline level during the experiment was 44.0 +/- 1.1 micrograms/mL serum. Esmolol then was given by IV infusion in these animals in doses of 25, 50, and 100 micrograms/kg/min. It returned the heart rate to the preintoxication baseline in a dose-related manner. Esmolol did not decrease cardiac output or lower blood pressure.     

Myocardial infarct size-limiting effect of ischemic preconditioning was not attenuated by oxygen free-radical scavengers in the rabbit

BACKGROUND. The limiting effect of ischemic preconditioning on infarct size has been reported in canine hearts, which contain considerable amounts of xanthine oxidase, a free radical-producing enzyme. Furthermore, a recent study suggested that free radicals generated during preconditioning may contribute to the cardioprotective effect of preconditioning. The present study examined 1) whether preconditioning limits infarct size in rabbits, which, like humans, lack myocardial xanthine oxidase and 2) whether the cardioprotective effect of PC is mediated by free radicals. METHODS AND RESULTS. A branch of the circumflex coronary artery in rabbits was occluded for 30 minutes and then reperfused for 72 hours. Myocardial infarct size and area at risk were determined by histology and fluorescent particles, respectively. Five groups were studied: an untreated control group, a preconditioned group (PC group), a high-dose superoxide dismutase (SOD)-treated preconditioned group (high-dose SOD-PC group), a low-dose SOD-treated preconditioned group (low-dose SOD-PC group), and a SOD-plus-catalase-treated preconditioned group (SOD/CAT-PC group). Preconditioning was performed with four episodes of 5 minutes of ischemia and 5 minutes of reperfusion. The free radical scavengers (30,000 units/kg SOD for high-dose SOD-PC group, 15,000 units/kg SOD for low-dose SOD-PC group, and 30,000 units/kg SOD plus 55,000 units/kg catalase for SOD/CAT-PC group) were infused intravenously over 60 minutes starting 20 minutes before preconditioning. Infarct size as the percentage of area at risk was 45.1 +/- 3.5% (mean +/- SEM) in the control group (n = 11), 13.3 +/- 3.0% in the PC group (n = 12), 9.7 +/- 1.8% in the high-dose SOD-PC group (n = 8), 11.9 +/- 2.2% in the low-dose SOD-PC group (n = 6), and 9.6 +/- 2.3% in the SOD/CAT-PC group (n = 6) (p less than 0.05 versus control for the last four values). The differences in infarct size as the percent of area at risk among the PC, high-dose SOD-PC, low-dose SOD-PC, and SOD/CAT-PC groups were not significant. CONCLUSION. Ischemic preconditioning delays ischemic myocardial necrosis regardless of myocardial xanthine oxidase content. Free radicals are unlikely to have a major role in the mechanism of the preconditioning in rabbits.     

Effects of amrinone on cardiac index, venous oxygen saturation and venous admixture in patients recovering from cardiac surgery

The hemodynamic and oxygen transport effects of low-dose (0.75 mg/kg loading dose + 10 micrograms/kg/min infusion, n = 12) and high-dose (2.25 mg/kg loading dose + 20 micrograms/kg/min infusion, n = 12) amrinone were evaluated in extubated patients 24 h after CABG. At both doses, amrinone significantly (p less than 0.05) increased HR, but decreased mean arterial, mean pulmonary artery, central venous and pulmonary artery occlusion pressures. High-dose amrinone significantly decreased systemic vascular resistance. Arterial oxygen saturation decreased significantly following both low- (97.8 +/- 0.4 to 95.6 +/- 0.9 percent) and high- (98.8 +/- 3.4 to 93.9 +/- 1.2 percent) dose amrinone. Pulmonary shunt increased significantly following low-dose amrinone and markedly increased Qs/Qt after high-dose amrinone. Although amrinone significantly increased cardiac index in a dose-dependent fashion (low:3.0 +/- 0.2 to 3.3 +/- 0.3 L/min/m2; high:2.7 +/- 0.2 to 3.4 +/- 0.2 L/min/m2), mixed venous oxygen saturation did not change. Thus, mixed venous oxygen saturation may not predict the hemodynamic response to amrinone infusion in postoperative surgical patients.     

Development of a new hydrocarbon extract from the medicinal raw material of Circassian walnut (Juglans regia) and study of its antiparasitic activity

The authors developed a technology for preparing a hydrocarbon extract from the medicinal raw material of Circassian walnut (Juglans regia), including its green fruits, green leaves, and fresh roots. To prepare the preparation, they obtained for the first time a new extragent called petroleum Russia that was found to contain more than hundred chemical compounds by chromatography mass spectrometry. The new agent was named irillen. Experiments on albino mice and albino rats established that the new agent was low toxic. The lethal doses of irillen were calculated: LD50 was 16377 +/- 457.5 mg/kg; LD16 = 12986.4 mg/kg; LD84 was 18976.6 mg/kg for albino mice; LD50 was 16998.0 +/- 535.4 mg/kg; LD16 = 12875.3 mg/ kg; LD84 = 18583.4 mg/kg for albino rats. The irillen prepared by the authors should be referred to as a low toxic and practically nontoxic agent (Toxicity Class IV and V). Irillen has a broad spectrum of antiparasitic activity. It is effective in treating toxocariasis in dogs, larval alveolar echinococcosis, ascaridiasis, and eimeriasis in chickens, and siphachiasis.     

Suppression of intimal hyperplasia with low molecular weight heparin in a sheep model.

BACKGROUND: Both unfractionated heparin (UH) and low molecular weight heparin (LMWH) in therapeutic anticoagulant doses have been shown to inhibit the development of intimal hyperplasia (IH) but with an increased risk of haemorrhage. In this study we investigated the effect of a "low dose" and "high dose" of UH and LMWH on the inhibition of IH together with their effect on plasma anti-Xa activity (AXa) and activated partial thromboplastin time (APTT) using a carotid artery sheep model. METHODS: A gelatin sealed Dacron patch graft was implanted into the common carotid artery of sheep which were randomly allocated to a control group (Group 1, n=10) or to one of four treatment groups receiving either low-dose LMWH enoxaparin 1 mg/kg/day (group 2, n=11), high-dose LMWH enoxaparin 2 mg/kg/day (Group 3, n=13), low-dose UH 125 u/kg/day (Group 4, n=10) or high-dose UH 250 u/kg/day (Group 5, n=10). The LMWH was administered subcutaneously once daily for four weeks and the UH in two divided doses per day for four weeks. During the treatment period, AXa and APTT were assayed from blood collected prior to and at 1 and 2 h after heparin administration on day 3, 7, 14, 21 and 28. On day 28, all animals were sacrificed and grafts were collected for analysis after taking blood samples prior to, then at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h following the last injection. Measurements of intimal thickness were obtained under light microscopy from eight transverse sections of each grafted artery using an eyepiece graticule. RESULTS: IH measurements (Mean+/-SD) were: Group 1 (controls) 288+/-86 microm, Group 2 (low-dose LMWH) 222+/-50 mm (p<0.05 compared to Group 1), Group 3 (high-dose LMWH) 203+/-78 microm (p<0.01), Group 4 (low-dose UH) 275+/-61 microm, and Group 5 (high-dose UH) 206+/-71 microm (p<0.01). There was no significant difference between Groups 2, 3 and 5. Groups 2, 3 and 5 demonstrated significant AXa during the 28 days period of which Groups 2 and 5 showed a significant increase in AXa levels with time. In the 24 h study after the last dose of treatment both Groups 2 and 3 showed longer AXa than group 5 (12-24 h vs 8 h). When compared to the control group, significant elevation of APTT was demonstrated in Groups 3 and 5. Group 5 had significantly longer APTT than Group 3. In the 24 h study, APTT reflected the changes of AXa in all groups. CONCLUSIONS: In this study the LMWH enoxaparin was effective in reducing the formation of IH both at a standard anticoagulant therapeutic dose of 2 mg/kg/day and also at a lower dose of 1 mg/kg/day.     

The influence of theophylline on polyamine metabolism and colonic carcinogenesis induced by 1.2-dimethylhydrazine in mice

The administration of theophylline (120 mg/kg.day, 14 wk) to the drinking water of female BALB/c mice after treatment with 1,2-dimethylhydrazine (DMH) (30 mg/kg.sc, 1/wk, 14 wk) resulted in both an increase in number of colon carcinoma and increases in ornithine decarboxylase (ODC) activities and polyamine (PA) levels in colon tissue. This increase in number of colon carcinoma was about 3-fold to mice receiving same amount of DMH and drinking water without theophylline. ODC activities (pmoles 14CO2/hr/mg prot, mean +/- SD) in colon tissue were 122 +/- 10.6 (n = 6) in DMH with theophylline group, 28.3 +/- 2.13 (n = 8) in DMH alone group, 21.3 +/- 1.67 (n = 6) in control group respectively. Putrescine and spermidine levels (nmoles/g, mean +/- SD) were 31.0 +/- 10.5, 527 +/- 86.6 (n = 11) in DMH with theophylline group, 24.0 +/- 11.4, 464 +/- 129 (n = 11) in control group respectively. Thus with marked increase of ODC activities and slight increase of PA levels, theophylline has shown to significantly enhance the promoting phase of carcinogenic process with DMH.     

Comparison of efficacy and safety of lower-dose to higher-dose oral prednisone after percutaneous coronary interventions (the IMPRESS-LD study)

This study assessed clinical and angiographic efficacies of oral treatment with prednisone at low-dose (LD) versus the previous high-dose (HD) immunosuppressive dosage used after percutaneous coronary interventions (PCIs) with bare metal stents in patients with multivessel coronary artery disease. Forty-three patients with multivessel disease successfully treated with multiple PCIs were matched to the previous HD IMPRESS-2/MVD study population. The 43 patients were treated for 103 coronary stenoses and received 30-day oral prednisone treatment (LD group 1 mg/kg for 5 days, 0.5 mg/kg for 10 days, 0.25 mg/kg for 15 days) and were compared retrospectively with the 43 patients in the HD IMPRESS-2/MVD study with 116 treated coronary lesions (HD group 1 mg/kg for 10 days, 0.5 mg/kg for 20 days, 0.25 mg/kg for 15 days). The primary clinical end point was 12-month event-free survival rate (defined as freedom from death, myocardial infarction, and need for target vessel revascularization). The secondary end point was angiographic restenosis at 8 months assessed by quantitative coronary angiography. Event-free survival rates were 74% and 93% in the LD and HD groups, respectively (relative risk 4.6, 95% confidence interval 1.18 to 17.8, p = 0.019). Restenosis was observed in 4 lesions (4%) in the HD group and in 20 lesions (22%) in the LD group (p <0.001). Mean late lumen loss was 0.61 +/- 0.35 mm, and the loss index was 31.3 +/- 21.6% in the HD group compared with 0.87 +/- 0.61 mm and 52.03 +/- 25.1% in the LD group (p = 0.03 and 0.02, respectively). In conclusion, antirestenotic efficacy of oral treatment with prednisone after conventional PCI is dose sensitive. A 50% dose decrease in oral prednisone, as tested in this study, is less effective than the previously tested HD IMPRESS therapeutic scheme.     

Comparison of intraosseous and intravenous routes of anticonvulsant administration in a porcine model

During status epilepticus, rapid IV access for the administration of anticonvulsant drugs can be a very difficult and time-consuming procedure. Our study evaluated whether therapeutic serum levels of phenobarbital and phenytoin could be obtained by the intraosseous route. Twenty domestic swine weighing 10 to 20 kg were divided into two groups (ten each). In one group, phenobarbital 20 mg/kg was administered either intravenously (five) or intraosseously (five). The second group received phenytoin 15 mg/kg either intravenously (five) or intraosseously (five). All animals had samples for anticonvulsant levels drawn from an indwelling arterial cannula at one, three, five, seven, ten, 15, and 30 minutes after dosing. Anticonvulsant levels were found to be statistically significantly higher with IV administration (P less than .01). However, phenobarbital levels were therapeutic by the intraosseous route, while phenytoin levels were below the therapeutic range after the ten-minute interval. Bone marrow levels 45 minutes after infusion were 13.5 micrograms/mL (phenobarbital) and 11.5 micrograms/mL (phenytoin). Our study demonstrates that current IV dosing of phenobarbital 20 mg/kg given intraosseously obtains and maintains therapeutic serum levels. Phenytoin 15 mg/kg does not maintain therapeutic levels and cannot be recommended for intraosseous administration.     

Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats

We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202+/-4 mm Hg), serum creatinine, and albuminuria (34+/-5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115+/-6 and 139+/-5 mm Hg) and albuminuria (0.4+/-0.1 and 1.6+/-0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148+/-4 mm Hg) and albuminuria (2.1+/-0.7 mg per day), low-dose Val reduced BP (182+/-3 mm Hg) and albuminuria (24+/-3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4+/-0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and beta-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR.     

Growth retardation and depigmentation of hair after high-dose busulfan and congenic hematopoietic cell transplantation in mice.

Busulfan, a myeloablative but non-immunosuppressive alkylating agent, is used extensively in clinical bone marrow transplantation (BMT), but the effects of high-dose administration have not been previously evaluated in preclinical BMT settings with young murine recipients. We compared the survival and growth of C57BL/6 mice given graded single doses of busulfan (10-100 mg/kg) or total body irradiation (TBI; 900 cGy) at age 9 days and hematopoietic cell transplantation (HCT; transplantation of congenic bone marrow and spleen cells) 24 h later. The 30-day survival was 87-100% in mice transplanted after 10-40 mg/kg busulfan and 79% after TBI, but fell to 54% and 33%, respectively, after 80 mg/kg and 100 mg/kg busulfan, suggesting that this latter dosage range represents the LD50 for single-dose busulfan in young C57BL/6 mice given stem cell rescue. The weights of 10-week-old mice given HCT after lower doses of busulfan ranged from 87% of control at 10 mg/kg to 64-69% of control in mice conditioned with 35-65 mg/kg busulfan or TBI. Impairment of weight gain was most striking (approximately 50% of control) in mice transplanted after 80-100 mg/kg busulfan. Despite retardation of somatic growth, the brain weights of busulfan-conditioned mice remained at least 90% of control, and there were no obvious neuropathological alterations in the brains of these animals. All mice treated with at least 20 mg/kg busulfan or TBI lost hair by 3-4 weeks after transplant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Steady-state interaction between amiodarone and phenytoin in normal subjects

Amiodarone has been reported to increase phenytoin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction at steady-state. Pharmacokinetic parameters for phenytoin were determined after 14 days of oral phenytoin, 2 to 4 mg/kg/day, before and after oral amiodarone, 200 mg daily for 6 weeks in 7 healthy male subjects. During amiodarone therapy, area under the serum concentration time curve for phenytoin was increased from 208 +/- 82.8 (mean +/- standard deviation) to 292 +/- 108 mg.hr/liter (p = 0.015). Both the maximum and 24-hour phenytoin concentrations were increased from 10.75 +/- 3.75 and 6.67 +/- 3.51 micrograms/ml to 14.26 +/- 3.97 (p = 0.016) and 10.27 +/- 4.67 micrograms/ml (p = 0.012), respectively, during concomitant amiodarone treatment. Amiodarone caused a decrease in the oral clearance of phenytoin from 1.29 +/- 0.30 to 0.93 +/- 0.25 liters/hr (p = 0.002). These results were due to a reduction in phenytoin metabolism by amiodarone as evidenced by a decrease in the urinary excretion of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, 149 +/- 39.7 to 99.3 +/- 40.0 mg (p = 0.041) and no change in the unbound fraction of the total phenytoin concentration expressed as a percentage, 10.3 +/- 2.7 versus 10.7 +/- 2.1% (p = 0.28) during coadministration of amiodarone. The alterations in phenytoin pharmacokinetics suggest that steady-state doses of phenytoin of 2 to 4 mg/kg/day should be reduced at least 25% when amiodarone is concurrently administered. All dosage reductions should be guided by clinical and therapeutic drug monitoring.     

Melatonin in vivo prolongs cardiac allograft survival in rats

Melatonin, secreted by the pineal gland, is a multifunctional agent which (i) protects tissues from damage through free radical scavenging and attenuates ischemia/reperfusion injury in organ grafts; (ii) acts synergistically with cellular antioxidants; and (iii) displays complex, dose-dependent immunoenhancing and suppressing effects in vitro and in vivo. We analyzed the immunomodulatory effect of melatonin on acute allograft rejection. Cardiac grafts were transplanted from LBNF1 to LEW rats and anastomosed to the abdominal great vessels. The effect of low-dose (LD; 20 mg/kg/day) and high-dose (HD; 200 mg/kg/day) melatonin treatment in recipients compared with untreated controls was investigated. HD melatonin therapy abrogated acute rejection, significantly prolonging allograft survival (mean survival: 12.3 +/- 1 days S.D., n = 8, P < 0.0001) compared with untreated controls, which rapidly reject the transplant (6.3 +/- 1 days n = 12). LD therapy did not extend survival significantly (7.3 +/- 1.1 days, n = 12). Allospecific IgM showed a significant decrease in animals receiving HD therapy versus untreated recipients at days 10 and 14 post-transplantation (P < 0.01), whereas in the LD group at day 10, a significant increase in allospecific IgM (P < 0.01) over the HD cohort was demonstrated. HD treatment markedly reduced lymphocyte proliferative capacity compared with controls and the LD group. HD melatonin treatment abrogated acute allograft rejection and significantly prolonged graft survival. Our results suggest an involvement of melatonin in humoral and cellular immune pathways following perfused organ transplantation. These findings may indicate a novel therapeutic approach, based on modulation of the neuroendocrine/immune axis through melatonin as a possible future immunosuppressant in organ transplantation.     

Partial liquid ventilation in adult patients with acute respiratory distress syndrome

RATIONALE: Despite recent clinical trials demonstrating improved outcome in acute respiratory distress syndrome (ARDS), mortality remains high. Partial liquid ventilation (PLV) using perfluorocarbons has been shown to improve oxygenation and decrease lung injury in various animal models. OBJECTIVE: To determine if PLV would have an impact on outcome in patients with ARDS. METHODS: Patients with ARDS were randomized to (1) conventional mechanical ventilation (CMV; n=107), (2) "low-dose" perfluorocarbon (10 ml/kg; n=99), and (3) "high-dose" perfluorocarbon (20 ml/kg; n=105). Patients in all three groups were ventilated using volume ventilation, Vt or= 0.5, and positive end-expiratory pressure >or= 13 cm H(2)O. RESULTS: The 28-d mortality in the CMV group was 15%, versus 26.3% in the low-dose (p=0.06) and 19.1% in the high-dose (p=0.39) PLV groups. There were more ventilator-free days in the CMV group (13.0+/-9.3) compared with both the low-dose (7.4+/-8.5; p<0.001) and high-dose (9.9+/-9.1; p=0.043) groups. There were more pneumothoraces, hypoxic episodes, and hypotensive episodes in the PLV patients. CONCLUSIONS: PLV at both high and low doses did not improve outcome in ARDS compared with CMV and cannot be recommended for patients with ARDS.     

Clinical relevance of the interaction of theophylline with diltiazem or nifedipine

The results of previously published studies indicate that calcium channel blockers are capable of competitively inhibiting cytochrome P-450 activity in hepatic microsomes, the pathway of theophylline metabolism. In addition, case reports have suggested that theophylline serum concentrations change when a calcium channel blocker has been added to or deleted from a stable theophylline regimen. To determine the clinical relevance of this potential interaction in patients with chronic asthma, we measured a peak steady-state theophylline serum concentration in 21 subjects while receiving theophylline alone (400 to 1,500 mg/day), and again, at least seven days later, after the addition of continuous therapy with maximally tolerated doses of either diltiazem (n = 18) or nifedipine (n = 16). The diltiazem dose was increased in 120 mg/day increments, as tolerated, to a maximum of 240 to 480 mg/day, while the nifedipine dose was increased in increments of 40 mg/day, to a maximum dose of 80 to 160 mg/day. The mean +/- SEM theophylline serum concentrations were 13.6 +/- 1.4 micrograms/ml before and 14.0 +/- 1.2 micrograms/ml during concurrent diltiazem therapy, and 12.6 +/- 1.0 micrograms/ml before and 12.2 +/- 1.1 micrograms/ml during nifedipine (p greater than 0.05). With this sample size there is a 5 percent chance that we missed a 20 percent change in serum concentration (type II error). Thus, maximum tolerated doses of diltiazem or nifedipine do not impair the metabolism of theophylline to a clinically relevant degree and adjustment of theophylline dosage is not required after the addition or discontinuation of diltiazem or nifedipine. In addition, these data suggest that currently available in vitro techniques for evaluating drug interactions in the hepatocyte do not predict the clinical relevance of such an interaction in patients who might require both drugs for different therapeutic indications.     

Effects of low-dose and high-dose glucagon on glucose production and gluconeogenesis in humans

The analysis of mass isotopomers in blood glucose and lactate can be used to estimate gluconeogenesis (Gneo), glucose production (GP), and, by subtraction, nongluconeogenic glucose release by the liver. At 6 AM, 18 normal subjects received a 7-hour primed constant infusion of [U-13C6] glucose. After a 3-hour baseline period (12 hours of fasting), somatostatin, insulin, hydrocortisone, growth hormone (GH), and glucagon were infused for 4 hours. Glucagon was infused at a low-dose (n = 6) or high-dose (n = 6) concentration for 4 hours and was compared with fasting alone (n = 6). Low-dose glucagon infusion increased plasma glucagon (64 +/- 3 v 44 +/- 7 ng/L, low glucagon v baseline). GP increased above baseline (15.5 +/- 0.5 v 13.8 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11 .5 +/- 0.6 micromol/kg/min, P < .05). The elevation in GP was due to a near doubling of nongluconeogenic glucose release compared with fasting alone (8.3 +/- 0.6 v 4.7 +/- 0.5 micromol/kg/min, P < .01). High-dose glucagon infusion (125 +/- 25 ng/L) increased GP above baseline (15.8 +/- 0.6 v 13.5 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11.5 +/- 0.6 micromol/kg/min, P < .05). The increase in GP was due to an increase in Gneo (8.5 +/- 0.5 v 6.8 +/- 0.7 micromol/kg/min, P < .05) and nongluconeogenic glucose release (7.4 +/- 0.5 v 4.7 +/- 0.4 micromol/kg/min, P < .05) compared with fasting. Low-dose glucagon increases GP only by stimulation of nongluconeogenic glucose release. High-dose glucagon increases GP by an increase in both Gneo and nongluconeogenic glucose release.     

短期过量饮酒对大鼠心功能的影响及缬沙坦的保护作用

目的 探讨短期过量饮酒对大鼠心功能的影响机制以及血管紧张素Ⅱ受体拮抗剂(缬沙坦)的保护作用.方法 20周龄、雄性Wistar大鼠42只随机分成4组,对照组10只、酒精组10只、低剂量缬沙坦组(LD组)11只和高剂量缬沙坦组(HD组)11只;各组喂养饲料相同,对照组给予清水灌胃,其余3组给予浓度40%(V/V)食用洒灌胃(6.4 g/kg),LD(15 mg/kg)和HD组(30 mg/kg)再给予不同剂量的缬沙坦.9周后,应用超声心动图观察大鼠心功能的变化,称量体质量(BW)和全心质量(HW),应用样本碱水解法测定大鼠心肌羟脯氨酸含量.结果 9周后超声心动显示,酒精组心脏收缩功能左室射血分数(LVEF)、短轴缩短率(FS)、每搏输出量(SV)与对照组、LD组、HD组比较,差异无统计学意义(P＞0.05);左室舒张早期血流充盈速度(E)及多普勒超声显像二尖瓣内环舒张早期运动速度(Ea)、舒张晚期运动速度(Aa)和舒张早期晚期速度比(Ea/Aa)明显下降,与对照组、LD组、HD组比较差异有统计学意义(P＜0.05),对照组E峰、Ea/Aa高于LD组和HD组(P＜0.05);酒精组的HW/BW、心肌羟脯氨酸含量明显高于其他各组(P＜0.01),而对照组、LD组和HD组间比较,差异无统计学意义(P＞0.05).结论 短期过量饮酒可引起大鼠心肌损伤,导致心脏舒张功能降低,血管紧张索Ⅱ受体拮抗剂缬沙坦对其具有保护作用.     

Comparative effects of tissue plasminogen activator, streptokinase, and staphylokinase on cerebral ischemic infarction and pulmonary clot lysis in hamster models

BACKGROUND: The effects of alteplase (rtPA), streptokinase, and staphylokinase (rSak) on focal cerebral ischemia (FCI) and on pulmonary clot lysis (PCL) were studied in hamsters. METHODS AND RESULTS: ++FCI was produced by ligation of the left middle cerebral artery (MCA) and common carotid artery (CCA) and a 10-minute occlusion of the right CCA. FCI was measured after 24 hours by 2,3, 5-triphenyltetrazolium chloride staining. (125)I-fibrin-labeled plasma clots were injected via the jugular vein, and clot lysis was determined from residual radioactivity at 90 minutes. Study drugs were given intravenously over 60 minutes. FCI increased from 1.2 (0. 27 to 2.3) mm(3) (median and 17th to 83rd percentile range, n=24) in controls to 19 to 27 mm(3) with thrombolytic agent, with maximal rates at 0.13+/-0.05 mg/kg rtPA, 0.23+/-0.09 mg/kg streptokinase, and 0.037+/-0.025 mg/kg rSak. PCL increased from 18+/-2% (mean+/-SEM, n=27) in controls to approximately 85% with thrombolytics, with maximal rates at 0.12+/-0.03 mg/kg rtPA, 0.17+/-0.05 mg/kg streptokinase, and 0.018+/-0.002 mg/kg rSak. All agents caused maximal FCI and PCL rates at similar doses without alpha(2)-antiplasmin and fibrinogen depletion. Injection of 6 mg/kg human plasminogen combined with streptokinase caused a "systemic fibrinolytic state" with fibrinogen depletion. Maximal rates of FCI were obtained with 0.097+/-0.077 mg/kg streptokinase (P=0.26 versus streptokinase alone) and of PCL with 0.010+/-0.002 mg/kg (P=0.006 versus streptokinase alone). CONCLUSIONS: Thrombolytic agents cause similar dose-related extension of FCI after MCA ligation and PCL, irrespective of the agent or systemic plasmin generation.     

Intravenous recombinant tissue-type plasminogen activator in patients with unstable angina pectoris. Results of a placebo-controlled, randomized trial

Because thrombus formation may contribute to coronary obstruction in patients with unstable angina pectoris, we performed a pilot investigation to determine whether thrombolytic therapy can relieve coronary narrowing in this acute ischemic syndrome. Sixty-seven patients with rest angina and angiographic evidence of coronary stenosis were randomly assigned to receive either low-dose intravenous recombinant tissue-type plasminogen activator (rt-PA) (0.75 mg/kg over 1 hour), high-dose intravenous rt-PA (0.75 mg/kg over 1 hour; total dose, 100 mg over 6 hours), or intravenous placebo followed by repeat coronary angiography at 24-48 hours to assess change in the severity of coronary narrowing. Each patient also received oral aspirin and intravenous heparin. Mean values of coronary stenosis severity (percent of diameter reduction) declined to a similar extent in each group: placebo, 75 +/- 14% to 72 +/- 14% (p = 0.07); low-dose rt-PA, 75 +/- 16% to 71 +/- 18% (p = 0.03), and high-dose rt-PA, 82 +/- 11% to 77 +/- 17% (p = 0.18), with only the low-dose rt-PA group achieving statistical significance. Resolution of intracoronary filling defects, increase in antegrade flow grade, or both also occurred equally among the three groups. There was considerable variation in individual patient response. Between 29% and 50% of patients within each group demonstrated a decrease in stenosis severity, whereas 50% to 57% noted either improvement in antegrade flow or resolution of intracoronary thrombus. There was no difference in incidence of major bleeding events among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Theophylline clearance in patients with severe chronic obstructive pulmonary disease receiving supplemental oxygen and the effect of acute hypoxemia

The effect of hypoxemia on the disposition of theophylline was examined in 10 stable patients with chronic obstructive pulmonary disease (COPD) receiving chronic theophylline and supplemental home oxygen therapy. Pharmacokinetics after intravenous theophylline were estimated on the second day of supplemental oxygen (PaO2, 69 +/- 4 mmHg; mean +/- SEM) and on the second day of room air breathing (PaO2, 43 +/- 3) using a randomized cross-over design. On each occasion stable isotope-enriched theophylline (10 mg, m/z 183) was administered intravenously along with the regular oral dose of theophylline (m/z 180). Concentrations of both forms of theophylline in plasma samples obtained over 24 h were measured using mass spectrometry. Theophylline clearance during oxygen therapy (0.048 +/- 0.005 L/h/kg) was similar to that during room air breathing (0.050 +/- 0.004 L/h/kg). Values for elimination half-life (7.6 +/- 0.8 versus 6.8 +/- 0.6 h) and volume of distribution at steady state (0.450 +/- 0.021 versus 0.429 +/- 0.024 L/kg) were also unchanged. The volume of distribution of theophylline was inversely related to arterial pH during oxygen therapy (pH range, 7.32 to 7.44) and during room air breathing (pH range, 7.33 to 7.47). Although hypoxemia does not alter theophylline clearance in patients with COPD, theophylline loading doses may need adjustment according to arterial pH because of an effect on volume of distribution.