Ahuva Golik

Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema

BACKGROUND Nitrates and furosemide, commonly administered in the treatment of pulmonary oedema, have not been compared in a prospective clinical trial. We compared the efficacy and safety of these drugs in a randomised trial of patients with severe pulmonary oedema and oxygen saturation below 90%. METHODS Patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. 110 patients were randomly assigned either to group A, who received isosorbide dinitrate (3 mg bolus administered intravenously every 5 min; n=56) or to group B, who received furosemide (80 mg bolus administered intravenously every 15 min, as well as isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h; n=54). Six patients were withdrawn on the basis of chest radiography results. Treatment was continued until oxygen saturation was above 96% or mean arterial blood pressure had decreased by 30% or to below 90 mm Hg. The main endpoints were death, need for mechanical ventilation, and myocardial infarction. The analyses were by intention to treat. FINDINGS Mechanical ventilation was required in seven (13%) of 52 group-A patients and 21 (40%) of 52 group-B patients (p=0.0041). Myocardial infarction occurred in nine (17%) and 19 (37%) patients, respectively (p=0.047). One patient in group A and three in group B died (p=0.61). One or more of these endpoints occurred in 13 (25%) and 24 (46%) patients, respectively (p=0.041). INTERPRETATION High-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, is safe and effective in controlling severe pulmonary oedema. This treatment regimen is more effective than high-dose furosemide with low-dose isosorbide nitrate in terms of need for mechanical ventilation and frequency of myocardial infarction.

High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema

OBJECTIVE To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND Although noninvasive ventilation is increasingly used in the treatment of pulmonary edema, its efficacy has not been compared prospectively with newer treatment modalities. METHODS We enrolled 40 consecutive patients with severe pulmonary edema (oxygen saturation <90% on room air prior to treatment). All patients received oxygen at a rate of 10 liter/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Thereafter patients were randomly allocated to receive 1) repeated boluses of IV isosorbide-dinitrate (ISDN) 4 mg every 4 min (n = 20), and 2) BiPAP ventilation and standard dose nitrate therapy (n = 20). Treatment was administered until oxygen saturation increased above 96% or systolic blood pressure decreased to below 110 mm Hg or by more than 30%. Patients whose conditions deteriorated despite therapy were intubated and mechanically ventilated. All treatment was delivered by mobile intensive care units prior to hospital arrival. RESULTS Patients treated by BiPAP had significantly more adverse events. Two BiPAP treated patients died versus zero in the high dose ISDN group. Sixteen BiPAP treated patients (80%) required intubation and mechanical ventilation compared to four (20%) in the high dose ISDN group (p = 0.0004). Myocardial infarction (MI) occurred in 11 (55%) and 2 (10%) patients, respectively (p = 0.006). The combined primary end point (death, mechanical ventilation or MI) was observed in 17 (85%) versus 5 (25%) patients, respectively (p = 0.0003). After 1 h of treatment, oxygen saturation increased to 96 +/- 4% in the high dose ISDN group as compared to 89 +/- 7% in the BiPAP group (p = 0.017). Due to the significant deterioration observed in patients enrolled in the BiPAP arm, the study was prematurely terminated by the safety committee. CONCLUSIONS High dose ISDN is safer and better than BiPAP ventilation combined with conventional therapy in patients with severe pulmonary edema.

A prospective study of posttraumatic stress symptoms and nonadherence in survivors of a myocardial infarction (MI)

We examined a novel hypothesis that links symptoms of MI-related posttraumatic stress disorder (PTSD) to nonadherence. According to this hypothesis, patients who are traumatized by their medical illness do not take their medications as prescribed. As a part of the avoidance dimension of PTSD, patients who are traumatized may avoid being reminded of the MI by not taking the medication. MI survivors were prospectively followed for 6 months to 1 year. Adherence was assessed by pill count of Captopril. Demographic variables, medical risk factors, PTSD, and other psychiatric symptom dimensions were evaluated during follow-up. One hundred two of 140 recruited patients completed follow-up. Nonadherence to Captopril was associated with poor medical outcome (r=.93, P=.006). Above-Threshold PTSD symptoms were associated with nonadherence to medications (P=.05). No other psychiatric symptom dimensions were independently associated with nonadherence. Nonadherence to medications predicts adverse outcome during the first year after an acute MI. Nonadherence is associated with PTSD symptoms, which may either be a marker for or a cause of nonadherence. Treatment of PTSD may prove to be a useful approach for improving adherence.

L-NMMA (a nitric oxide synthase inhibitor) is effective in the treatment of cardiogenic shock.

BACKGROUND The objective was to assess the safety and efficacy of L-NMMA in the treatment of cardiogenic shock. METHODS We enrolled 11 consecutive patients with cardiogenic shock that persisted after >24 hours from admission, despite coronary catheterization and primary percutaneous transluminal coronary revascularization, when feasible, and treatment with mechanical ventilation, intraaortic balloon pump (IABP), and high doses of catecholamines. L-NMMA was administered as an IV bolus of 1 mg/kg and continuous drip of 1 mg. kg(-1). h(-1) for 5 hours. Treatment with catecholamines, mechanical ventilation, and IABP was kept constant throughout the study. RESULTS Within 10 minutes of L-NMMA administration, mean arterial blood pressure (MAP) increased from 76+/-9 to 109+/-22 mm Hg (+43%). Urine output increased within 5 hours from 63+/-25 to 156+/-63 cc/h (+148%). Cardiac index decreased during the steep increase in MAP from 2. 0+/-0.5 to 1.7+/-0.4 L/(min. m(2)) (-15%); however, it gradually increased to 1.85+/-0.4 L/(min. m(2)) after 5 hours. The heart rate and the wedge pressure remained stable. Twenty-four hours after L-NMMA discontinuation, MAP (+36%) and urine output (+189%) remained increased; however, cardiac index returned to pretreatment level. No adverse events were detected. Ten out of eleven patients could be weaned off mechanical ventilation and IABP. Eight patients were discharged from the coronary intensive care unit, and seven (64%) were alive at 1-month follow-up. CONCLUSIONS L-NMMA administration in patients with cardiogenic shock is safe and has favorable clinical and hemodynamic effects.

Increased toxicity of high‐dose furosemide versus low‐dose dopamine in the treatment of refractory congestive heart failure

To evaluate the safety and efficacy of low‐dose dopamine, high‐dose furosemide, and their combination in the treatment of refractory congestive heart failure.

Effects of captopril and enalapril on zinc metabolism in hypertensive patients.

OBJECTIVE To investigate the effect of chronic captopril and enalapril treatment on zinc metabolism in hypertensive patients by assessing zinc levels in serum, urine and monocytes. METHODS Patients with newly diagnosed essential hypertension were randomly divided into two treatment groups: those treated with captopril only (n = 16) and those treated with enalapril only (n = 18). Ten healthy subjects served as controls. Prior to the start of treatment and again 6 months later, zinc was assessed in the serum, in urine collected over 24 hours, and in peripheral blood monocytes. RESULTS Significant enhancement of 24-hour urinary zinc excretion (micrograms/24 hour) after 6 months of treatment was observed only in the captopril-treated group (p < 0.01). However, intramonocytic zinc levels decreased significantly in both of the treated groups over the same period (p < 0.01 and P < 0.04 in the captopril- and enalapril-treated groups, respectively). CONCLUSION Treatment of hypertensive patients with captopril or enalapril may result in zinc deficiency.

Effect of grapefruit juice on the pharmacokinetics of losartan and its active metabolite E3174 in healthy volunteers.

Grapefruit juice (GJ), a cytochrome P450 (CYP) 3A4 inhibitor, may affect the pharmacokinetics of drugs metabolized through CYP 3A4. Losartan, an angiotensin II antagonist, is converted into its main active metabolite E3174 by CYP 3A4 and CYP 2C9. The effect of GJ on losartan pharmacokinetics was assessed in a randomized crossover trial. Losartan was given to 9 volunteers with and without GJ. Concentrations of losartan and its E3174 metabolite were determined in serum by a high-performance liquid chromatography method (HPLC). Significant differences were observed in some of the pharmacokinetic parameters of losartan and its metabolite E3174 after losartan administration with and without co-administered GJ. The lag time (time to drug appearance in serum) of losartan increased significantly with co-administered GJ. The mean residence time (MRT) and half-life (t1/2) of the E3174 metabolite were significantly longer and the area under the concentration–time curve (AUC) of the E3174 metabolite was significantly smaller after concomitant GJ administration. The ratio AUClosartan/AUCE3174 was significantly increased after concurrent grapefruit juice intake. The increased lag time of losartan and the increased MRT and t1/2 and decreased AUC of E3174 were considered indicative of simultaneous CYP 3A4 inhibition and P-glycoprotein activation. The significantly increased AUClosartan/AUCE3174 ratio, however, indicates reduced losartan conversion to E3174 by CYP 3A4 metabolism as a result of co-administered GJ.

Type II diabetes mellitus, congestive heart failure, and zinc metabolism

Zinc status was assessed in patients with type II diabetes mellitus and congestive heart failure (CHF). Three groups of patients were enrolled into the study: Group 1: 15 patients with type II diabetes mellitus and CHF; Group 2: 20 patients with isolated type II diabetes mellitus; and Group 3: nine patients with isolated CHF. Twenty-four-hour urine was measured for creatinine, protein, and zinc, and blood was drawn for creatinine, proteins, liver enzymes, hemoglobin A1c, and zinc. Insulin treatment and hemoglobin A1c were comparable in the diabetic patients of groups 1 and 2, but group 1 was also treated with captopril and diuretics like the CHF patients of group 3. Plasma zinc levels were statistically similar in all three groups, but urinary zinc excretion (μmol/24 h) and urinary zinc: creatinine (μmol/mmol) ratio were significantly higher in the type II diabetics and CHF group (27.2±1.5; 1.69±0.6, respectively) compared to the diabetic patients alone (19.4±0.76; 0.97±0.3, respectively) and the CHF patients (9.7±0.3; 0.62±0.3, respectively). Patients with type II diabetes mellitus and CHF were treated with higher doses of captopril than the CHF patients (56.25±24 mg vs 18.8±11 mgP<0.05). Thus, patients with type II diabetes mellitus and CHF excrete larger amounts of zinc, which may eventually lead to zinc deficiency.

The effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipids, and inflammation in type 2 diabetes mellitus patients.

AIM This study evaluated the effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipid profile, oxidative stress, and high-sensitivity C-reactive protein (hsCRP) in type 2 diabetes mellitus patients. SUBJECTS AND METHODS Forty diabetes patients, inadequately controlled on metformin, were randomly assigned to either sitagliptin (100 mg/day) or glibenclamide (5 mg/day) for 3 months. Following a 1-month washout period, a crossover switch from glibenclamide to sitagliptin and vice versa was performed for an additional 3 months. Arterial stiffness, 24-h ambulatory blood pressure monitoring, lipids, hsCRP, glycated hemoglobin, fasting glucose, STAT-8-isoprostane (a measure of oxidative stress), body mass index (BMI), and waist circumference were measured at baseline and at 3 months with each of the study drugs. RESULTS Thirty-four patients completed the study. Glibenclamide had a better glucose-lowering effect than sitagliptin, but this was associated with more hypoglycemic events. BMI increased following glibenclamide treatment, whereas sitagliptin proved weight-neutral. Mean BMI gain was +0.5±1.0 kg/m(2) for glibenclamide versus -0.01±0.9 kg/m(2) for sitagliptin (P<0.001). Triglyceride levels significantly dropped following sitagliptin, although they remained unaltered after glibenclamide treatment. Mean triglyceride decrease was -18.4±45 mg/mL after sitagliptin but -0.2±57 mg/dL following glibenclamide treatment (P=0.018). There was no change in low-density lipoprotein, high-density lipoprotein, arterial stiffness, blood pressure monitoring, hsCRP, or STAT-8-isoprostane with each of the study drugs. CONCLUSIONS Sitagliptin, but not glibenclamide, demonstrated a significant beneficial effect on BMI and triglyceride levels. However, arterial stiffness, blood pressure, oxidative stress, and inflammatory status were not significantly affected by adding sitagliptin or glibenclamide to metformin-treated type 2 diabetes patients.

The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil

AbstractObjective: To investigate the effect of grapefruit juice (GJ) on the pharmacokinetics of orally administered verapamil in hypertensive patients. Methods: Ten hypertensive patients on chronic verapamil treatment participated in a two-day study. On day 1 200 ml of water was given 1 hour before, and together with the morning verapamil dose; on the day 2, water was replaced by GJ in the same order. Serial blood samples were collected and the concentrations of verapamil and its main dealkylated metabolite (D-617) were determined by high-performance liquid chromatography (HPLC). The area under the concentration versus time curve of verapamil (AUCv) and its metabolite D-617 (AUCM) were calculated before and after GJ ingestion. The peak serum concentration (Cmax) and the time until its appearance (tmax) were also determined. Results: GJ did not affect Cmax, tmax, AUCv or AUVm. The AUCv/AUCm ratio (AUCR) was slightly, but significantly, increased after GJ (1.67 vs 1.92). Conclusions: A single administration of GJ with short-acting verapamil has no significant effect on the pharmacokinetics, of verapamil.