Loading Dose Group Research Articles

Role of Clopidogrel Loading Dose in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Angioplasty: Results From the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial

Our aim was to determine whether a 600-mg loading dose of clopidogrel compared with 300 mg results in improved clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). A 600-mg loading dose of clopidogrel compared with 300 mg provides more rapid and potent inhibition of platelet activation. In the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, 3,602 patients with STEMI undergoing primary PCI were randomized to bivalirudin (n = 1,800) or unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (n = 1,802). Randomization was stratified by thienopyridine loading dose, which was determined before random assignment. Patients in the 600-mg (n = 2,158) compared with the 300-mg (n = 1,153) clopidogrel loading dose group had significantly lower 30-day unadjusted rates of mortality (1.9% vs. 3.1%, p = 0.03), reinfarction (1.3% vs. 2.3%, p = 0.02), and definite or probable stent thrombosis (1.7% vs. 2.8%, p = 0.04), without higher bleeding rates. Compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin monotherapy resulted in similar reductions in net adverse cardiac event rates within the 300-mg (15.2% vs. 12.3%) and 600-mg (10.4% vs. 7.3%) clopidogrel loading dose subgroups (p(interaction) = 0.41). By multivariable analysis, a 600-mg clopidogrel loading dose was an independent predictor of lower rates of 30-day major adverse cardiac events (hazard ratio: 0.72 [95% confidence interval: 0.53 to 0.98], p = 0.04). In patients with STEMI undergoing primary PCI with contemporary anticoagulation regimens, a 600-mg loading dose of clopidogrel may safely reduce 30-day ischemic adverse event rates compared with a 300-mg loading dose. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966).

Clopidogrel pretreatment before primary percutaneous coronary stenting in patients with acute ST-segment elevation myocardial infarction: comparison of high loading dose (600 mg) versus low loading dose (300 mg)

Aggressive platelet inhibition is crucial to reduce myocardial injury and early cardiac events after coronary intervention. As compared with the conventional 300-mg dose, pretreatment with a 600-mg loading dose of clopidogrel significantly reduced periprocedural myocardial infarction (MI) in patients undergoing percutaneous coronary intervention (PCI). We investigated that the advantage of the 600-mg dose in inhibiting platelet aggregation more rapidly than the 300-mg dose may actually have special value for acute ST-segment elevation MI patients. A total of 171 patients with ST-segment elevation MI underwent primary PCI. A 600-mg (n=73) or 300-mg (n=98) loading regimen of clopidogrel was given before the procedure. We did a follow-up of all patients clinically for 30 days after coronary intervention. The primary endpoint was the 30-day occurrence of death, MI, urgent revascularization, or stroke. The primary endpoint occurred in 1.4% (1 of 73) of patients in the high dose versus 11.2% (11 of 98) of those in the conventional loading dose group (P=0.013). Death, recurrent MI, urgent revascularization, and stroke were lower in patients treated with the high dose of clopidogrel compared with conventional dose. Safety endpoints were similar in the two groups. Pretreatment with a 600-mg loading dose of clopidogrel before the procedure is safe and, as compared with the conventional 300-mg dose, significantly reduces recurrent MI and urgent revascularization in patients with primary PCI.

Intraoperative low dose ketamine reduce postoperative pain after combined anesthesia with propofol and remifentanil in mastectomy patients.

Remifentanil is a useful opioid, but it induces postoperative hyperalgesia and acute tolerance associated N-methyl-D-aspartate (NMDA) receptor. This study was aimed to investigate whether small dose ketamine, NMDA receptor antagonist, prevent remifentanil induced postoperative hyperalgesia or acute tolerance after combined anesthesia with propofol and remifentanil using target controlled infusion (TCI) in patients undergoing mastectomy. Fourty ASA physical status 1 or 2 women, undergoing mastectomy were randomly assigned to two groups to receive intraoperative infusion of ketamine at 3microgram/kg/min rate after injection of ketamine 0.3 mg/kg as a loading dose (Group K) or saline infusion after saline loading at the same rate and dose (Group C). All the patients were anesthetized with propofol and remifentanil to maintain bispectral index (BIS) 40-60, mean arterial pressure within 20% of basal values. Remifentanil was infused with target controlled infusion (TCI) to the effect site (concentration: 2.0 ng/ml). Postoperative paine scores (visual analog scale: VAS), morphine requirements, and sedation scores were recorded for 48 hours postoperatively. The VAS scores and morphine requirements of the Group K were significantly lower than those of the Group C at the postanesthetic care unit and at the ward for 24 hours postoperatively. The extubation time was delayed in Group K compared with Group C. Intraoperative infusion of small dose ketamine reduced postoperative pain and morphine requirements after combined anesthesia with propofol and remifentanil in patients undergoing mastectomy.

Abstract 1717: Impact of a 600-mg Loading Dose of Clopidogrel on 30-Day Outcome in Unselected Patients Undergoing Percutaneous Coronary Intervention

Background: Based on biological studies of platelet reactivity (PR), the recent ACC/AHA guidelines recommend a 600-mg loading dose (LD) of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). However, there is lack of studies addressing the clinical impact of such a LD of clopidogrel. Objective: We aimed to compare the clinical efficacy and safety of a 600-mg LD of clopidogrel compared to a 300-mg LD in an unselected cohort of patients undergoing PCI. Methods: A cohort of 4105 unselected patients undergoing PCI in our institution was included in the study and divided according to the LD used: the high LD group (600mg) included 3146 patients and the low LD (300mg) group included 959. The primary endpoint was the rate of major adverse cardiovascular events (MACE) at 1 month. Results: Patients in lthe ow LD group more often had diabetes mellitus and a history of myocardial infarction (36.8 vs 31.9%; p = 0.01). Left ventricular ejection fraction was similar (0.49 ± 0.14 vs 0.48 ± 0.14; p = 0.25). Angiographic and procedural characteristics were identical between the 2 groups. Patients in the high LD group had fewer MACE after 1 month (2.9 vs 5.2%; p < 0.001). In multivariate analysis, a 600-mg LD of clopidogrel was significantly associated with MACE at 1-month follow-up, with an odds ratio of 0.62 (95% CI 0.41– 0.95; p = 0.03). Conclusions: A 600-mg LD was associated with a significant decrease in the rate of post PCI-MACE at 1 month without any increase in bleeding complications. The results of our study therefore support the current guideline of a 600-mg LD of clopidogrel in patients undergoing PCI.

A study comparing two protocols of treatment with intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration

Aims:The aim of this study was to compare two treatment options for choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD): (1) bevacizumab administered once a month for 3 months...

Complementary effects of thienopyridine pretreatment and platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention; Results from the ESPRIT trial

This analysis sought to investigate the complementary effect of thienopyridine pretreatment and platelet glycoprotein (GP) IIb/IIIa integrin blockade in coronary stent intervention. Definitive evidence supporting combined antiplatelet therapy consisting of thienopyridine pretreatment and GP IIb/IIIa receptor blockade in patients undergoing percutaneous coronary intervention (PCI) with stent implantation is limited. We retrospectively analyzed clinical outcomes by thienopyridine use in the 2,040 patients randomized to eptifibatide or placebo who underwent PCI in the ESPRIT trial. A total of 901 patients received a loading dose of thienopyridine before PCI (group 1), 123 received thienopyridine pretreatment without a loading dose (group 2), and 1,016 were not treated with thienopyridine before PCI (group 3). The composite incidence of death or myocardial infarction at 30 days was significantly lower in group 1 than in groups 2 and 3 combined (OR, 0.71 [95%CI, 0.52-0.99]; P = 0.0417). A similar trend was seen for the composite of death, myocardial infarction, or urgent target vessel revascularization (unadjusted OR, 0.77 [0.57-1.05]; P = 0.1025). After adjusting for baseline characteristics, these differences were no longer significant. No interactions were identified with eptifibatide assignment for any of the group comparisons. Pretreatment with a loading dose of thienopyridine lowers the rate of ischemic complications regardless of treatment with a GP IIb/IIIa inhibitor. Conversely, the efficacy of eptifibatide is maintained whether or not a loading dose of a thienopyridine is administered. Optimal outcomes are achieved in patients receiving thienopyridine pretreatment along with platelet GP IIb/IIIa inhibitor therapy.

Platelet Function Profiles in Patients With Type 2 Diabetes and Coronary Artery Disease on Combined Aspirin and Clopidogrel Treatment

To assess platelet function profiles in diabetic and nondiabetic patients on aspirin and clopidogrel therapy, two patient populations were included to investigate the 1) acute effects of a 300-mg clopidogrel loading dose (group 1, n = 52) and 2) long-term effects of clopidogrel (group 2, n = 120) on platelet function in diabetic compared with nondiabetic patients already on aspirin treatment. Patients were stratified according to the presence of type 2 diabetes. Platelet aggregation was assessed using light transmittance aggregometry (groups 1 and 2). Platelet activation (P-selectin expression and PAC-1 binding) was determined using whole-blood flow cytometry (group 2). Clopidogrel response was also assessed. In group 1, platelet aggregation was significantly increased in diabetic (n = 16) compared with nondiabetic (n = 36) patients at baseline and up to 24 h following a 300-mg loading dose (P = 0.005). In group 2, platelet aggregation and activation were increased in diabetic (n = 60) compared with nondiabetic (n = 60) subjects (P < 0.05 for all platelet function assays). Diabetic subjects had a higher number of clopidogrel nonresponders (P = 0.04). Diabetic patients have increased platelet reactivity compared with nondiabetic subjects on combined aspirin and clopidogrel treatment. Reduced sensitivity to antiplatelet drugs may contribute to the increased atherothombotic risk in diabetic patients.

Intérêt pharmacodynamique de la perfusion continue vs l'administration intermittente de ceftazidime dans les pneumonies nosocomiales sévères

Goal of the study. – It is well known today that the main determinant of beta-lactam antibiotics efficacy is the duration of the time that concentrations remain in excess of the minimum inhibitory concentration (MIC) of susceptible organism over the course of therapy. This prospective study aimed to evaluate the efficacy, in term of pharmacodynamic profile, of continuous infusion versus intermittent administration of ceftazidime in intensive care unit patients with severe nosocomial pneumonia. Patients and methods. – 16 patients under mechanical ventilation with nosocomial pneumonia were randomised to receive either 60 mg/kg/day ceftazidime by constant rate infusion following a 20 mg/kg loading dose (Group A) or 20 mg/kg every 8 hour by intravenous bolus injection (Group B). In both groups, serial blood samples were collected during 48 hours (12 and 18 samples in Group A and B, respectively) after the start of drug administration. Plasma concentrations of ceftazidime were measured by high performance liquid chromatography. Based on our local bacteriological conditions, the pharmacodynamic profile of ceftazidime was assessed as the duration of time the plasma concentration remained above a desired target concentration of 20 mg/l for each regimen. Results. – The mean time (expressed as a percentage) for which plasma ceftazidime concentrations were above 20 mg/l was 100% for the continous infusion group (Group A) and 56 ± 33% for the intermittent administration group (Group B). Conclusion. – These findings show that ceftazidime administered by continuous infusion in critically ill patients under mechanical ventilation with nosocomial pneumonia appears to substantially improve the pharmacodynamic profile of this beta-lactam compared to the intermittent regimen.

Randomized Trial of High Loading Dose of Clopidogrel for Reduction of Periprocedural Myocardial Infarction in Patients Undergoing Coronary Intervention

Aggressive platelet inhibition is crucial to reduce myocardial injury and early cardiac events after coronary intervention. Although observational data have suggested that pretreatment with a high loading dose of clopidogrel may be more effective than a conventional dose, this hypothesis has never been tested in a randomized trial. A total of 255 patients scheduled to undergo percutaneous coronary intervention were randomized to a 600-mg (n=126) or 300-mg (n=129) loading regimen of clopidogrel given 4 to 8 hours before the procedure. Creatine kinase MB, troponin I, and myoglobin levels were measured at baseline and at 8 and 24 hours after intervention. The primary end point was the 30-day occurrence of death, myocardial infarction (MI), or target vessel revascularization. The primary end point occurred in 4% of patients in the high loading dose versus 12% of those in the conventional loading dose group (P=0.041) and was due entirely to periprocedural MI. Peak values of all markers were significantly lower in patients treated with the 600-mg regimen (P< or =0.038). Safety end points were similar in the 2 arms. At multivariable analysis, the high loading regimen was associated with a 50% risk reduction of MI (OR 0.48, 95% CI 0.15 to 0.97, P=0.044). An incremental benefit was observed in patients randomized to the 600-mg dose who were receiving statins, with an 80% risk reduction. Pretreatment with a 600-mg loading dose of clopidogrel 4 to 8 hours before the procedure is safe and, as compared with the conventional 300-mg dose, significantly reduced periprocedural MI in patients undergoing percutaneous coronary intervention. These results may influence practice patterns with regard to antiplatelet therapy before percutaneous revascularization.

Lack of association between the P2Y 12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease

Introduction Clopidogrel inhibits the ADP subtype P2Y 12 receptor. Recently, polymorphisms of this receptor have been associated with different degrees of platelet aggregation in healthy volunteers and have been suggested to modulate clopidogrel response. However, the role of gene sequence variations of the P2Y 12 receptor in patients treated with clopidogrel has not yet been assessed. Materials and methods The T744C polymorphism of the P2Y 12 receptor gene was assessed in 119 patients: 36 undergoing coronary stenting receiving a 300 mg loading dose (Group A) and 83 on long-term clopidogrel (75 mg/day) treatment (Group B). Patients were divided into 2 subgroups according to the presence or absence of the C allele: carriers (CT heterozygotes and CC homozygotes) and non-carriers (TT homozygotes). Platelet aggregation, assessed by light transmittance aggregometry following ADP, collagen, TRAP and epinephrine stimuli, and platelet activation (GP IIb/IIIa activation and P-selectin expression), assessed by whole blood flow cytometry in ADP and TRAP-stimulated platelets, were performed. Platelet function was assessed at baseline and 4 and 24 h following clopidogrel loading dose in Group A and when patients where on clopidogrel treatment for at least 1 month in Group B. Results The genotype distribution of Group A was: 22 / 36 (61.1%) non-carriers and 14 / 36 (38.9%) carriers of the C allele; Group B: 57 / 83 (68.7%) non-carriers and 26 / 83 (31.3%) carriers of the C allele. There were no differences between groups for all the assessed platelet function assays. Conclusions The T744C polymorphism of the P2Y 12 receptor gene does not modulate platelet response to clopidogrel either in the early or long-term phases of treatment. This specific gene polymorphism alone is therefore unlikely to be the cause of variability in individual response to antiplatelet therapy.

Reduced thrombus cohesion in an ex vivo human model of arterial thrombosis induced by clopidogrel treatment: kinetics of the effect and influence of single and double loading-dose regimens

Objective: To compare the effects of clopidogrel on ex vivo thrombogenesis with those on ADP-dependent platelet aggregation, and to compare single and double loading-dose regimens. Methods and Results— Step 1: Volunteers ( n=12) received clopidogrel 75 mg/day for 8 days. ADP-induced platelet aggregation was measured in platelet-rich plasma (PRP). Thrombogenesis was measured in an ex vivo model. Clopidogrel produced rapid platelet inhibition, increasing up to day 5. Maximal intensity of platelet aggregation correlated with density of platelet thrombus, surface of collagen covered by platelets and thrombus cross-sectional surface ( p<0.001). Step 2: On day 1, volunteers ( n=60) randomly received clopidogrel 75 mg, a single 300-mg loading dose or two 300-mg loading doses separated by a 12-h interval. On day 2, all volunteers received clopidogrel 75 mg. Both loading dose regimens enhanced platelet inhibition at all time points ( p<0.03 vs. clopidogrel 75 mg). After 3 h, the antiplatelet effect of a loading dose was substantial, and the mean decrease in dense thrombus surface was greater in the loading-dose groups than in the 75 mg group ( p=0.041 for the single loading dose). Ex vivo, there were no significant differences between loading-dose groups. Conclusions: Clopidogrel reduces arterial thrombus cohesion by an effect that correlates with inhibition of ADP-induced platelet aggregation. A single 300-mg loading dose provides a rapid onset of such an antithrombotic effect, which was more significant at 24 h with the double loading dose.

Late-Breaking Clinical Trial Abstracts

Late-Breaking Clinical Trial Abstracts

Traitement du paludisme cérébral de l’enfant africain par les sels de quinine : comparaison d’un schéma avec dose de charge à un schéma classique sans dose de charge

Objective. – To compare in a randomized study the efficacy and the toxicity of the new WHO intravenous quinine treatment of cerebral malaria including a loading dose regimen to a regimen without loading dose. Patients and methods. – Seventy-two children eight months to 15 years of age with cerebral malaria were included. Quinine formiate was administered to a group of 35 patients in an initial loading dose of 20 mg salt/kg (equivalent to 17.5 mg/kg of the base) in 10 mL/kg of 5% glucose over four hours, followed eight hours later by a maintenance dose quinine of 10 mg salt/kg (equivalent to 8.7 mg/kg of the base) dissolved in 15 mL/kg of 5% glucose over and every 12 hours. The second group of 37 patients received intravenous quinine 15 mg salt/kg (13.1 mg of base) dissolved in 15 mL/kg of 5% glucose infused over 6 to 8 hours, every 12 hours. In both groups this treatment was continued until the patient could swallow, then quinine tablets were given to complete seven days treatment. The assessment of cardiovascular side effects was made by an ECG at admission, the 4th hour, the 24th hour and at the end of treatment for each patient. Results. – Coma mean durations were similar in the two groups: 35.5 ± 17.8 hours and 28.6 ± 14.4 hours respectively for the loading dose group and the group without loading dose. The two groups were comparable also for the decrease evolution of parasitemia. Case-fatality rates were also similar : 95 % of healing at the 72th hour and a lethality rate between 5 and 6% in the two groups. But a significant increase of the body temperature was noted between the 51th and the 63th hour in the group without loading dose. No significant cardiovascular toxicity was noticed in the two groups. The mean cost of the loading dose regimen was less than that of the second regimen. Conclusion. – The loading dose regimen of quinine is well tolerated and it seemed slightly more effective than the regimen without loading dose. In cases of contra-indications (patients who recently received quinine, mefloquine or halofantrine), regimens without loading dose, which remains effective, should be used.

Comparison of two methods to obtain a desired first isepamicin peak in intensive care patients

A randomized multicenter study in intensive care unit (ICU) patients, evaluated the capacity of a Bayesian method to obtain an optimal first isepamicin (ISP) peak of 80 mg/L in comparison to a fixed loading dose (LD). Patients (n=236) over 18 years of age were enrolled from 6 September 1997 to 17 July 1999 and randomly assigned to received ISP in a calculated dose (CD) or a loading dose (LD) of 25 mg/kg body weight. The CD was estimated using a specific population model with Bayesian methodology implemented in the PKS program (Abbott PKS, Abbott Diagnostics, Rungis, France). The data required included age, body weight, height, gender and serum creatinine. ISP disposition is described by a one-compartment model. Blood samples were drawn 1 and 24 h after the start of infusion for fluorescence polarization immunoassay measurement of serum ISP concentrations. The predictive performance was assessed by computing bias and precision. Peak concentrations were significantly higher in CD group than the LD group (84.2 +/- 28.6 vs. 74.7 +/- 24.1 mg/L, respectively; P=0.008), but trough levels were comparable. The optimal ISP peak was attained by a significantly higher percentage of CD patients (P=0.018), and by significantly more CD patients on mechanical ventilation (P=0.025), and with simplified acute physiological scores (SAPS) > 35 (P=0.002). Pharmacokinetic parameters were similar for the two groups with large interindividual variations. Mean (+/- SD) volume of distribution of ventilated patients (72%) was significantly higher than of nonventilated patients (23.31 +/- 7.35 vs. 20.60 +/- 6.30 L, respectively; P=0.001). No relationship was found between the volume of distribution and SAPS. Total clearance was significantly correlated with estimated CLCR (creatinine clearance) (P=0.0001). Precision (RMSE) is better for CD than for LD strategy, respectively 27.96 and 28.66 mg/L. The Bayesian method was significantly more accurate and performed particularly well in ventilated patients and patients with high SAPS, compare to an LD of 25 mg/kg to obtain a first ISP peak of 80 mg/L in ICU patients. Therefore, a fixed dose of 28.5 mg/kg would be also adequate to reach a peak of 80 mg/L.

Pharmacodynamic effects of milrinone with and without a bolus loading infusion

Background Milrinone is a positive inotropic agent with vasodilatory and lusitropic activity. Milrinone dosed as a 50 μg/kg bolus followed by a continuous infusion provides an immediate and sustained hemodynamic response. The comparative pharmacodynamics of a placebo bolus and a milrinone bolus followed by a continuous milrinone infusion in patients with decompensated heart failure are unknown. Methods Nineteen patients with decompensated heart failure underwent right heart catheterization and were randomized to receive an intravenous infusion of milrinone at a rate of 0.50 μg/kg/min with (n = 9) or without (n = 10) a preceding 50 μg/kg bolus. Pulmonary capillary wedge pressure, cardiac index, and plasma milrinone levels were measured serially over 24 hours. Results In the milrinone bolus group, maximal effects on plasma concentration (352.3 ng/mL), cardiac index (+0.97 L/min/m2, P =.02), and pulmonary capillary wedge pressure (–11.25 mm Hg, P <.001) were seen after the loading dose. In the placebo loading dose group, significant hemodynamic effects were observed starting at 30 minutes after the start of the continuous infusion. Changes in pulmonary capillary wedge pressure (placebo –8.6 vs milrinone –8.78 mm Hg, P not significant [NS]) were similar in both groups at 2 hours, whereas changes in cardiac index (placebo loading +0.81 vs milrinone loading +0.78 L/min/m2, P NS) and milrinone levels (placebo loading 168.0 vs milrinone loading 165.6 ng/mL, P NS) were similar at 3 hours. One patient randomized to a milrinone bolus demonstrated a marked decrease in blood pressure and was discontinued from therapy. Conclusions A milrinone infusion without a bolus appears to be a rapidly effective inotropic strategy that may have an improved safety profile during the initiation of therapy compared with a continuous infusion strategy initiated with a bolus. (Am Heart J 2000;141:e6.)

Long-term magnesium sulfate treatment as protection against hypoxic-ischemic brain injury in seven-day-old rats

Objective: Our purpose was to study the effects of long-term treatment with magnesium sulfate on hypoxic-ischemic brain damage in newborn rats. Study Design: Seven-day-old rat pups (n = 120) were exposed to unilateral carotid artery ligation and 2 hours of hypoxia (8% oxygen in 92% nitrogen). Neuronal loss was evaluated in 4 groups. The loading dose group (n = 25) received a bolus injection of 270 mg/kg magnesium sulfate intraperitoneally. The maintenance group (n = 26) received 3 days of continuous infusion of magnesium sulfate with a micro-osmotic pump at a rate of 72 mg/kg per hour. The loading dose–plus–maintenance group (n = 23) received both. The control group (n = 46) did not receive magnesium. Seven days after the injury the pups were killed and the brains were removed for analysis. Severity of neuronal loss was evaluated in the cerebral cortex and hippocampus and compared among groups by χ2 test. Results: Cyst formation resulting from necrosis was significantly decreased in the maintenance group (15%) and loading dose–plus–maintenance group (9%) but not in the loading dose group (52%) relative to the control group (46%). Severity of neuronal loss in the cerebral cortex and the hippocampus was also significantly improved in the maintenance group and the loading dose–plus–maintenance group but not in the loading dose group. Mortality rates were not different among the groups. Magnesium ion concentrations at 24 hours were significantly decreased from the preinfusion value of 0.49 ± 0.01 mmol/L in the control group (0.34 ± 0.03 mmol/L) but remained within normal ranges in the maintenance group (0.46 ± 0.02 mmol/L with a pump infusing 72 mg/kg per hour and 0.56 ± 0.05 mmol/L with a pump infusing 24 mg/kg hour). There was an inverse relationship between the maintenance dose and neuronal loss but not between the maintenance dose and mortality rate. Conclusion: Long-term magnesium administration had neuroprotective effects against hypoxia-ischemia in newborn rats. (Am J Obstet Gynecol 2001;184:185-90.)

Withdrawn

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale—Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS—Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in mis study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.

Withdrawn

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale—Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS—Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in mis study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.

Down's syndrome patients: Alzheimer-like implication of the immune system?

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale—Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS—Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in mis study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.

Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer's disease: A randomized, double-masked, placebo-controlled trial

This prospective, randomized, double-masked, placebo-controlled, parallel-group study assessed the safety and efficacy of 2 dosage regimens of once-daily metrifonate in patients with probable Alzheimer's disease (AD) of mild-to-moderate severity. A total of 395 patients were randomized to receive placebo (n = 134) or metrifonate in 1 of 2 regimens. The loading-dose group (n = 133) received a daily loading dose of metrifonate 100 mg or 150 mg (by weight) for 2 weeks, followed by a daily maintenance dose of metrifonate 50 mg for 4 weeks; the no-loading-dose group (n = 128) received the daily maintenance dose of metrifonate 50 mg for 6 weeks. The primary measure of efficacy was the Alzheimer's Disease Assessment Scale—Cognitive Subscale (ADAS-Cog); secondary measures of efficacy included the Mini-Mental State Examination (MMSE), the Clinician's Interview Based Impression of Change with Caregiver Input (CIBIC-Plus), the Clinician's Interview Based Impression of Severity with Caregiver Input (CIBIS-Plus), and the ADAS—Noncognitive Subscale (ADAS-Noncog). Safety was assessed by the prevalence of premature study termination and treatment-emergent adverse events, as well as by changes in vital signs, findings on electrocardiographic and neurologic examinations, and abnormalities on laboratory tests. At 4 weeks of treatment, defined by the protocol as the target efficacy determination, the mean ADAS-Cog scores of the intent-to-treat population (last observation carried forward) favored the loading-dose group versus the placebo group, but the difference was not statistically significant. However, at week 6, the difference in mean ADAS-Cog scores was statistically significant compared with placebo. At neither week 4 nor week 6 was there a statistically significant difference in the mean ADAS-Cog scores of the no-loading-dose and placebo groups. For the CIBIC-Plus, the treatment difference between the placebo and loading-dose groups significantly favored metrifonate at week 6 but not at week 4, whereas the treatment difference between the placebo and no-loading-dose groups was statistically significant at both time points. For the MMSE, CIBIS-Plus, and ADAS-Noncog, treatment differences for both groups versus placebo did not reach statistical significance at either week 4 or 6. Assessment of the frequency of adverse events in metrifonate-treated patients revealed that the no-loading-dose regimen was better tolerated than the loading-dose regimen. Given the overall similar efficacy and more favorable safety profile associated with the no-loading-dose regimen versus the loading-dose regimen observed in mis study, the no-loading-dose regimen appears to be the better strategy for initiating metrifonate treatment in patients with probable AD of mild-to-moderate severity.