Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin.

Essentials MEDI2452 is a specific antidote of the platelet P2Y12 receptor antagonist ticagrelor. Hemostatic effects of MEDI2452 were evaluated in pigs treated with ticagrelor and aspirin. MEDI2452 eliminated free ticagrelor within 5 min and gradually normalized platelet aggregation. Improvements in blood pressure (significant) and in blood-loss and survival (non-significant) were observed. SUMMARY: Background Ticagrelor, a P2Y12 antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective To explore the hemostatic effects of MEDI2452, an antidote for ticagrelor. Methods Pigs, pre-treated with aspirin, were given an intravenous infusion of ticagrelor or vehicle. At the end of the infusion, a piece of a liver lobe was cut off and a bolus of MEDI2452 or vehicle was administered intravenously. Blood was collected to monitor blood loss, mean arterial blood pressure (MAP) was recorded and survival time was observed over 4 h. Blood samples for drug plasma exposures and platelet aggregation were collected. Results MEDI2452 eliminated the free concentrations of ticagrelor and its active metabolite AR-C124910XX within 5 min. ADP-induced platelet aggregation was close to normal at 60 min, which was not significantly different from aspirin alone. MEDI2452 numerically reduced ticagrelor-mediated effects: body-weight-adjusted blood loss in the 15- to 90-min interval, 12 (confidence interval [CI] 95% 7-28] vs. 17 (CI 95% 5-31) (ticagrelor and aspirin) vs. 5 (CI 95% 3-9) mL kg-1 (aspirin alone), survival 70% (CI 95% 47-100) vs. 45% (CI 95% 21-92) (ticagrelor and aspirin) vs. 100% (CI 95% 100-100) (aspirin alone), and median survival time, 240 (CI 95% 180-240) vs. 169 (CI 95% 64-240) (ticagrelor and aspirin) vs. 240 (CI 95% 240-240) min (aspirin alone). Finally, MEDI2452 significantly attenuated the decline in MAP, 0.08 (CI 95% 0.07-0.09) vs. 0.141 (CI 95% 0.135-0.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.03-0.05) mmHg per min (aspirin alone) and maintained MAP at a significantly higher level, 73 (CI 95% 51-95) vs. 48 (CI 95% 25-70) (ticagrelor and aspirin) vs. 115 (CI 95% 94-136) mmHg (aspirin alone). Conclusion MEDI2452 eliminated free ticagrelor and AR-C124910XX within 5 min. This translated into a gradual normalization of ADP-induced platelet aggregation and significant improvement in blood pressure and numerical but non-significant improvements in blood-loss and survival.

Unraveling the pharmacokinetic interaction of ticagrelor and MEDI2452 (Ticagrelor antidote) by mathematical modeling.

The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.

Rapid protection of the gastroduodenal mucosa against aspirin-induced damage by rabeprazole.

BACKGROUND: The ability of a proton pump inhibitor to reduce or prevent NSAID-induced gastroduodenal damage during the first 24 h has not been tested. AIM: To determine, whether oral rabeprazole, administered 5 h before the initiation of therapeutic dosing of aspirin protects the gastroduodenal mucosa. METHODS: Normal subjects were randomized into two groups - one received rabeprazole, 20 mg at 07:00 hours and the other placebo, before initiation of aspirin 650 mg at 12:00 hours, and then q4 h for 3 days. Upper endoscopic examinations were performed on all subjects at baseline, 24 and 72 h after initiation of aspirin. Gastroduodenal mucosal damage was scored. RESULTS: Thirty subjects were compliant with study medications and underwent three endoscopic examinations. Salicylate concentrations were similar for the placebo and the rabeprazole groups at all times. On rabeprazole, the Lanza scores were significantly lower compared with placebo at 24 h (1.3 +/- 0.26 vs. 2.1 +/- 0.26, P < 0.05) and at 72 h (1.3 +/- 0.29 vs. 2.3 +/- 0.28, P < 0.05). Gastric antral erosion counts were less with rabeprazole than placebo at 24 (4.1 +/- 1.3 vs. 7.6 +/- 2.0, P > 0.05) and 72 h (5.3 +/- 1.8 vs. 8.0 +/- 1.5; P > 0.05). CONCLUSIONS: Rabeprazole, initiated 5 h before the start of therapeutic dosing with aspirin, decreased Lanza scores and antral erosion counts at 24 h. These findings suggest that prophylaxis with rabeprazole could start concurrently with aspirin administration.

Can WHO therapy failure criteria for non-severe pneumonia be improved in children aged 2-59 months?

SETTING: In the recent past, there have been reports of rising treatment failure rates for non-severe pneumonia. It is felt that World Health Organization (WHO) criteria for therapy failure are too sensitive and that many children are unnecessarily classified as failures. We studied alternative, less sensitive therapy failure criteria. METHODS: In this nested study we followed the clinical course of non-severe pneumonia in children aged 2-59 months using alternative therapy failure criteria. All children received amoxicillin and were followed up on days 3, 5 and 14 after enrollment. On day 3, children were labelled as therapy failure only if their condition had deteriorated. These failure rates were compared with those using WHO definitions. RESULTS: During the study period, 876 children with non-severe pneumonia were followed up until day 14. On day 3, using alternative therapy failure criteria, 31 (3.5%) children were labelled as therapy failure compared to 95 (10.8%) using current WHO criteria. The difference was statistically significant (P = 0.001). CONCLUSIONS: The alternative therapy failure criteria work reasonably well, without causing any higher risk to children with non-severe pneumonia. Antibiotics should be changed only in those children who show signs of deterioration on day 3. This would prevent unnecessary changes in antibiotic treatment in many children.

Comparison of clinical outcome with oral and inhaled bronchodilators in the management of wheezy children aged 1-59 months in the community: a randomised trial in Pakistan.

BACKGROUND: Wheeze is a significant problem in children. There is a gradual trend of switching from oral to inhaled bronchodilator therapy. No randomised trials have been carried out in the community to compare the clinical outcome of two modes of therapy. If outcome with oral and inhaled bronchodilators is the same in young wheezers in developing countries, it will be easier to manage them. METHODS: In a randomised multicentre trial, wheezy children aged 1-59 months with fast breathing and/or lower chest indrawing received oral or inhaled salbutamol at home after responding to up to three cycles of inhaled bronchodilators. They were re-assessed on days 3 and 5 for clinical outcome. RESULTS: From May 2001 to August 2002, 780 children were enrolled; 390 each were randomised to oral and inhaled salbutamol. On day 5, 324 (83.1%) children in the oral and 328 (84.1%) in the inhaled group were completely well. There were no differences in clinical outcome of both modes of therapy. CONCLUSIONS: The clinical outcome of children aged 1-59 months with wheeze is similar when treated with oral or inhaled salbutamol. Acute respiratory infection control programmes in developing countries should continue to use oral bronchodilators for the management of wheeze to save both time and money.

Assessment and management of children aged 1-59 months presenting with wheeze, fast breathing, and/or lower chest indrawing; results of a multicentre descriptive study in Pakistan.

BACKGROUND AND AIMS: Using current WHO guidelines, children with wheezing are being over prescribed antibiotics and bronchodilators are underutilised. To improve the WHO case management guidelines, more data is needed about the clinical outcome in children with wheezing/pneumonia overlap. METHODOLOGY: In a multicentre prospective study, children aged 1-59 months with auscultatory/audible wheeze and fast breathing and/or lower chest indrawing were screened. Response to up to three cycles of inhaled salbutamol was recorded. The responders were enrolled and sent home on inhaled bronchodilators, and followed up on days 3 and 5. RESULTS: A total of 1622 children with wheeze were screened from May 2001 to April 2002, of which 1004 (61.8%) had WHO defined non-severe and 618 (38.2%) severe pneumonia. Wheeze was audible in only 595 (36.7%) of children. Of 1004 non-severe pneumonia children, 621 (61.8%) responded to up to three cycles of bronchodilator. Of 618 severe pneumonia children, only 166 (26.8%) responded. Among responders, 93 (14.9%) in the non-severe and 63 (37.9%) children in the severe pneumonia group showed subsequent deterioration on follow ups. No family history of wheeze, temperature >100 degrees F, and lower chest indrawing were identified as predictors of subsequent deterioration. CONCLUSIONS: Two third of children with wheeze are not identified by current WHO ARI (acute respiratory infections) guidelines. Antibiotics are over prescribed and bronchodilators under utilised in children with wheeze. Children with wheeze constitute a special ARI group requiring a separate management algorithm. In countries where wheeze is common it would be worthwhile to train health workers in use of the stethoscope to identify wheeze.

Clinical and bacteriologic efficacy of amoxycillin b.d. (45 mg/kg/day) versus amoxycillin t.d.s (40 mg/kg/day) in children with group A beta-hemolytic streptococcal tonsillopharyngitis.

This randomized, observer-blind, multicenter, parallel-group study compared the clinical and bacteriologic efficacy and safety of amoxycillin, 45 mg/kg/day b.d. and amoxycillin, 40 mg/kg/day t.d.s. after 7 days of treatment in 517 children with acute bacterial tonsillopharyngitis. At the end of treatment, a successful clinical response was recorded in more than 96% of patients in each of the treatment groups. A similar result was obtained at follow-up. Among those patients who were bacteriologically evaluable at the end of treatment, a successful bacteriologic response was achieved in more than 94% in each treatment group. Both treatments were well tolerated. Drug-related adverse events were recorded in just 12 patients (4.6%) in the b.d. group and six (2.4%) in the t.d.s. group. The study demonstrated that a twice-daily regimen of amoxycillin, 45 mg/kg/day, was as effective and as well tolerated as the standard three-times-daily regimen of amoxycillin, 40 mg/kg/day, in the treatment of acute bacterial tonsillopharyngitis in children.

Management of acute respiratory infections by mothers in the community.

Home treatments are important in the management of acute respiratory infection (ARI). In order to examine how urban mothers in Lahore, managed ARI, a study was carried out within 1-km radius of a teaching hospital. A total of 50 mothers who had at least one child aged 2 months-5 years with an ARI from each of three settings-a lower class locality, a middle class locality and the outpatient department of the hospital were interviewed during the winters of 1992-93. A substantial proportion of mothers, particularly those from the lower class locality (44%), did not use home treatment for acute respiratory infection. The majority of mothers indicated that they would not use home treatment if their child had an ARI in the future. The importance of home treatment has to be introduced into the community probably by programmes conducted by health professionals.

Modified BFM protocol for childhood acute lymphoblastic leukemia: a retrospective analysis.

Childhood acute lymphoblastic leukemia (ALL) has a 5-year disease-free survival (DFS) of more than 70%. This fact is not reflected in developing countries due to the lack of proper supportive care. A modified version of the standard Berlin-Frankfurt-Munich (BFM) protocol for pediatric ALL was developed to achieve balance between toxicity and favorable response rates. Modification included a dose reduction of asparaginase and methotrexate during the consolidation and reinduction phase. Forty-two patients younger than 15 years of age were put on the modified BFM protocol between November 1990 and November 1993. Thirty-nine patients were 2-10 years of age and 3 were older than 10 years. Male to female ratio was 3.2:1. 71.4% had L1 and 28.6% had L2 morphology. Univariate analysis factors revealed central nervous system (CNS) involvement and late complete remission (CR) during induction as poor prognostic factors. In multivariate analysis, CNS disease (P < 0.0083) was the only prognostic variable for prolonged DFS. All patients went into CR. Eleven patients have relapsed. Life table analysis of these patients shows a 59.4% probability of overall survival (OS) and a 52.5% probability of DFS at 48 months.

Haemolytic uraemic syndrome in children.

Of the 4070 children admitted in the department of paediatrics, 830 (24%) presented with diarrhoea. Eleven of these had haemolytic ureamic syndrome (HUS) characterised by microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure. Only 3 had positive stool cultures (E. Coli 2, shigella dysenteriae 1). Two children expired while the rest recovered with conservative management and peritoneal dialysis. Thus HUS should be remembered as a complication of diarrhoea and a cause of acute renal failure in children.

Hematologic abnormalities after oral trimethoprim-sulfamethoxazole therapy in children.

The development of hematologic abnormalities was prospectively evaluated in 50 children treated for ten days each with oral trimethoprim-sulfamethoxazole and compared with a control group of 20 children with similar infections treated with amoxicillin trihydrate. Neutropenia (polymorphonuclear neutrophilic leukocyte counts, less than or equal to 1,500/cu mm) developed in 17 (34%) of the 50 children treated with trimethoprim-sulfamethoxazole compared with one (5%) in the control group of 20 children (P less than 0.001). Thrombocytopenia (platelet count, less than 150,000/cu mm) developed in six (12%) of the children treated with trimethoprim-sulfamethoxazole, but it did not develop in any of the amoxicillin-treated children (P less than .01). Neutropenia occurred mostly during the first week of treatment and lasted a mean of 8.9 days. Thrombocytopenia was noted between the seventh and 16th day (mean, 10.3 days) and lasted a mean of 12.7 days. Both side effects resolved spontaneously without ill effects. Children treated with oral trimethoprim-sulfamethoxazole should be followed up with biweekly leukocyte and platelet counts, and treatment should be discontinued if severe neutropenia or thrombocytopenia develops.

Tine test compliance in a clinic setting.

Parental compliance in keeping a return appointment for the purpose of having their child's Tuberculin Tine test read was studied in the setting of a large urban pediatric clinic. This compliance rate was found to be 72%. Various factors which could potentially affect compliance with this procedure were examined, and the only factor which correlated significantly was family size. A modified system whereby parents read their child's Tine test in the home setting and reported the test results to the clinic by mail (a method used today in many pediatric outpatient departments) was implemented and evaluated. With this new system, the compliance rate increased to 90%.

Treatment of trichuriasis with a new drug, mebendazole.

Effectiveness of mebendazole, a new anthelminthic drug recommended for treatment of Trichuris trichiura infection, was evaluated in 50 children attending a pediatric outpatient clinic in New York City. Mebendazole, 100 mg. administered orally twice daily for three days resulted in an apparent cure of 48 children. Posttreatment stools of the remaining two children had a substantial reduction in the number of eggs. A second course of treatment, identical to the first, led to the elimination of eggs in the stool specimens of these two children. Mebendazole appears to be an effective drug against Trichuris trichiura.