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.

Baseline evaluation of routine HIV testing among tuberculosis patients in Botswana.

In January 2004, the government of Botswana introduced a policy of routine, non-compulsory human immunodeficiency virus (HIV) testing to increase testing and access to antiretroviral treatment (ART) for individuals presenting for medical treatment. Before a systematic implementation of the policy, we conducted a cross-sectional survey of tuberculosis (TB) record data from 46 clinics in 10 districts to assess baseline HIV testing rates among TB patients. Recorded HIV results from the facility TB register and TB treatment card were reviewed. Of the 1242 TB patients entered in the register, 47% had a recorded HIV result and 84% of these were co-infected with HIV. TB treatment cards were available for 862 (69%) registered patients. Among the 411 (47%) with test results recorded on the treatment card, 341 (83%) were HIV-infected; of these, 12% were reported to be receiving ART.

Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children?

OBJECTIVE: To determine whether an antihistamine-decongestant combination (ADC) is superior to placebo in temporarily relieving symptoms of upper respiratory tract infection (URI) in preschool children. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Four pediatric offices in the Seattle, Wash, area. PARTICIPANTS: Children 6 months through 5 years of age with a URI of less than 7 days' duration. METHODS: Children were randomly assigned to receive an ADC (brompheniramine maleate-phenylpropanolamine hydrochloride) or placebo as needed for URI symptoms. Two hours after each dose of study medication, changes in the child's runny nose, nasal congestion, cough, and sleep status were assessed by means of a standardized questionnaire. RESULTS: A total of 175 responses were recorded for 59 patients. There were no statistically significant differences in symptom improvement between the ADC and the placebo group (runny nose, p = 0.48; nasal congestion, p = 0.94; cough, p = 0.66). However, the proportion of children asleep 2 hours after receiving the ADC was significantly higher than the proportion receiving placebo (46.6% vs 26.5%; p = 0.01). Results were unchanged after control for the correlated nature of repeated responses, age, symptom duration, use of acetaminophen, time that the medication was given, and parental desire for medication. CONCLUSIONS: The ADC was equivalent to placebo in providing temporary relief of URI symptoms in preschool children. However, the ADC did have significantly greater sedative effects than did placebo.

A virulent nonencapsulated Haemophilus influenzae.

Nontypeable Haemophilus influenzae strain INT1 was isolated from the blood of a young child with clinical signs of meningitis following acute otitis media. No immunologic or anatomic predisposition of this child for invasive bacterial infection with an unusual organism was documented. Sensitive ELISA proved the absence of intra- or extracellular capsular polysaccharide production by INT1 and Southern blot analysis confirmed the lack of an intact capsulation (cap) gene locus within the chromosome. Nevertheless, INT1 established bacteremia and meningitis in infant and weanling rat models of invasive H. influenzae infection. High-molecular-weight DNA isolated from INT1 was shown to confer an invasive phenotype on transformation of a nonencapsulated, avirulent laboratory strain of H. influenzae. Together these findings imply the presence of one or more as-yet-undiscovered, noncapsular virulence factors of H. influenzae that are capable of mediating invasive disease and resistance to immunologic clearance.

Health and weight control management among wrestlers. A proposed program for high school athletes.

Weight loss is a part of any competitive sport which matches participants of equal weight or sports where participating at lower weights or with a thinner body habitus is considered an advantage. For some wrestlers, weight loss is excessive and often accomplished by methods that lead to loss of lean body mass and total body water. There is convincing evidence that this excessive weight loss is unhealthy for all individuals who follow these practices. Even greater harm is experienced by high school wrestlers who have not yet completed their growth and development. These health consequences include growth retardation, decreased academic performance, altered endocrine or hormonal function and damage to many vital organs. "cycling" of weight results in decrease in strength, power and endurance which would effect adversely a wrestler's likelihood of success. The VHSL has begun an educational program to inform coaches, wrestlers and parents about the hazards inherent in these weight loss practices. History suggests that education alone will not alter the present practices of weight loss. Therefore a weight management program similar to ones initiated in other states is being pursued by the VHSL. The pilot program this year is scheduled to be followed next year by a more wide-spread voluntary program across the Commonwealth.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of cough suppressants in children.

To test the hypothesis that codeine and dextromethorphan are effective in alleviating the symptoms of acute cough, we conducted a randomized, controlled trial. Eligible patients were children 18 months to 12 years of age, seen in private pediatric practices, with significant night cough of less than 14 days' duration. Study patients were randomly selected to receive codeine, dextromethorphan, or placebo at bedtime for 3 consecutive nights. Outcomes were assessed by the use of a parent questionnaire rating the severity of symptoms at the initiation of therapy, and after each night of the study. Every patient had a cough score (range 0 to 4) and composite symptom score (range 0 to 9) computed for each day of the study. One hundred forty-one doses of study medication were evaluated in 49 patients, including 13 children receiving placebo, 19 dextromethorphan, and 17 codeine. Mean cough and composite symptom scores decreased in each of the three treatment groups on each day of the study; there were no significant differences. Regression analysis, with reduction in cough score as the outcome of interest, showed that neither dextromethorphan nor codeine was significantly more effective than placebo (p = 0.41 and 0.70, respectively). Reduction in cough score was positively correlated with the severity of cough at the start of treatment (p = 0.007). Our data suggest that, in the doses used, neither codeine nor dextromethorphan is superior to placebo in treating night cough in children.

Influence of cooling rates and extenders upon post-thaw viability of bovine spermatozoa packaged in .25- and .5-ml French straws.

Post-thaw survival of bovine spermatozoa was compared for semen packaged in either .25- or .5-ml French straws and frozen at three different cooling rates in moving N2 vapor. Using a split ejaculate technique, nine ejaculates were extended in heated skim milk, egg yolk-citrate and egg yolk-Tris and packaged in .25- and .5-ml French straws. Semen packaged in the .25- and .5-ml straws was frozen simultaneously at initial N2 vapor temperatures of -140, -110 or -80 C. Semen was thawed in a water bath at 35 C for 1 min. Recovery of spermatozoa was evaluated immediately post-thaw (0 h) and again after 3 h of incubation at 37 C. Motility estimates and motility counts were made using phase contrast microscopy; percentage of spermatozoa possessing intact acrosomes was quantitated using differential interference contrast microscopy. There was a packaging unit X cooling rate interaction (P less than .05) for all three viability measures. However, there was no consistent trend with regard to cooling rate or packaging unit among the three extenders examined. Post-thaw viability for each characteristic varied (P less than .01) among extenders, but not for cooling rate or packaging unit (P greater than .05). Spermatozoa extended and frozen in egg yolk-Tris had greater (P less than .05) post-thaw viability than those extended in skim milk or egg yolk-citrate regardless of cooling rate or volume of the seminal package.

Effect on fertility of freezing large numbers of straws of bovine spermatozoa in a mechanical freezer.

Fertility of semen frozen in a mechanical forced-vapor freezer was compared with that frozen in static nitrogen (N) vapor. Semen from 10 Holstein bulls was extended in milk-10% glycerol at 30 x 10(6) progressively motile spermatozoa/ml and packaged in .5-ml French straws. Straws were divided into three equal groups . bull-1 . collection day-1 and frozen in a mechanical freezer at full or half loads (7,250 +/- 250 or 3,500 +/- 250 straws in 5-straw goblets on metal canes) or in static N vapor (330 +/- 30 straws held singly on horizontal racks). For field distribution, straws frozen in static N vapor also were placed in 5-straw goblets on canes after being frozen. Each of the two goblets on a cane held a different treatment. Based on 75-d nonreturn rates for 23,137 first service inseminations, fertility was 1.6 percentage points higher (P less than .05) for semen frozen in static vapor (66.3%) than that frozen in a fully loaded mechanical freezer (64.7%). The difference of 1.3 percentage points in fertility favoring static vapor over freezing a half load in a mechanical freezer (65.0%) approached significance (P = .06); half and full loads did not vary (P greater than .05). In conclusion, the small increase in fertility favoring static over forced-vapor freezing supports use of the static vapor method unless the savings in time and labor of freezing large numbers of straws at one time in a mechanical freezer are considered to offset the small difference in fertility.

Effect of long term ejaculation at high frequency on output of sperm, sexual behavior, and fertility of Holstein bulls; relation of reproductive capacity to high nutrient allowance.

Eighteen Holstein bulls were used to determine the long term effect of high frequency ejaculation on reproductive performance. From 1 to 7 yr of age, six bulls were ejaculated weekly, and six pairmates were ejaculated six times weekly. For comparison, six bulls were ejaculated one or six times weekly from 1 to 2 yr of age, placed on sexual rest, and then ejaculated six times weekly for 6 wk and twice daily for 14 days at 3, 4, and 5 yr of age. Six time bulls yielded 3.3 times more motile sperm per week than one time bulls. Sexual activity, which was similar for one and six time bulls, was relatively constant to 5 yr of age and then gradually decreased. Sexual rest did not affect subsequent weekly output of sperm. Postthaw motility of sperm was similar for the one time, six time, and sexually rested groups. Fertility at 4, 6, or 8 yr of age did not differ between one and six time bulls. In conclusion, continuous high frequency of ejaculation from 1 to 7 yr of age greatly increased the harvest of sperm from a bull without harming his growth, reproductive capacity, or fertility. Ten other Holstein bulls fed concentrate ad libitum from 17 wk to 2 yr of age attained puberty 2 wk earlier (37 wk of age) and yielded 1.4 times more sperm per week on six times at 3 yr of age than the six time bulls fed limited energy. Raising bulls on maximum energy allowance enables sampling in a progeny testing program by 13 to 14 mo of age.

Effect of bulk freezing straws of bovine spermatozoa in a programmed freezer on post - thaw survival.

Twelve ejaculates were extended both in skimmilk and Tris-yolk, packaged in .5-ml French straws and frozen vertically in bulk (10,000 straws/freeze) in a programmed mechanical freezer (Linde CRFC-3). Cooling rates and post-thaw spermatozoal survival in the upper and lower thirds of straws at the following six chamber positions were compared: corner and middle within-goblet positions at center, intermediate and outer chamber locations. Cooling rates generally were faster in the upper third of straws than in the lower third and at the corner rather than the middle within-goblet positions. For combined postthaw incubation periods of 0, 3 and 6 hr at 37 C, motility (photographic and visual) and acrosomal retention (fixed and unfixed samples) were both higher (P greater than .01) for sperm in each extender in the upper third of straws than in the lower third. Spermatozoal motility and acrosomal retention generally were higher (P greater than .05) in each extender at the center rather than at the outer chamber location. Among within-goblet positions, post-thaw survival of sperm was higher (P greater than .05) at the corner than at the middle positions for Tris-yolk but not skimmilk. For comparison semen was frozen in static N vapor in straws held singly (258-straw load) on horizontal racks. For combined incubation periods, post-thaw survival of sperm did not differ (P less than .05) between bulk and static vapor- systems. There also was no difference when each of the six chamber positions was compared individually with static vapor. In conclusion, 33% more straws of semen can be frozen in a mechanical freezer than previously reported, with post-thaw spermatozoal survival comparable to that of sperm in straws frozen conventionally in static vapor.

Combinations of glycerol percent, glycerol equilibration time, and thawing rate upon freezability of bull spermatozoa in plastic straws.

Twelve ejaculates were used in a central composite experiment to test 15 combinations of glycerol (7, 9, 11, 13, or 15%), glycerol equilibration times (1, 2, 4, 8, or 16 h) and thawing rates (water at 35 C for 15 s, 50 C for 13 s, 65 C for 11 s, 80 C for 9 s, or 95 C for 7 s). Semen was diluted in heated skim milk-glycerol, packaged in .3-ml. Continental U.S. straws and frozen in liquid nitrogen vapor. Based on post-thaw progressive sperm motility after storage at -196 C for 9 to 11 days, estimated optima from multiple regression were 10.7% for glycerol, 2.0 h for glycerol equilibration time, and 76 C for thawing bath temperature. Only the linear effect for each variable was significant. Much faster thawing rates and shorter glycerol equilibration times than those for freezing bull spermatozoa in glass ampules should be used for maximum post-thaw sperm motility in straws.

Effect of sperm numbers on fertility of frozen bull spermatozoa in skim milk diluent.

Insemination doses of 10, 15, and 20 million progressively motile spermatozoa prior to freezing were compared in a split-ejaculate fertility experiment involving 4,603 first service inseminations to 34 semen samples from six Angus bulls. Based on 60- to 90-day nonreturn rates, fertility was significantly lower for inseminating doses of 10 and 15 times 10-6 than 20 times 10-6 motile sperm (61, 62, and 70%). The 1-ml doses of skim milk diluted semen were frozen in glass ampules. The post-thaw number of motile sperm per ampule after freezing and storage for 3 wk in liquid nitrogen averaged 5.5, 8.4, and 12.4 times 10-6 for corresponding pre-freeze numbers of 10, 15 and 20 times 10-6 motile sperm/ml and ranged from 4.0 to 15.7 times 10-6/ml. Frozen semen packaged in ampules should contain more than 8.4 times 10-6 motile cells post-thaw per ampule.