Intranasal DDAVP induced increases in plasma von Willebrand factor alter the pharmacokinetics of high-purity factor VIII concentrates in severe haemophilia A patients

Because native circulating factor VIII (FVIII) is maximally stabilized when it is bound to von Willebrand factor (vWf), increased plasma vWf levels may enhance the infused FVIII concentrate intravascular survival and efficacy in severe haemophiliacs. To assess whether the kinetic characteristics and recovery of high purity, plasma-derived (Monoclate-P, Centeon) and recombinant (Bioclate , Centeon) FVIII concentrates are enhanced by increased plasma vWf concentrations, we compared the pharmacokinetic response to a bolus of FVIII infused alone with the response to a bolus infused 2 h after the intranasal delivery of 300 microg of desmopressin acetate (DDAVP) High Concentration Nasal Spray (Stimate, Centeon) in 10 adult severe haemophiliacs. FVIII activity was determined using a one-stage clotting assay on cryopreserved plasma specimens obtained at baseline and at 14 distinct time points (0.25-48 h) following the FVIII infusions. Ristocetin co-factor activity (RCoFA) and vWf antigen levels were assayed at baseline and 2 h after Stimate. FVIII kinetic parameters were calculated using standard, noncompartmental kinetic methods. Statistical analysis was performed using a paired t-test with 95% confidence limits. The mean rises in RCoFA (0.65+/-0.44 IU mL(-1)) and vWf antigen (0.19+/-0.07 IU mL-1) induced by Stimate were significant (P<0.01 and P<0.0001, respectively). The mean increases in the volume of distribution at steady state (Vss) (13.2+/-9.3 dL) and mean residence time (MRT) (4.4+/-3.9 h) between the FVIII-only arm and the FVIII plus Stimate arm were highly significant (P = 0.0015 and P = 0. 0059, respectively). The mean differences in recovery, area under the curve (AUC), half-life, and clearance (Cl) were not significantly altered. Subgroup analysis revealed statistically significant increases in Vss and MRT (P = 0.025 and P = 0.012, respectively) following the administration of intranasal DDAVP in the Monoclate-P cohort, but not in the Bioclate group. These data suggest that even modest pharmacologically induced increases in plasma vWf can favourably affect the kinetics of high-purity, plasma-derived FVIII concentrates in severe haemophiliacs.     

FINDING MEANING IN A CHILD'S VIOLENT DEATH: A FIVE-YEAR PROSPECTIVE ANALYSIS OF PARENTS' PERSONAL NARRATIVES AND EMPIRICAL DATA

Finding meaning in the death of a loved one is thought to be extremely traumatic when the circumstances surrounding the death is perceived to be due to negligence, is intentional, and when the deceased suffered extreme pain and bodily harm immediately prior to death. We addressed this assumption by obtaining personal narratives and empirical data from 138 parents 4, 12, 24, and 60 months after an adolescent's or young adult child's death by accident, suicide, or homicide. Using the Janoff-Bulman and Frantz's(1997) framework ofmeaning-as-comprehensibility and meaning-as-significance, the purposes were to identify the time course to find meaning, present parents' personal narratives describing finding meaning in their experiences, identify predictors of finding meaning, and compare parents who found meaning versus those who did not on five health and adjustment outcomes. The results showed that by 12 months postdeath, only 12% of the study sample had found meaning in a child's death. By 60 months postdeath, 57% of the parents had found meaning but 43% had not. Significant predictors of finding meaning 5 years postdeath were the use of religious coping and support group attendance. Parents who attended abereavement support group were 4 times more likely to find meaning than parents who did not attend. Parents who found meaning in the deaths of their children reported significantly lower scores on mental distress, higher marital satisfaction, and better physical health than parents who were unable to find meaning. Recommendations for future research are made.     

A Dose-Response Analysis of Methoxychlor-Induced Alterations of Reproductive Development and Function in the Rat

A Dose-Response Analysis of Methoxychlor-Induced Alterationsof Reproductive Development and Function in the Rat. GRAY, L.E., JR., OSTBY, J., FERRELL, J., REHNBERG, G., LINDER, R., COOPER,R., GOLDMAN, J., SLOTT, V., AND LASKEY, J. (1989). Fundam. Appl.Toxicol12, 92–108. In the present study rats were dosed fromweaning, through puberty and gestation, to Day 15 of lactationwith methoxychlor at 25, 50, 100, or 200 mg/kg/day. Morphologicallandmarks of puberty were measured, including the ages at vaginalopening, first estrus, and first estrous cycle in females andat preputial separation in males. In the female, estrous cyclicity,fertility, litter size, number of implantation sites, organweights, and ovarian and uterine histology were also measured.The viability of the offspring (F1) and their fertility wereevaluated using a continuous breeding protocol. Males were necropsiedafter breeding, the reproductive organs were weighed, and thecauda epididymal sperm counts were determined. One testis wasused for histopathology, while the other was used to quantifyinterstitial fluid (IF) content, IF testosterone concentration,and testicular sperm production. Testosterone and an drogen-bindingprotein were measured in the caput epididymis, and sperm motilityand morphology were evaluated from a caudal sample. The serumand pituitary were saved for hormonal determinations. Methoxychloraccelerated the age at vaginal opening and first estrus, andthe vaginal smears were cornified. Growth was retarded at 100and 200 mg/kg/day and fertility was reduced when the femaleswere bred with untreated or similarly treated males. In thehighest- dose group, the mated females went from constant estrusinto pseudopregnancy following mating, but they had no implants.In males, methoxychlor treatment markedly reduced growth, seminalvesicle weight, cauda epididymal weight, caudal sperm content,and pituitary weight. Puberty was delayed in the two highest-dosagegroups. Testicular sperm measures were much less affected thancaudal measures. Testis weight and histology were slightly affected,and testicular sperm production, sperm morphology, and motilitywere unaffected. Endocrine function of the testes and pituitarywas altered by methoxychlor administration. Leydig cell testosteroneproduction, in response to human chorionic gonadotropin challenge,was reduced and pituitary levels of prolactin, thyroid-stimulatinghormone (TSH), and follicle-stimulating hormone (FSH) were altered.In contrast, serum levels of prolactin, FSH, and luteinizinghormone were unaffected. Serum TSH was reduced by 50% of controlat 100 and 200 mg/kg/day, while pituitary levels were increased.Gonadotropin-releasing hormone concentration in the mediobasalhypothalamus was also elevated. In spite of the many reproductivealterations, the fertility of treated males was not reducedwhen they were mated with untreated females. Growth and viabilityof the offspring (F1) from the 50 mg/kg/day treatment groupwere normal, but in the females, vaginal opening was accelerated,estrous cyclicity was abnormal in the rats during middle age,and fecundity was reduced.     

Developmental Toxicology Studies of Fluoxetine Hydrochloride Administered Orally to Rats and Rabbits

Pregnant Fischer 344 rats were given fluoxetine orally at doselevels of 0, 2, 5, or 12.5 mg/kg on Gestation Days (GD) 6–15;pregnant Dutch Belted rabbits were given 0, 2.5, 7.5, or 15mg/kg orally on GD 6–18. Cesarean sections were performedon rats and rabbits on GD 20 and 28, respectively. In rats,maternal toxicity was indicated at 12.5 mg/kg by depressionof weight gain and food consumption. Fetal viability, weight,and morphology were not affected at any dose level. Maternaland developmental No Observed Adverse Effect Levels (NOAELs)in the rat were 5 and 12.5 mg/kg, respectively. In rabbits,weight loss occurred at 2.5,7.5, and 15 mg/kg. Food consumptionwas also depressed at 7.5 and 15 mg/kg; abortions and maternalmortality occurred secondarily to anorexia and cachexia at 15mg/kg. Fetal viability, weight, and morphology were not affectedat any dose level. A NOAEL for maternal effects was not establishedin the rabbit; the NOAEL for developmental effects in the rabbitwas 15 mg/kg. Based on these data, fluoxetine did not exhibitany toxicity toward the developing rat or rabbit conceptus atdoses that were maternally toxic.     

A Worksite Program for Overweight Middle-Aged Men Achieves Lesser Weight Loss With Exercise Than With Dietary Change

Objective To compare changes in total and regional body composition using dual energy X-ray absorptiometry (DEXA) after subjects lost weight through change in diet or exercise.Design A 12-month, randomized, controlled study of two weight-loss interventions — low-fat diet ad libitum or moderate, unsupervised exercise — in free-living, middle-aged men. Compliance was determined at monthly measurement sessions through food records and activity logs; DEXA scans were performed every 3 months.Subjects/setting Fifty-eight overweight men (mean body mass INDEX=29.0±2.6; mean AGE=43.4±5.7 years) recruited from a national corporation were assigned randomly to diet, exercise, or control groups.Interventions One group reduced dietary fat to 26.4% of energy intake but kept activity unchanged; another group self-selected aerobic exercise (three sessions per week at 65% to 75% maximum heart rate) but kept diet unchanged. A control group maintained weight.Main outcome measures At 12 months, measurements of weight, total and regional fat mass and lean mass, energy intake, and percentage dietary fat; physical activity indexes. Statistical analyses Results were analyzed using paired t tests and analysis of variance.Results Mean weight loss was 6.4±3.3 kg in dieters and 2.6+3.0 kg in exercisers; control subjects maintained weight. DEXA scans revealed that 40% of dieters’ weight loss was lean tissue; more than 80% of weight lost by exercisers was fat. Exercisers maintained limb lean tissue and lost fat mass.Conclusions Greater total weight and lean tissue loss occurred when subjects lost weight through a low-fat diet consumed ad libitum than when subjects participated in unsupervised aerobic exercise. Use of DEXA enabled identification of progressive total and regional changes in fat and lean tissue. J Am Diet Assoc. 1997; 97:37–42.     

Prolonged inhibition of acid secretion causes hypergastrinaemia without altering pH inhibition of gastrin release in humans

Hypergastrinaemia induced by potent inhibitors of acid secretion is thought to occur as a result of the elimination of the inhibitory effects of intragastric acid on gastrin release. The present study was designed to determine if the mechanisms responsible for feedback inhibition of gastrin release and acid secretion by intragastric acid are preserved during four weeks of varying degrees of drug-induced acid inhibition. Forty-eight healthy male volunteers were randomly assigned to one of four treatments for four weeks: 10 mg omeprazole o.m., 20 mg omeprazole o.m., 40 mg omeprazole o.m. or 150 mg ranitidine b.d. Gastrin release and acid secretion in response to peptone meals maintained at pH 2.5 and pH 5.5 by intragastric titration, and 24-hour gastrin profiles in response to standard meals were determined before treatment, at the fourth week of treatment and two weeks after discontinuing treatment. As expected, omeprazole produced dose-related effects on acid secretion and gastrin concentrations that were largely reversed after treatment was discontinued. Gastrin release in response to pH 5.5 peptone meals remained significantly greater than gastrin release in response to pH 2.5 meals during treatment with all doses of omeprazole. The ratio of pH 5.5/pH 2.5 peptone meal-stimulated gastrin release was approximately 1.5, and remained constant for all treatment groups throughout the study period. These data indicate that four weeks of drug induced hypochlorhydria causes an apparent increase in overall G-cell function, but it does not interfere with normal feedback inhibition of gastrin release and acid secretion mediated by intragastric acidity.     

Evaluation of awakening and recovery characteristics following anaesthesia with nitrous oxide and halothane fentanyl or both for brief outpatient procedures in infants

This study compared recovery characteristics and postoperative ventilatory function when halothane, fentanyl or combination of halothane and fentanyl in addition to N₂O were used for intraoperative anaesthesia in term infants undergoing hernia repair as outpatients. Sixty-six full term ASA PS I infants ages 1–12 months were studied. All received inhalation induction with N₂O, O₂ and halothane, followed by intravenous atropine and atracurium, tracheal intubation, and controlled ventilation. For anaesthesia maintenance, patients were randomized into one of three groups. Group I received 70% N₂O, 30% O₂ and halothane. Group II received 70% N₂O, 30% O₂, halothane and 2 μg·kg^?1 fentanyl. Group III received 70% N₂O, 30% O₂ and 10 μg·kg^?1 fentanyl. Awakening times were similar in all three groups, however, Group I patients had significantly shorter recovery and discharge times than those of Group II and III. None of the patients experienced postoperative apnoea or periodic breathing. One patient in Group III experienced two brief episodes of bradycardia not associated with apnoea or arterial desaturation (Spo ₂ >90% for greater than 30 s). Decreased Spo ₂ occurred less frequently in Group I (5.9%) compared to Group II (22.7%) and Group III (19.0%) patients, however, the group differences were not significant. Transcutaneous CO₂ (TcCO₂) values were not statistically different among the three groups. Pain scores were initially lower in Groups II and III, but at 120 min the differences were not significant. Postoperative apnoea was not observed in this study. Spo ₂ <90% and TcCO₂ >9 kPa (70 mmHg) was more common in infants receiving 2 and 10 μg·kg^?1 fentanyl than in infants receiving halothane and nitrous oxide anaesthesia. Infants <3 months old did not have a higher incidence of Spo ₂ <90% or significantly higher TcCO₂ values when compared to infants >3 months old. Fentanyl in doses used in this study did not prolong awakening time but did prolong recovery and discharge times in outpatient infants.     

Teratology Studies of Compound Lyn 171883 Administered Orally to Rats and Rabbits

Teratology Studies of Compound LY171883 Administered Orallyto Rats and Rabbits. HA-GOPIAN, G. S., HOOVER, D. M., AND MARKHAM,J. K. (1988). Fundam Appl Toxicol. 10, 672–681. The teratogenicpotential of the leukotriene antagonist LY171883, a novel antiasthmaagent, was investigated in CD rats and Dutch Belted rabbits.Mated female rats were dosed with 0, 10, 65, or 425 mg/kg/dayon gestation days 6 through 15 and killed on gestation day 20.Mated female rabbits were dosed with 0, 20, 65, or 200 mg/kg/dayon gestation days 6 through 18 and killed on gestation day 28.Maternal toxicity was indicated at 425 mg/kg in rats and 200mg/kg in rabbits by depressed body weight gain and food consumption.In the rabbit study four abortions occurred at 200 mg/kg, mostlikely secondarily to maternal toxicity. LY171883 did not causeembryo/fetal toxicity or teratogenicity in rats or rabbits atdoses up to and including those that were maternally toxic.     

Long-Term Pacing in Heart Transplant Recipients is Usually Unnecessary

The indications for and timing of permanent pacing were reviewed in all 17 of 154 adult heart transplant recipients at this center who have had permanent pacemakers implanted. Resting 12-lead ECGs recorded during routine follow-up were examined. A prospective study of pacing requirement was then undertaken. Holter monitoring was performed before and after reprogramming the pacemakers to VVI mode at 50 beats/min. Exercise responses in various pacing modes were then assessed in seven patients with rate responsive pacemakers using a standard Bruce protocol treadmill test. The indication for pacing was sinus node dysfunction in 59% (10/17) and atrioventricular (AV) block in 41% (7/17). The majority of pacemakers were implanted between seven and 21 days after transplantation. There was a progressive reduction in the frequency of pacing on 12-Jead ECGs with time after transplantation. Eight of 14 patients with empirically selected programming paced during Holter monitoring. After reprogramming to 50 beats/ min VVI mode only three of 14 patients, all with sinus node dysfunction, paced. Rate responsive pacing made no difference to exercise time. The requirement for long-term pacing in cardiac transplant recipients is small (3/154) and is limited lo patients with sinus node dysfunction. Rate responsive pacing did not increase exercise tolerance.