Long-Term Outcome of Indomethacin Treatment in Pediatric Patients with Paroxysmal Hemicrania—A Case Series

Paroxysmal Hemicrania is a rare form of primary headache in children and adolescents, belonging to the group of trigeminal autonomic cephalalgias. Patients suffer from severe, short-lasting unilateral headaches accompanied by symptoms of the autonomic system on the same side of the head. The short duration of attacks distinguishes Paroxysmal Hemicrania from other trigeminal autonomic cephalalgias. Indomethacin is the treatment of choice, and its effectiveness provides a unique diagnostic criterion. However, the long-term outcomes in children are highly underreported. In this case-series, n = 8 patients diagnosed with Paroxysmal Hemicrania were contacted via telephone 3.1 to 10.7 years after initial presentation. A standardized interview was conducted. n = 6 patients were headache-free and no longer took indomethacin for 5.4 ± 3.4 years. The mean treatment period in these patients was 2.2 ± 1.9 years. Weaning attempts were undertaken after 1.7 ± 1.3 months; in n = 3 patients, more than one weaning attempt was necessary. n = 2 patients were still taking indomethacin (4.5 and 4.9 years, respectively). Both unsuccessfully tried to reduce the indomethacin treatment (two and six times, respectively). Adverse effects appeared in n = 6 (75%) patients and led to a discontinuation of therapy in n = 2 patients. Our long-term follow-up suggests that in a substantial proportion of pediatric patients, discontinuing indomethacin therapy is possible without the recurrence of Paroxysmal Hemicrania.

Early pregnancy loss in 15-hydroxyprostaglandin dehydrogenase knockout (15-HPGD−/−) mice due to requirement for embryo 15-HPGD activity

Prostaglandins (PGs) have critical signaling functions in a variety of processes including the establishment and maintenance of pregnancy, and the initiation of labor. Most PGs are non-enzymatically degraded, however, the two PGs most prominently implicated in the termination of pregnancy, including the initiation of labor, prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α), are enzymatically degraded by 15-hydroxyprostaglandin dehydrogenase (15-HPGD). The role of PG metabolism by 15-HPGD in the maintenance of pregnancy remains largely unknown, as direct functional studies are lacking. To test the hypothesis that 15-PGDH-mediated PG metabolism is essential for pregnancy maintenance and normal labor timing, we generated and analyzed pregnancy in 15-HPGD knockout mice (Hpgd−/−). We report here that pregnancies resulting from matings between 15-HPGD KO mice (Hpgd−/− X Hpgd−/−KO mating) are terminated at mid gestation due to a requirement for embryo derived 15-HPGD. Aside from altered implantation site spacing, pregnancies from KO matings look grossly and histologically normal at days post coitum (dpc) 6.5 and 7.5 of pregnancy. However, virtually all of these pregnancies are resorbed by dpc 8.5. This resorption is preceded by elevation of PGF2∝ but is not preceded by a decrease in circulating progesterone, suggesting that pregnancy loss is a local inflammatory phenomenon rather than a centrally mediated phenomena. This pregnancy loss can be temporarily deferred by indomethacin treatment, but treated pregnancies are not maintained to term and indomethacin treatment increases maternal mortality. We conclude that PG metabolism to inactive products by embryo derived 15-HPGD is essential for pregnancy maintenance in mice, and may serve a similar function during human pregnancy.

Measurement of mechanical withdrawal threshold on full-thickness cutaneous wounds in rats using the von Frey test

Objective: A method for measuring mechanical withdrawal threshold of full-thickness cutaneous wound pain in animal models is lacking. This study aimed to confirm the validity and reactivity of the von Frey test in full-thickness cutaneous wounds in rats. Method: A 1.5cm-diameter wound was established on the dorsal areas of male Sprague-Dawley rats and subcutaneously injected with either morphine hydrochloride (5.0mg/kg) or indomethacin (2.5mg/kg) with a 27-gauge needle on day three post-wounding. On day five post-wounding, an injection of morphine hydrochloride, indomethacin or lambda-carrageenan (1.0%) into the granulation tissue was also administered. The withdrawal threshold of mechanical stimulation of the wound edge was compared in each group before treatment with injection and at two, four, eight and 24 hours after injection. Results: A total of 40 rats were used in the study. Since more severe inflammation in and around the wound was induced on day three post-wounding than that of day five, the withdrawal threshold measured on day three post-wounding was significantly lower than that of day five. The decrease of the withdrawal threshold was depressed by morphine hydrochloride and indomethacin treatment on day three post-wounding. While there was no significant difference between the changes in the withdrawal threshold after indomethacin treatment on day five post-wounding, we observed an increased withdrawal threshold after morphine hydrochloride treatment and decreased withdrawal threshold after lambda-carrageenan treatment on day five post-wounding. Conclusion: The results suggest that the von Frey test can be applied to measure the mechanical withdrawal threshold of full-thickness dorsal wounds in rats.

CYP2C9*2 is associated with indomethacin treatment failure for patent ductus arteriosus

Aims: To identify clinical andgenetic factors associated with indomethacin treatment failure in preterm neonates with patent ductus arteriosus (PDA). Patients & Methods: This is a multicenter cohort study of 144 preterm infants (22–32 weeks gestational age) at three centers who received at least one treatment course of indomethacin for PDA. Indomethacin failure was defined as requiring subsequent surgical intervention. Results: In multivariate analysis, gestational age (AOR 0.76, 95% CI 0.60–0.96), surfactant use (AOR 9.77, 95% CI 1.15–83.26), and CYP2C9*2 (AOR 3.74; 95% CI 1.34–10.44) were each associated with indomethacin failure. Conclusion: Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome in preterm infants with PDA. This combination of clinical and genetic factors may facilitate targeted indomethacin use for PDA.

Dosing regimen of gentamicin and the effect of antenatal steroids on clearance in preterm infants

ABSTRACTObjectiveDetermine the gentamicin pharmacokinetic and pharmacodynamic (PK/PD) profiles of once daily dosing (ODD) versus every 18-hour (q18h) regimens and to characterize the effect of antenatal steroid on gentamicin clearance (GentCL).Study DesignRetrospective cohort of preterm infants (≤34 weeks gestation; ≤7 days) who received gentamicin for >48 hours from January 2005 to June 2007. Serum gentamicin peak and trough concentrations were determined, and PK/PD profiles calculated using standard noncompartmental methods.Result122 (63%) infants received ODD and 73 (37%) received q18h regimen. Desired gentamicin peak (5 to 12 mcg/mL) and trough (<2 mcg/mL) concentrations were achieved in 80% (95%CI, 72-86) on ODD vs. 47% (95%CI, 36-58) on q18h (p<0.001). Target drug exposure (AUC >72 mcg/mL/hr) was achieved in 73% (89/122) of infants on ODD vs. 22% (16/73) on q18h (p < 0.001). GentCLwas significantly lower in those who receive antenatal steroid (37+/-8 mL/kg/hr vs. 42+/-13 mL/kg/hr,p=0.04)but not affected by postnatal indomethacin treatment (p>0.86).ConclusionPK/PD profile of gentamicin is improved by ODD in preterm infants. GentClwas significantly less in infants exposed to antenatal steroids but not in those treated with indomethacin.

Antenatal Indomethacin Treatment for Congenital Myotonic Dystrophy

Myotonic dystrophy is an autosomal-dominant disorder. Its congenital type is the most severe form, with respiratory failure that can be a life-threatening event after birth. There are no antenatal treatments that can improve neonatal outcomes of myotonic dystrophy. We treated a fetus with congenital myotonic dystrophy by administering indomethacin to the 31-year-old Japanese mother affected by myotonic dystrophy and polyhydramnios. We observed increased fetal breathing movement and a reduction of the amniotic fluid volume. The baby was born at 37 weeks and discharged from the neonatal intensive care unit with a favorable outcome. Indomethacin treatment is likely to improve fetal lung function and to control the amniotic fluid volume. This report emphasizes the importance of further investigations regarding the optimal management of congenital myotonic dystrophy.