Drug-induced hyperprolactinemia: a case-non-case study from the national pharmacovigilance database

Hyperprolactinaemia is a relatively common endocrine abnormality caused by an increased secretion of prolactin from the pituitary gland. There are many causes of hyperprolactinaemia; drug therapy is a common cause in clinical practice. The present pharmacoepidemiological study conducted an analysis of the French Pharmacovigilance Database from January 1, 1985, to December 2000. We investigated the rates of hyperprolactinaemia according to therapeutic drug class, particularly where the Summaries of Product Characteristics (SPC) did not mention hyperprolactinaemia, and estimated the risk of developing hyperprolactinaemia during treatment. We calculated the odds ratio (OR) of reports associated with hyperprolactinaemia for all drugs. Of the 182,836 spontaneous adverse drug reactions reported to the French Pharmacovigilance network, 159 were hyperprolactinaemia. The sex ratio was 5.9 (136 women and 29 men), and mean age was 40 (range 14-85) years. Of the total number of adverse reactions, 31% were associated with neuroleptics, 28% with neuroleptic-like drugs, 26% with antidepressants, 5% with H2-receptor antagonists, and 10% with other drugs. Neuroleptics are not the only class of drugs for which hyperprolactinaemia is reported. Some drugs are clearly associated with an increased risk of hyperprolactinaemia, particularly the following: veralipride (OR = 108.7; IC 95%: 51.82-228), indoramin (OR = 78.68; IC 95%: 33.93-182.48), sertraline (OR = 15.74; IC 95%: 5.80-42.75), and ranitidine (OR = 4.43; IC 95%: 1.82-10.81). All these drugs are reported in the literature as inducing hyperprolactinaemia, although this adverse effect is not mentioned in the SPC. It is thus necessary to harmonise the SPC and encourage health professionals to notify all adverse reactions to their pharmacovigilance centres.     

Multiple DICER1‐related tumors in a child with a large interstitial 14q32 deletion

Germ‐line interstitial deletions involving the 14q32 chromosomal region, resulting in 14q32 deletion syndrome, are rare. DICER1 is a recently described cancer‐predisposition gene located at 14q32.13. We report the case of a male child with a ～5.8 Mbp 14q32.13q32.2 germ‐line deletion, which included the full DICER1 locus. We reviewed available clinical and pathological material, and conducted genetic analyses. In addition to having congenital dysmorphic features, the child developed multiple DICER1 syndrome‐related tumors before age 5 y: a pediatric cystic nephroma (pCN), a ciliary body medulloepithelioma (CBME), and a small lung cyst (consistent with occult pleuropulmonary blastoma Type I/Ir cysts seen in DICER1 mutation carriers). He also developed a cerebral spindle‐cell sarcoma with myogenous differentiation. Our investigations revealed that the deletion encompassed 31 protein‐coding genes. In addition to the germ‐line DICER1 deletion, somatic DICER1 RNase IIIb mutations were found in the CBME (c.5437G > A, p.E1813K), pCN (c.5425G > A, p.G1809R), and sarcoma (c.5125G > A, p.D1709N). The sarcoma also harbored a somatic TP53 mutation: c.844C > T, p.R282W. Additional copy number alterations were identified in the CBME and sarcoma using an OncoScan array. Among the 8 cases with molecularly‐defined 14q32 deletions involving DICER1 and for whom phenotypic information is available, our patient and one other developed DICER1‐related tumors. Biallelic DICER1 mutations have not previously been reported to cause cerebral sarcoma, which now may be considered a rare manifestation of the DICER1 syndrome. Our study shows that DICER1‐related tumors can occur in children with 14q32 deletions and suggests surveillance for such tumors may be warranted.     

Neuroprotective activity of stiripentol with a possible involvement of voltage‐dependent calcium and sodium channels

A growing body of data has shown that recurrent epileptic seizures may be caused by an excessive release of the excitatory neurotransmitter glutamate in the brain. Glutamatergic overstimulation results in massive neuronal influxes of calcium and sodium through N‐methyl‐D‐aspartate (NMDA), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid, and kainic acid glutamate subtype receptors and also through voltage‐gated calcium and sodium channels. These persistent and abnormal sodium and calcium entry points have deleterious consequences (neurotoxicity) for neuronal function. The therapeutic value of an antiepileptic drug would include not only control of seizure activity but also protection of neuronal tissue. The present study examines the in vitro neuroprotective effects of stiripentol, an antiepileptic compound with γ‐aminobutyric acidergic properties, on neuronal–astroglial cultures from rat cerebral cortex exposed to oxygen–glucose deprivation (OGD) or to glutamate (40 µM for 20 min), two in vitro models of brain injury. In addition, the affinity of stiripentol for the different glutamate receptor subtypes and the interaction with the cell influx of Na⁺ and of Ca²⁺ enhanced by veratridine and NMDA, respectively, are assessed. Stiripentol (10–100 µM) included in the culture medium during OGD or with glutamate significantly increased the number of surviving neurons relative to controls. Stiripentol displayed no binding affinity for different subtypes of glutamate receptors (IC₅₀ > 100 µM) but significantly blocked the entry of Na⁺ and Ca²⁺ activated by veratridine and NMDA, respectively. These results suggest that Na⁺ and Ca²⁺ channels could contribute to the neuroprotective properties of sitiripentol. © 2015 Wiley Periodicals, Inc.     

Taurine deficiency damages photoreceptors and retinal ganglion cells in vigabatrin-treated neonatal rats

The anti-epileptic drug vigabatrin induces an irreversible constriction of the visual field, but is still widely used to treat infantile spasms and some forms of epilepsy. We recently reported that vigabatrin-induced cone damage is due to a taurine deficiency. However, optic atrophy and thus retinal ganglion cell degeneration was also reported in children treated for infantile spasms. We here show in neonatal rats treated from postnatal days 4 to 29 that the vigabatrin treatment triggers not only cone photoreceptor damage, disorganisation of the photoreceptor layer and gliosis but also retinal ganglion cell loss. Furthermore, we demonstrate in these neonatal rats that taurine supplementation partially prevents these retinal lesions and in particular the retinal ganglion cell loss. These results provide the first evidence of retinal ganglion cell neuroprotection by taurine. They further confirm that taurine supplementation should be administered with the vigabatrin treatment for infantile spasms or epilepsy.     

Dramatically decreased therapeutic efficacy of chloroquine and sulfadoxine-pyrimethamine, but not mefloquine, in southern Benin

OBJECTIVE: To evaluate the in vivo therapeutic efficacy of chloroquine (CQ), sulfadoxine-pyrimethamine (SP) and mefloquine (MQ) in children presenting with uncomplicated malaria in Benin. METHODS: Drug efficacy was tested according to the WHO in vivo 28-day protocol. For failures that occurred after 7 days of follow-up, paired pre- and post-treatment blood samples were genotyped at msp1 and msp2 loci to distinguish new infections and recrudescent strains. Children enrolled were randomly assigned to a therapeutic group (CQ, n=14; SP, n=42; MQ, n=44). The number of CQ treatment was intentionally restricted after 1 month, as its use was considered to constitute a danger for children. RESULTS: Chloroquine and SP showed very high failure rates (85.7% and 50%, respectively), whereas MQ treatment was successful in 97.5%. The molecular tool allowed to re-evaluate two new infections previously considered as failures. CONCLUSIONS: Chloroquine should no longer be used to treat children presenting with Plasmodium falciparum malaria in Benin.     

The simultaneous occurrence of mucinous cystadenomas in liver and pancreas

The occurrence of mucinous cystadenomas localized to the liver and pancreas simultaneously and treated with a single surgical procedure has been described for the first time in this report. A 47-year-old woman attended the outpatient clinic complaining of abdominal pain and the appearance of an abdominal mass. On clinical examination, hepatomegaly was found. An abdominal computed tomography scan showed a large cystic lesion of the left lobe of the liver, thus causing the hepatomegaly. Moreover, the computed tomography scan showed a cystic lesion of the pancreas. Both lesions had thick walls and septa. Magnetic resonance imaging of the liver and pancreas confirmed the presence of septa within the cysts. Surgery was performed owing to the suspected malignancy. It should be emphasized that the patient had preoperatively received prophylactic treatment for hydatosis. A hepatic pericystectomy and enucleation of the pancreatic lesion were performed during the surgery. Pathology showed a mucinous cystadenoma without sign of malignancy. At the 4-year follow-up, no recurrence was found. This case is of interest for several reasons: the unusual double presentation, the treatment, and the follow-up. This case report confirms the common origin of mucinous cystic tumours of liver and pancreas.     

New strategy for alerting central nervous system toxicity: Integration of blood–brain barrier toxicity and permeability in neurotoxicity assessment

The combination of an in vitro BBB model (4d/24w) with a neuronal cell line (SH-SY5Y) provides a convenient approach to explore the importance of BBB permeability in neurotoxicity assessment of compounds. The toxicity of 16 compounds on SH-SY5Y cells was evaluated after 24 h incubation with each compound and compared to their toxicity on SH-SY5Y after passage through the BBB model. Nine out of 16 compounds were found toxic after direct exposure at 100 μM while only three still induced toxicity on SH-SY5Y cells after BBB transport.The BBB permeability values of each compound revealed that in the case of compounds that did not induce toxicity, the amount that crossed the BBB was not enough to exert a toxic effect on the neuronal cells. Since disrupting the BBB may also cause unwanted effect on brain cells, the BBB toxicity of these compounds have been assessed. Our results prompted the importance of BBB permeability assessment in neurotoxicity evaluation, as it allows a better estimation of the actual concentration at the target site.