Assuming that the claimed effect of meclizine in male mice

Assuming that the claimed effect of meclizine in male mice on renal ischemia–reperfusion injury is real, there are still a couple of uncertainties that hinder translation to humans. The observation might be species and/or gender specific (). Replication in larger mammals including both sexes is therefore warranted before doing an (expensive) clinical trial. More importantly, Kishi et al. applied a very high intraperitoneal dose of 100mg/kg. Unfortunately, we are not informed about the achieved plasma levels of meclizine in these animals. Although the mice may have tolerated this high dose surprisingly well, we are not sure whether this exposure to meclizine can be replicated in humans without inducing serious and unacceptable adverse events such as coma, epileptic insults and hypotension, known adverse events of meclizine overdose in humans. To overcome this problem, we may need more specific inhibitors of phosphoethanolamine harpagoside which should be fully evaluated both pre-clinically and in phases 1–3 clinical studies before they can be applied in practice. Another issue is the age and health status of the animals. The healthy and relatively young animals as used by Kishi et al. differ from the aged population of patients with co-morbidity and co-medication who are at particular risk for renal ischemia–reperfusion injury. Replication of findings in more representative animal models are essential for appropriate translation to the clinic. Finally, meclizine was tested in an optimized and highly standardized experimental design with respect to timing of the intervention and duration of ischemia and reperfusion. This differs from the clinical reality in which patients experience a variable duration and severity of renal hypoperfusion and often present after the ischemic event has already taken place.
Many studies have documented the reduction of HPV vaccine type prevalence, cervical lesions, and genital warts in adolescent girls in the years since the introduction of the first HPV vaccine in 2006 (). In addition, HPV vaccines have been found to be quite safe: clinical trials and numerous post-licensure safety studies have found no consistent evidence of causal association of HPV vaccination with prespecified health conditions including Guillain–Barré syndrome, stroke, venous thromboembolism, appendicitis, seizures, allergic reactions, anaphylaxis, autoimmune disorders, or a variety of neurologic conditions (). However, a number of countries have received, and continue to receive, reports alleging the association of HPV vaccination with a variety of adverse health events, many of which have been systematically investigated and no causal relationships found (). Reports have engendered a spectrum of immunization program responses (). In 2013, subsequent to a concern about Complex Regional Pain Syndrome (CRPS) after receipt of HPV 16/18 vaccine, Japan temporarily suspended the national HPV vaccination recommendation. In this issue of EBioMedicine, the risk of CRPS after receipt of HPV 16/18 vaccine is explored in a study by . CRPS is a condition of chronic, severe, often burning pain, usually in one or more extremities, that is often accompanied by swelling, skin discoloration, allodynia, abnormal sweating, and impaired motor function in the affected area. The pathogenesis of CRPS has not been definitively determined; CRPS develops following trauma or injury in over 90% of cases. In Japan, a 40-person case-series of peripheral sympathetic nerve dysfunction in adolescent girls after HPV vaccination was described; 18 of the cases were considered to have CRPS (). More research into the possible association of HPV vaccination and CRPS is needed, and Huygen et al. used the worldwide GSK safety database, a proprietary passive reporting system, to conduct such research (). Huygen identified 18,391 adverse event reports regarding persons who received HPV 16/18 vaccine (). Of these, 17 were reports of CRPS; 5 were classified as confirmed CRPS. Additional database searches were conducted to assess the possibility that different pain-related diagnostic codes may include patients with CRPS; no additional cases were identified. Huygen concludes that evidence suggesting an increased risk for CRPS after HPV 16/18 vaccination is lacking. The uncertainty in Huygen\'s observed vs expected analysis illustrates the challenge of using a spontaneous reporting system, in which the reported fraction is unknown, to quantify an adverse event after immunization (AEFI).