The Consequences Of Refractory Epilepsy And Its Treatment.

Seizures in some 30% to 40% of patients with epilepsy fail to respond to antiepileptic drugs or other treatments. While much has been made of the risks of new drug therapies, not enough attention has been given to the risks of uncontrolled and progressive epilepsy. This critical review summarizes known risks associated with refractory epilepsy, provides practical clinical recommendations, and indicates areas for future research. Eight international epilepsy experts from Europe, the United States, and South America met on May 4, 2013, to present, review, and discuss relevant concepts, data, and literature on the consequences of refractory epilepsy. While patients with refractory epilepsy represent the minority of the population with epilepsy, they require the overwhelming majority of time, effort, and focus from treating physicians. They also represent the greatest economic and psychosocial burdens. Diagnostic procedures and medical/surgical treatments are not without risks. Overlooked, however, is that these risks are usually smaller than the risks of long-term, uncontrolled seizures. Refractory epilepsy may be progressive, carrying risks of structural damage to the brain and nervous system, comorbidities (osteoporosis, fractures), and increased mortality (from suicide, accidents, sudden unexpected death in epilepsy, pneumonia, vascular disease), as well as psychological (depression, anxiety), educational, social (stigma, driving), and vocational consequences. Adding to this burden is neuropsychiatric impairment caused by underlying epileptogenic processes (essential comorbidities), which appears to be independent of the effects of ongoing seizures themselves. Tolerating persistent seizures or chronic medicinal adverse effects has risks and consequences that often outweigh risks of seemingly more aggressive treatments. Future research should focus not only on controlling seizures but also on preventing these consequences.

Predictive Value Of Phase I Trials For Safety In Later Trials And Final Approved Dose: Analysis Of 61 Approved Cancer Drugs.

Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012). The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting ± 20% of the RP2D for targeted vs. other classes; P = 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n = 374) were described in phase I. A significant relationship (P = 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials.

Triatominae Survey (hemiptera: Heteroptera: Reduviidae) In The South-central Region Of The State Of Bahia, Brazil Between 2008 And 2013.

Triatomine surveillance in rural areas, artificial ecotypes, and natural ecotopes of the cities of Caturama, Ibipitanga, Macaúbas, and Seabra in the south-central region of the Brazilian state of Bahia was carried out between 2008 and 2013. Natural infection by Trypanosoma cruzi was evaluated in the specimens collected to monitor vectors of Chagas disease. A total of 1,357 specimens were collected, and four species were identified: Triatoma sordida (83%), Triatoma lenti (16.4%), Triatoma pseudomaculata (0.5%), and Panstrongylus geniculatus (0.1%). Triatoma sordida was found in four cities, only 0.7% in intradomiciliary environments. Triatoma lenti was found only in Macaúbas; 8.5% were found in intradomiciliary environments, 88.3% in peridomiciliary environments, and 3.1% in sylvatic environments. Natural infection by T. cruzi was 0.5% for T. sordida and 3.1% T. lenti. All of these cases were found in peridomiciliary environments of Macaúbas. As the results show, triatomines were found in intradomiciliary environments in three cities that were surveyed in the south-central region of the state of Bahia. Thus, an epidemiologic survey should be performed to avoid the risk of transmission to the population.