Antiepileptic drugs: evolution of our knowledge and changes in drug trials.

Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evidence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938-1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970-1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized during the intermediate period, which also saw major improvements in trial methodology. The last period (1989-2019) was dominated by the introduction of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials. The expansion of the pharmacological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. However, there is still inadequate evidence from controlled trials to guide treatment selection for most epilepsy syndromes, particularly in children. Second-generation drugs had a very modest impact on drug resistance, and a change in paradigm for drug discovery and development is needed, focusing on treatments that target the causes and mechanisms of epilepsy rather than its symptoms. Testing potential disease modifying agents will require innovative trial designs and novel endpoints, and will hopefully lead to introduction of safer and more effective therapies.

The History of Target-Controlled Infusion.

Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted ("target") drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. We also describe the launch of the current clinically available systems.

El mercado de las publicidades de medicamentos e insumos médicos especializados en el interior de Argentina: el caso de la Revisat del Círculo médico de Córdoba y la Revista Médica de Córdoba, Argentina, 1912-1938 / The advertising market of medication and specialized medical supply in the countryside of Argentina. The case study of the Revista del Círculo Médico de Córdoba and the Revista Médica de Córdoba, Argentina, 1912-1938

Se propone un análisis hermenéutico y un abordaje socio-semiótico alrededor de una amplia selección de anuncios de medicamentos e insumos médicos especializados colocados en la «Revista del Círculo Médico de Córdoba» y luego en su sucesora, la «Revista Médica de Córdoba». Las publicidades - como dispositivos estratégicos - y el mercado de ofertas que se configura entraman en una trayectoria histórica cambiante y específica donde lo local, lo nacional e inclusive lo internacional se articulan de manera particular. Por una parte, dichas características se consideran de la creación de la publicación en 1912 hasta 1938, asociándolas a las dinámicas relativas a ciertas variables clave de la transformación de la única revista médica especializada que existió en la provincia de Córdoba y que a lo largo de esos años fue el espacio exclusivo de colocación de publicidades gráficas orientadas a la elite médica. Por otra parte, se considera la influencia que tienen sobre la configuración del mercado publicitario - tradicionalmente monopolizado por «lo extranjero» - los procesos de industrialización argentina - vistos especialmente desde el sector farmacéutico - y la competencia en el contexto del reacomodamiento internacional que trajo el final de la Primera Guerra Mundial (AU)

The article proposes an hermeneutic analysis as well as a socio-semiotic approach around a broad selection of advertisements published of medication and specialized medical supplyin the "Revista del Círculo Médico de Córdoba" and then its successor the "Revista Médica de Córdoba". The advertisement - as an strategic mechanism - and the sailing market are organized around a changing as well as an specific historical trajectory where the local, the national and also the international are articulated in a particular way. On the one hand, that particularity is considered from the beginning of the publication in 1912 until 1938. In this historical period, the publication is associated to the dynamics of the transformation of the only specialised medical magazine published in the province of Córdoba, that in those years, it became an exclusive space of graphic advertisement that targeted medical elites. On the other hand, the article considers the argentine industrialized process' influence on the advertising market configuration, traditionally monopolized by the foreign market - from the point of view of the pharmaceutical sector - and the competence of the pharmaceutical market, within the context of the international reconfiguration that brought the end of the First War World (AU)

Clinical utility of drug measurement and pharmacokinetics: therapeutic drug monitoring in psychiatry.

Based on the assumption that a relationship between blood levels and clinical effects (therapeutic effects, adverse events and toxicity) can be defined and considering that after equal doses plasma concentrations vary markedly between individual patients, therapeutic drug monitoring (TDM) can assist to personalize dose adjustment. Taken together, drug levels and a knowledge of the pharmacological profile of the administered drugs can enable the optimal dosage to be tailored according to the need of the individual patient. Therapeutic drug monitoring has been established for a limited number of drugs. In psychiatry, it has a 40-year-long history, which started with nortriptyline. Evidence has accumulated which shows that TDM is a valid tool for the optimization of psychopharmacotherapy. When used adequately, TDM is helpful for many patients and in many situations. Combined with pharmacogenetic tests, the metabolic status of a patient can be well characterized. Several new observations have been made during routine TDM that have stimulated clinical pharmacological research, such as investigations on inherited differences in drug metabolism that are closely linked to TDM in psychiatry. The contributions of individual forms of cytochrome P450 (CYP) to the metabolism of drugs was elicited by clinical observations on pharmacokinetic drug interactions. Therapeutic drug monitoring requires a close collaboration between the prescribing physician, the laboratory specialist, the clinical pharmacologist and the patient. This complexity may result in errors which can be detected by analysing the appropriate use of TDM in clinical practice. More education has to be provided to the prescribing clinicians on the pharmacology of the drugs and the algorithm of TDM. Moreover, clinical trials should include measurements of blood concentrations during drug development to generate valid data on the relationships between drug concentrations and clinical outcomes under well-controlled conditions. This would merely increase the amount of work and costs, as high-throughput methods are now available in many laboratories. Any progress in TDM has direct benefits for the treatment of many individual patients.

Therapeutic drug monitoring assay development to improve efficacy and safety.

The development of therapeutic drug management (TDM) utilizing diagnostic assays as biomarker tests is described. TDM can be useful in establishing an individual patient's optimal blood concentration range, and benchmarking blood concentrations at which seizures are controlled, as well as those associated with AED-specific adverse effects. TDM requires the application of pharmacokinetic, pharmacodynamic, pharmacogenomic, pathophysiological and clinical principles to the management of patients in order to achieve safe and effective therapy. Optimal therapy requires rational application of all these principles to personalize patient care.

History of C2 monitoring in heart and liver transplant patients treated with cyclosporine microemulsion.

Therapeutic drug monitoring of CsA has evolved since the introduction of CsA microemulsion. The purpose of the present review is to summarize the history of CsA concentration 2 hours postdose (C2) monitoring in heart and liver transplantation. C2 has been shown to be the best single time point that correlates with the area-under-the-curve, with a correlation coefficient (r2) ranging between .83 and.93. C2 monitoring (300 to 600 ng/mL) has resulted in a significant clinical benefit in long-term heart and liver transplant patients compared to trough level (C0) monitoring. Moreover, a C2 range of 300 to 600 ng/mL resulted in a similar calcineurin inhibition compared to a C2 range of 700 to 1000 ng/mL or a C0 range of 100 to 200 ng/mL while being less injurious to renal function. In de novo liver transplant patients not receiving induction therapy, the achievement of a target C2 of 850 to 1400 ng/mL by postoperative day 3 has resulted in a low acute rejection rate. Furthermore, C2 monitoring has been associated with a lower rejection rate in hepatitis C virus (HCV)-negative patients and with an overall lesser severity of acute rejection compared to C0 monitoring. In de novo heart transplant patients who receive antithymocyte globulin induction, a lower C2 range may be sufficient to prevent rejection and renal dysfunction. Future studies should help to fine-tune the optimal C2 range in heart or liver transplant patients receiving induction therapy and different maintenance immunosuppressive combinations.

The evolution of therapeutic immunosuppression and the potential impact of drug concentration monitoring.

The major goal of immunosuppressive development is improved selectivity of the drug's inhibitory action against T and B cell-mediated as opposed to nonspecific granulocyte-, monocyte-, and macrophage-mediated resistance. This enterprise demands increased knowledge of alloantigen-induced stimulation, signal transduction, and/or maturation pathways of T and B cells. A second approach seeks to harness synergistic combinations of existent albeit not entirely specific agents in order to potentiate immunosuppressive and minimize drug-induced toxicity by using subtherapeutic doses of each agent. The development of synergistic regimens demands not only good estimates of drug effects but also precise measures of drug concentrations because therapeutic effects do not reflect administered doses. Therefore, until immunologic assays are available to assess biologic effects and until drug receptor concentrations can be estimated, there is an increasing need for therapeutic drug monitoring (TDM) to afford reliable surrogates that predict the clinical outcomes of therapeutic regimens. The application of mathematical models such as the median effect analysis provides a quantitative tool for this enterprise. Thus, TDM methodologies seem to present the best available approach to develop secure algorithms for clinical immunosuppression.