Immunosuppressive Pharmacotherapy Research Articles

Influence of Bronchopulmonary Diseases on the Course and Outcome of COVID-19: a Literature Review

The SARS-CoV‑2 coronavirus has become a major global health concern. Infection with SARS-CoV‑2 has caused millions of deaths worldwide, and the case fatality rate has been found to be largely related to pre-existing clinical conditions. The main clinical manifestation of COVID‑19 is the presence of respiratory symptoms. Severe complications of COVID‑19 are most often observed in people with significant medical histories. The SARS-CoV‑2 virus primarily attacks the respiratory system, causing pneumonia and acute respiratory distress syndrome, which can lead to severe systemic inflammation, multiple organ dysfunction, and death, especially in patients with pre-existing comorbidities. A number of meta-analyses strongly suggest that comorbid respiratory diseases, including chronic obstructive pulmonary disease and interstitial lung diseases, are factors in the development of severe forms of COVID‑19, worsening patient outcomes and survival rates. Studies have shown an association between adverse outcomes of COVID‑19 and the expression level of the angiotensin-­converting enzyme 2 (ACE2) in these patients. Regarding other respiratory system pathologies, such as bronchial asthma and cystic fibrosis, it is known that the main unfavorable factor is long-term immunosuppressive pharmacotherapy preceding infection. In this article, we highlight the main respiratory comorbidities to better understand the pathogenesis of COVID‑19.

Evaluation of the Pharmacotherapy Complexity Index in Patients of a Renal Transplant Clinic

Abstract:Objective: To evaluate the complexity of pharmacotherapy of kidney transplant patients in an outpatient clinic in the Brazilian Central-West region. Methods: This is a study that respects a descriptive cross-sectional design to evaluate the complexity index of pharmacological treatment through the documentary analysis of medical records. To calculate this index, the patient’s continuous use medications were considered, and the Pharmacotherapy Complexity Index (PCI) was adopted. To determine the PCI classification ranges, analysis of a larger group of patients (significant sample) was performed, and the quartiles of the PCI results were adopted. A pilot sample was used to describe the influence of drugs on PCI. Results: A total of 247 patients were included in the study to define the strata of treatment complexity. The PCI in the sample ranged from 10 to 83.5, and, by quartile analysis, up to 22.5 was considered low complexity, between 22.6 and 27.0 medium complexity, between 27.1 and 36.0 high complexity, and above 36.1 very high complexity. The case study for the PCI evaluation occurred with 20 patients and demonstrated that the complexity is not defined by the immunosuppressive treatment, but by the drugs used for the underlying diseases or the health problems arising from age and immunosuppression (comorbidities). Diabetes mellitus appears as the disease that contributes the most to complexity through the use of insulins. Conclusion: Patients with a higher number of drug doses and with conditions dependent on insulin therapy associated with immunosuppressive pharmacotherapy are the most complex and demand greater need for follow-up because of the difficulties faced in treatment.

Risk Factors, Treatment and Prognosis of Patients with Lung Cancer after Heart Transplantation.

Long-term survival after heart transplantation (HTX) is impacted by adverse effects of immunosuppressive pharmacotherapy, and post-transplant lung cancer is a common occurrence. This study aimed to examine the risk factors, treatment, and prognosis of patients with post-transplant lung cancer. We included 625 adult patients who received HTX at Heidelberg Heart Center between 1989 and 2018. Patients were stratified by diagnosis and staging of lung cancer after HTX. Analysis comprised donor and recipient characteristics, medications including immunosuppressive drugs, and survival after diagnosis of lung cancer. A total of 41 patients (6.6%) were diagnosed with lung cancer after HTX, 13 patients received curative care and 28 patients had palliative care. Mean time from HTX until diagnosis of lung cancer was 8.6 ± 4.0 years and 1.8 ± 2.7 years from diagnosis of lung cancer until last follow-up. Twenty-four patients (58.5%) were switched to an mTOR-inhibitor after diagnosis of lung cancer. Multivariate analysis showed recipient age (HR: 1.05; CI: 1.01–1.10; p = 0.02), COPD (HR: 3.72; CI: 1.88–7.37; p < 0.01), and history of smoking (HR: 20.39; CI: 2.73–152.13; p < 0.01) as risk factors for post-transplant lung cancer. Patients in stages I and II had a significantly better 1-year (100.0% versus 3.6%), 2-year (69.2% versus 0.0%), and 5-year survival (53.8% versus 0.0%) than patients in stages III and IV (p < 0.01). Given the poor prognosis of late-stage post-transplant lung cancer, routine reassessment of current smoking status, providing smoking cessation support, and intensified lung cancer screening in high-risk HTX recipients are advisable.

Myocardial Infarction and Three-Vessel Coronary Artery Disease as Presenting Features of Granulomatosis with Polyangiitis: A Case Report with Review of Literature

Granulomatosis with Polyangiitis (GPA) is a systemic, autoimmune disorder characterized by inflammatory insult and granulomatous processes in small and medium-sized vessels leading to various clinical presentations from underlying vasculitis. Underlying such inflammatory cascade is the overactivity of Antineutrophil Cytoplasmic Antibodies (c-ANCA) targeting serum Proteinase 3 (PR3), whose aberrant targeting classically modulates molecular signaling pathways leading to clinical manifestations of the Ear, Nose and Throat (ENT), in addition to renal impairment. Peripheral vessel involvement (i.e. limb vasculature) is not generally associated with GPA. With the exception of seldom reports in the literature, it is rare for GPA to present with coronary artery involvement. Moreover, reports of multi-vessel disease (e.g. triple-vessel disease) with GPA warranting Coronary Artery Bypass Graft (CABG) are lacking in such accounts. The latter with preceding iliac artery claudication makes such a presentation of GPA exceptionally novel and warrants contextual commentary regarding inflammation and Coronary Artery Disease (CAD). We report the case of a 55-year-old Caucasian male presenting with a 2 years history of right-sided groin cramping and an acute one-week history of claudication in the same area. After advised to follow up as an outpatient, this patient returned shortly thereafter to an acute care setting with hemoptysis and myocardial infarction worked up for GPA and triple-vessel disease. The patient was subsequently treated with immunosuppressive pharmacotherapy prior to CABG. We conducted a review of the literature underpinned in clinical and translational biology with a focus on the salient inflammatory pathways featured in both coronary artery disease and GPA.

Bilateral Pulmonary Cavitation as Predominant Phenotype in ANCA-Associated Disease

A 48-year-old female ex-smoker (30 pack years) with a history of lymphocytic colitis presented to a rheumatologist due to bilateral ankle pain and finger stiffness. Based on clinical and laboratory findings, rheumatoid arthritis was diagnosed. The patient reported no respiratory symptoms and no weight loss, night sweats, or febrile episodes. However, prior to intended immunosuppressive pharmacotherapy, thoracic imaging was performed. This surprisingly revealed large cavities in both lungs (Figure). Thereupon, the patient was referred to our Department of Pulmonary Medicine.

ANÁLISE DA SEGURANÇA DO USO DE IMUNOSSUPRESSORES POR PACIENTES INSUFICIENTES RENAIS

A insuficiência renal aguda (IRA) e a insuficiência renal crônica (IRC) consistem em patologias com incidência crescente ao longo dos últimos anos no Brasil. Segundo a Sociedade Brasileira de Nefrologia (2018), o número de pacientes com estas comorbidades tem aumentado cerca de 200% em 16 anos, tendo como alternativa de tratamento o transplante do órgão. Uma das principais terapias pós-transplante renal consiste no uso de imunossupressores, com o objetivo de conter a rejeição do enxerto. Em contrapartida, a segurança desta farmacoterapia ainda é bastante discutida, pela alta probabilidade de ocorrência de reações adversas. Esse estudo objetivou apresentar e analisar dados numéricos referentes à ocorrência de Reação Adversa a Medicamentos (RAM) relacionados a imunossupressores utilizados como farmacoterapia por pacientes com IRA ou IRC, internados em um Hospital Universitário do Município de Curitiba. PR. Trata-se de um estudo retrospectivo observacional, baseado na análise de prontuários físicos e eletrônicos de pacientes insuficientes renais agudos ou crônicos, por meio de busca ativa em tabelas de dispensação de imunossupressores. Este trabalho incluiu prontuários de 162 pacientes, sendo que 118 destes apresentaram uma ou mais possíveis reações adversas de imunossupressores. A RAM de maior prevalência no estudo foi “infecção oportunista” e a de menor prevalência “hipoalbuminemia”. Para maior confiabilidade dos resultados foi aplicado Algoritmo de Naranjo, onde “infecção” permaneceu relevante em 26% dos seus casos classificada pelo algoritmo como “provável”. Diante dos resultados expostos, observa-se a importância do farmacêutico clínico na otimização da farmacoterapia imunossupressora utilizada por pacientes insuficientes renais do hospital em questão.

Clinical correlates of nocardiosis

Nocardia is an opportunistic pathogen that most frequently affects the lungs. Evidence is limited regarding the risk factors for nocardiosis. The current study assessed clinical correlates of nocardiosis. A retrospective study was conducted based on medical records of consecutive adult patients (N = 60) with nocardiosis hospitalized during 2007–2018 at a tertiary hospital in central Israel. A matched comparison group of 120 patients was randomly selected among hospitalized patients with community-acquired pneumonia. Multivariable conditional logistic regression models were fitted. Immunosuppressive pharmacotherapy was positively associated with nocardiosis (matched odds ratio [OR] 4.40, 95% confidence interval [CI] 2.25–8.62, p < 0.001), particularly corticosteroid therapy (matched OR 4.69, 95% CI 2.45–8.99, p < 0.001). Systemic corticosteroid therapy was strongly associated with pulmonary nocardiosis (matched OR 5.90, 95% CI 2.75–12.66, p < 0.001). The positive association between solid organ transplantation and nocardiosis was attenuated following adjustment for systemic corticosteroids in a multivariable model. The association between corticosteroid therapy and nocardiosis appeared stronger in patients with chronic pulmonary disease (OR 5.74, 95% CI 2.75–12.66, p < 0.001) than in the pooled analysis of all nocardiosis cases. In conclusion, corticosteroid therapy was strongly correlated with nocardiosis, particularly among individuals with chronic pulmonary disease and in pulmonary nocardiosis.

Percepção dos pacientes transplantados renais sobre a farmacoterapia imunossupressora: perspectivas e dificuldades

Objetivo: Descrever a percepção dos pacientes transplantados renais sobre a farmacoterapia imunossupressora e quais suas principais dificuldades inseridas em seu contexto diário. Métodos: Trata-se de um estudo qualitativo, descritivo e exploratório. A entrevista ocorreu com auxílio de um questionário semiestruturado. Os dados foram submetidos a análise lexical no Software Iramuteq e analisados por meio da Classificação Hierárquica Descendente (CHD), Análise Fatorial por Correspondência (AFC), e por fim, foi gerada a Nuvem de palavras. Resultados: Foram entrevistados 21 pacientes, com idade entre 19 e 76 anos. O corpus textual foi separado em 448 segmentos de texto (ST), com aproveitamento de 360 ST (80,36%). Os dados inicialmente emergiram em quatro classes e subdividias em duas ramificações do corpus total da análise: Classe 1 (30,8%), Classe 2 (24,4%), Classe 3 (23,1%) e Classe 4 (21,7%). A AFC reproduziu as classes no plano cartesiano, onde as classes 2 e 3 difundem-se nos quadrantes superiores, enquanto as classes 1 e 4 representadas em quadrantes opostos. As evocações com maior frequência (“Tomar”, “Hora”, “Medicação”) foram consideradas e organizadas na nuvem de palavras. Conclusão: Conclui-se que os pacientes transplantados renais enfrentam dificuldades no regime imunossupressor e são susceptíveis a potenciais efeitos adversos.

Systemic Lupus Erythematosus–associated Diffuse Alveolar Hemorrhage: A Case Report and Review of the Literature

Systemic lupus erythematosus is associated with numerous pleuropulmonary complications. Although uncommon, diffuse alveolar hemorrhage represents a life-threatening cause of acute respiratory failure among patients with lupus. Here, we present a 24-year-old woman with a history of lupus who developed hemoptysis and respiratory failure associated with diffuse radiographic infiltrates and anemia. Bronchoscopy confirmed diffuse alveolar hemorrhage. She was managed with supportive care, plasmapheresis, and immunosuppressive pharmacotherapy leading to sustained resolution of her pulmonary hemorrhage and respiratory failure. We then review the available literature on the pathophysiology and management of lupus-associated diffuse alveolar hemorrhage, which centers on supportive care, reversal of coagulopathy, and immunosuppressive measures.

Epstein-Barr Virus+ Smooth Muscle Tumors as Manifestation of Primary Immunodeficiency Disorders.

Epstein–Barr virus positive (EBV+) smooth muscle tumors (SMTs) constitute a very rare oncological entity. They usually develop in the context of secondary immunodeficiency caused by human immunodeficiency virus infection or immunosuppressive treatment after solid organ transplantation. However, in a small fraction of predominantly pediatric patients, EBV+ SMTs may occur in patients with primary immunodeficiency disorders (PIDs), such as GATA2 and CARMIL2 deficiency. In secondary immunodeficiencies and when the underlying condition can not be cured, the treatment of EBV+ SMTs is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. Importantly, without definitive reconstitution of cellular immunity, long-term survival is poor. This is particularly relevant for patients with EBV+ SMTs on the basis of PIDs. Recently, allogeneic hematopoietic stem cell transplantation resulted in cure of immunodeficiency and EBV+ SMTs in a GATA2-deficient patient. We propose that in the absence of secondary immunodeficiency disorders patients presenting with EBV+ SMTs should be thoroughly evaluated for PIDs. Allogeneic hematopoietic stem cell transplantation should be taken into consideration, ideally in the setting of a prospective clinical trial.

Immunosuppressive pharmacotherapy in liver transplantation

The discovery of effective immunosuppressive medications, namely cyclosporine in the early 80’s, was the seminal event that dramatically improved patient and graft survival after liver transplantation and solidified its status as the treatment of choice for end-stage liver disease (ESLD). Over the ensuing 30 years, the immunosuppressive armamentarium has expanded dramatically leading to a significant decrease in acute cellular rejection (ACR), and hence improvements in graft and patient survival. Unfortunately, long-term exposure to immunosuppressive medications and their cumulative adverse effects, including renal dysfunction, metabolic syndrome, and malignancy, contribute to morbidity and mortality in the long-term transplant recipients leading to late graft loss. Therefore, judicious use of immunosuppressive medications, with utmost attention to their unique adverse event profiles, pharmacokinetics, and pharmacodynamics are essential in designing individualized regimens best suited for each transplant recipient. In this article, major classes of immunosuppressive medications used for induction and maintenance therapy in liver transplantation are reviewed, including their pharmacology, pharmacokinetics, drug interactions and common adverse drug reactions. The evidence for their preferential use is presented where available.

Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes

Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers. We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs. Patients with PIDs who have received VST therapy on previous or current protocols were reviewed in aggregate. Clinical information, including transplantation details, viral infections, and use of antiviral and immunosuppressive pharmacotherapy, were evaluated. Data regarding VST production, infusions, and adverse reactions were compared. Thirty-six patients with 12 classes of PID diagnoses received 37 VST products before or after HSCT. Twenty-six (72%) patients had received a diagnosis of infection with cytomegalovirus, EBV, adenovirus, BK virus, and/or human herpesvirus 6. Two patients were treated before HSCT because of EBV-associated lymphoproliferative disease. Partial or complete responses against targeted viruses occurred in 81% of patients overall. Time to response varied from 2weeks to 3months (median, 28days). Overall survival at 6months after therapy was 80%. Four patients had graft-versus-host disease in the 45days after VST infusion, which in most cases was therapy responsive. VSTs derived from either stem cell donors or third-party donors are likely safe and effective for the treatment of viral infections in patients with PIDs.

Treatment-emergent adverse events after infusion of adherent stem cells: the MiSOT-I score for solid organ transplantation

BackgroundCellular therapy after organ transplantation is emerging as an intriguing strategy to achieve dose reduction of classical immunosuppressive pharmacotherapy. Here, we introduce a new scoring system to assess treatment-emergent adverse events (TEAEs) of adherent stem cell therapies in the clinical setting of allogeneic liver transplantation (for example, the MiSOT-I trial Eudract CT: 2009-017795-25).MethodsThe score consists of three independent modalities (set of parameters) that focus on clinically relevant events early after intravenous or intraportal stem cell infusion: pulmonary toxicity, intraportal-infusional toxicity and systemic toxicity. For each modality, values between 0 (no TEAE) and 3 (severe TEAE) were defined. The score was validated retrospectively on a cohort of n=187 recipients of liver allografts not receiving investigational cell therapy between July 2004 and December 2010. These patients represent a control population for further trials. Score values were calculated for days 1, 4, and 10 after liver transplantation.ResultsGrade 3 events were most commonly related to the pulmonary system (3.5% of study cohort on day 4). Almost no systemic-related TEAEs were observed during the study period. The relative frequency of grade 3 events never exceeded 5% over all modalities and time points. A subgroup analysis for grade 3 patients provided no descriptors associated with severe TEAEs.ConclusionThe MiSOT-I score provides an assessment tool to score specific adverse events that may occur after adherent stem cell therapy in the clinical setting of organ transplantation and is thus a helpful tool to conduct a safety study.

Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I)

BackgroundLiver transplantation is the definitive treatment for many end-stage liver diseases. However, the life-long immunosuppression needed to prevent graft rejection causes clinically significant side effects. Cellular immunomodulatory therapies may allow the dose of immunosuppressive drugs to be reduced. In the current protocol, we propose to complement immunosuppressive pharmacotherapy with third-party multipotent adult progenitor cells (MAPCs), a culture-selected population of adult adherent stem cells derived from bone marrow that has been shown to display potent immunomodulatory and regenerative properties. In animal models, MAPCs reduce the need for pharmacological immunosuppression after experimental solid organ transplantation and regenerate damaged organs.MethodsPatients enrolled in this phase I, single-arm, single-center safety and feasibility study (n = 3-24) will receive 2 doses of third-party MAPCs after liver transplantation, on days 1 and 3, in addition to a calcineurin-inhibitor-free "bottom-up" immunosuppressive regimen with basiliximab, mycophenolic acid, and steroids. The study objective is to evaluate the safety and clinical feasibility of MAPC administration in this patient cohort. The primary endpoint of the study is safety, assessed by standardized dose-limiting toxicity events. One secondary endpoint is the time until first biopsy-proven acute rejection, in order to collect first evidence of efficacy. Dose escalation (150, 300, 450, and 600 million MAPCs) will be done according to a 3 + 3 classical escalation design (4 groups of 3-6 patients each).DiscussionIf MAPCs are safe for patients undergoing liver transplantation in this study, a phase II/III trial will be conducted to assess their clinical efficacy.

Obstructive sleep apnea in a patient with the Melkersson–Rosenthal syndrome

Melkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown etiology. It is characterized by the triad of macrocheilitis, peripheral facial palsy, and lingua plicata. A 48-year-old nonobese man with a diagnosis of MRS and marked macroglossia was evaluated because of clinically suspected obstructive sleep apnea (OSA). Established causes of OSA such as anatomic abnormalities of the upper airways or the facial skeleton were not present in this patient. Furthermore, hypothyroidism and acromegaly were excluded as underlying diseases. Polysomnography revealed moderate-to-severe OSA. As the swelling of the tongue had been unresponsive to immunosuppressive pharmacotherapy and surgery did not seem to be a reasonable therapeutic option, the patient was finally treated by continuous positive airway pressure therapy. To the best of our knowledge, this is the first report of OSA occurring in a patient with MRS.

Does Immunosuppressive Pharmacotherapy Affect Isoagglutinin Titers?

Objective Preoperative reduction of isoagglutinins leads to successful ABO-incompatible (ABOi) renal transplantation. The strategy includes pretransplantation plasmapheresis, more potent immunosuppressive drugs, splenectomy, and anti-CD20 antibody. It has been reported that low isoagglutinin antibody titers posttransplant were observed among ABOi renal transplants with favorable outcome. The isoagglutinin titers may increase slightly when plasmapheresis is discontinued; however, it never returns to the pretreatment level under immunosuppressive therapy. This raises the question of what occurs to the isoagglutinin titer in ABO-compatible renal transplants under maintenance immunosuppressive pharmacotherapy. Methods We analyzed 10 renal transplant recipients, including seven living and three cadaveric donors. Patients were treated with basiliximab (20 mg) intravenously on day 0 and day 4. Maintenance immunosuppressive therapy involved a calcineurin inhibitor, mycophenolate mofetil, and steroid. Anti-human globulin isoagglutinin titers were routinely examined 1 day before and day 0 and 1, 2, 3, 4, 8, 12, and 24 weeks posttransplant. No ALG or intravenous immunoglobulin or plasmapheresis treatment was provided in the follow-up period. Results Our preliminary data showed nearly no influence on isoagglutinin titer levels in 6-month follow-up under maintenance immunosuppressive therapy. In addition, no significant difference in isoagglutinin titer was observed between tacrolimus and cyclosporine groups. Conclusion Maintenance immunosuppressive pharmacotherapy did not affect isoagglutinin titer levels in ABO-compatible kidney transplants. Further study is needed to investigate the mechanisms of persistent low-level isoagglutinin titers among successful ABOi renal transplantation patients.

IMP dehydrogenase basal activity in MOLT‐4 human leukaemia cells is altered by mycophenolic acid and 6‐thioguanosine

Objective. Depletion of guanine and deoxyguanine nucleotides by inhibition of inosine 5'‐monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) or introduction of 6‐thioguanine nucleotide antimetabolites are two principles of retarding cell proliferation by interference with the cellular purine nucleotide pool. IMPDH activity may be a promising pharmacodynamic biomarker during immunosuppressive and anticancer pharmacotherapy. The aim of the study was to investigate the impact of mycophenolic acid (MPA) and 6‐thioguanosine (tGuO) on IMPDH basal activity. Material and methods. We studied the IMPDH basal activity (i.e. the enzyme activity following inhibitor exposure, but measured in absence of the inhibitor) in response to increasing concentrations of the IMPDH inhibitor MPA and the antimetabolite tGuO in MOLT‐4 human leukaemia cells. In parallel, IMPDH gene expression and cellular purine nucleotide concentrations were examined. Results. A biphasic concentration‐dependent influence of MPA on the IMPDH basal activity was observed. At concentrations⩽IC50, MPA increased the IMPDH basal activity. The increase was associated with elevated expression of IMPDH2. Despite increased expression, the basal enzyme activity decreased following exposure to high MPA concentrations. The IMPDH2 expression increased modestly in response to tGuO exposure. However, the IMPDH basal activity decreased when the cells were exposed to a proliferation‐blocking tGuO concentration. Conclusions. These findings demonstrate that IMPDH basal activity is influenced by MPA and tGuO, and suggest that reduced IMPDH basal activity is related to the proliferation‐blocking effects of these agents.

Pharmacokinetics of immunosuppressants: a perspective on ethnic differences.

Despite recent advancements in solid organ transplantation, African-American renal allograft recipients continue to exhibit poorer prognosis in long-term clinical outcome and graft survival compared to Caucasian patients. The role of immunosuppressants in post-transplant outcome is crucial, and associations between exposure-related pharmacokinetic parameters and clinical outcome have been made for several drugs in this class. Thus, ethnic differences in the pharmacokinetics of immunosuppressants are potentially a key factor in the observed differences in post-transplant outcome between African-Americans and Caucasians. Ethnic differences in pharmacokinetics of mycophenolate mofetil and azathioprine based on the current literature are either absent or only of minor relevance. Cyclosporine, tacrolimus, sirolimus and everolimus, however, have all been described to exhibit ethnicity-specific differences in bioavailability and/or dose-adjusted systemic exposure, although currently available reports are controversial for some of these drugs. Oral bioavailability of these drugs in African-Americans was between 20 and 50% lower than in Caucasians or Non-African-Americans, leading to higher dose requirements in African-Americans to maintain similar average concentrations of the respective immunosuppressant. Since all four drugs undergo extensive metabolism and are substrates for CYP3A isoenzymes as well as the drug transporter P-glycoprotein, interethnic variability in activity of these enzymes/transporter may provide a common mechanism for the observed ethnic differences. These ethnic differences are most likely mediated via several non-genetic as well as genetic factors, including known genetic variations that impair transporter/enzyme activity in genes such as CYP3A4, CYP3A5 and ABCB1 (MDR1). Appreciation of differences in immunosuppressant pharmacokinetics and dose requirements between African-Americans and Caucasians in clinical practice is expected to improve post-transplant immunosuppressive pharmacotherapy and may thus contribute to equalize prognostic outcome for all transplant patients.

Temporal Evolution of Rasmussen's Encephalitis.

The Natural History of Rasmussen's Encephalitis Bien CG, Widman G, Urbach H, Sassen R, Kuczaty S, Wiestler OD, Schramm S, Elger CE Brain 2002;125:1751–1759 Rasmussen's encephalitis (RE) is a chronic inflammatory disease of unknown origin, usually affecting one brain hemisphere. In the present study, a comprehensive assessment of the natural history of the disorder is presented. Seizure frequency, degree of hemiparesis, and degree of cerebral hemiatrophy in 13 patients with histopathologically proven RE were analyzed over the time course before resective epilepsy surgery or introduction of long-term immunosuppressive pharmacotherapy. For the assessment of the degree of cerebral hemiatrophy, on defined slices comprising the sylvian fissure of hard copies of serial magnetic resonance imaging (MRI) investigations, the hemispheric ratio (HR) was determined. The data show an initial prodromal phase with an intermediate frequency of focal onset seizures and mostly no hemiparesis. The occurrence of this stage was observed mainly in adolescent and adult patients. All patients went through an acute phase with a median duration of 8 months. During this stage, there were frequent simple partial motor seizures, development of hemiparesis, and volume loss of the affected hemisphere. After this, the patients passed into a residual stage with a marked decrease in seizure frequency. Twelve months after the onset of the acute stage, the average HR was 0.72. These data allow an estimation of the prognosis of newly affected patients and demonstrate that most of the brain damage in RE occurs during the first 8 to 12 months. These findings should be taken into consideration when future therapeutic approaches to RE are evaluated.

The natural history of Rasmussen's encephalitis.

Rasmussen's encephalitis (RE) is a chronic inflammatory disease of unknown origin, usually affecting one brain hemisphere. In the present study, a comprehensive assessment of the natural history of the disorder is presented. Seizure frequency, degree of hemiparesis and degree of cerebral hemiatrophy in 13 patients with histopathologically proven RE are analysed over the time course prior to resective epilepsy surgery or introduction of long-term immunosuppressive pharmacotherapy. For the assessment of the degree of cerebral hemiatrophy, on defined slices comprising the Sylvian fissure of hard copies of serial MRI investigations, the hemispheric ratio (HR) was determined. The data show an initial prodromal phase with an intermediate frequency of focal onset seizures and mostly no hemiparesis. The occurrence of this stage was mainly observed in the adolescent and adult patients. All patients went through an acute phase with a median duration of 8 months. During this stage, there were frequent simple partial motor seizures, development of hemiparesis and volume loss of the affected hemisphere. After this, the patients passed into a residual stage with a marked decrease in seizure frequency. Twelve months after the onset of the acute stage, the average HR was 0.72. These data allow an estimation of the prognosis of newly affected patients, and demonstrate that most of the brain damage in RE occurs during the first 8-12 months. These findings should be taken into consideration when future therapeutic approaches to RE are evaluated.