RESUMO
ABSTRACT: Vitamin B12 deficiency may present with diverse symptoms, complicating the differential diagnosis. Extrapyramidal movement disorders, for instance, are a rare manifestation of vitamin B12 deficiency. MRI of the brain frequently remains without conclusive findings. However, 18 F-FDG PET/CT may reveal characteristic changes in the metabolism of the basal ganglia and thus contribute to an accurate diagnosis. We demonstrate the case of a woman with left-sided hemichoreatic movements due to vitamin B12 deficiency showing a contralateral putaminal hypermetabolism, which normalized after vitamin B12 supplementation, ruling out other deviating causes, particularly Huntington disease.
Assuntos
Coreia , Doença de Huntington , Deficiência de Vitamina B 12 , Coreia/complicações , Coreia/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Doença de Huntington/complicações , Doença de Huntington/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/diagnósticoRESUMO
BACKGROUND: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%. SUMMARY: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/administração & dosagem , Testes Genéticos/métodos , Neoplasias/tratamento farmacológico , Antimetabólitos Antineoplásicos/efeitos adversos , Áustria , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Consenso , Feminino , Fluoruracila/efeitos adversos , Testes Genéticos/normas , Genótipo , Alemanha , Humanos , Masculino , Mutação , Neoplasias/genética , Fenótipo , Guias de Prática Clínica como Assunto , Suíça , Tegafur/administração & dosagem , Tegafur/efeitos adversosRESUMO
OATP2B1 is an intestinal and hepatic drug uptake transporter. Intestinal OATP2B1 has been elucidated as the mechanism of unexpected clinical drug-drug interactions (DDIs), where drug exposure was unexpectedly decreased with unchanged half-life. Hepatic OATP2B1 may be an understudied clinical DDI mechanism. The aim of the present work was to understand the prevalence of clinically relevant intestinal and hepatic OATP2B1 inhibitors in marketed drug space. HEK293 cells stably overexpressing human OATP2B1 or vector control were generated and cultured for 72 h in a 96-well format. OATP2B1-mediated uptake of dibromofluorescein (DBF) was found to be optimal at 10 µM concentration and 30 min incubation time. A total of 294 drugs (top 300 marketed drugs, excluding biologics and restricted drugs, supplemented with â¼100 small-molecule drugs) were screened for OATP2B1 inhibition at 10 µM. Drugs demonstrating ≥50% inhibition in this screen were advanced for IC50 determination, which was extrapolated to clinical intestinal and hepatic OATP2B1 inhibition as per 2017 FDA DDI guidance. Of the 294 drugs screened, 67 elicited ≥50% inhibition of OATP2B1-mediated DBF uptake at 10 µM screening concentration. For the 67 drugs flagged in the single-concentration inhibition screen, upon evaluation of a full concentration range, IC50 values could be determined for 58 drugs. OATP2B1 IC50 values established for these 58 drugs were extrapolated as potentially clinically relevant at the intestinal level for 38 orally administered drugs (Igut/IC50 ≥ 10), and 17 were flagged as potential clinical inhibitors of hepatic OATP2B1 uptake (1 + Iin,max,u/IC50 ≥ 1.1). This analysis of 294 drugs demonstrated prevalence of clinically relevant intestinal and hepatic OATP2B1 inhibitors to be 13 and 6%, respectively. As OATP2B1-inhibitor drugs are not exceedingly rare, these results suggest that clinical OATP2B1 DDIs have been rarely observed because OATP2B1 is uncommonly the predominant determinant of drug disposition.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transporte Biológico , Sobrevivência Celular/efeitos dos fármacos , Interações Medicamentosas , Cloridrato de Erlotinib/farmacologia , Fluoresceínas/metabolismo , Células HEK293 , Meia-Vida , Humanos , Concentração Inibidora 50 , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , TransfecçãoRESUMO
Thiamine is substrate of the hepatic uptake transporter organic cation transporter 1 (OCT1), and pathological lipid metabolism was associated with OCT1-dependent thiamine transport. However, it is unknown whether clinical pharmacokinetics of thiamine is modulated by OCT1 genotype. We analyzed thiamine transport in vitro, thiamine blood concentrations after high-dose and low-dose (nutritional) intake, and heritability of thiamine and thiamine-phosphate blood concentrations. The variant OCT1*2 had reduced and OCT1*3 to OCT1*6 had deficient thiamine uptake activity. However, pharmacokinetics of thiamine did not differ depending on OCT1 genotype. Further studies in primary human hepatocytes indicated that several cation transporters, including OCT1, OCT3, and THTR-2, contribute to hepatic uptake of thiamine. As much as 54% of the variation in thiamine and 75% in variation of thiamine monophosphate plasma concentrations was determined by heritable factors. Apparently, thiamine is not useful as a probe drug for OCT1 activity, but the high heritability, particularly of thiamine monophosphate, may stimulate further genomic research.
Assuntos
Hepatócitos/metabolismo , Fator 1 de Transcrição de Octâmero/genética , Tiamina/administração & dosagem , Adulto , Transporte Biológico , Relação Dose-Resposta a Droga , Feminino , Genótipo , Células HEK293 , Humanos , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Fator 1 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Tiamina/farmacocinéticaRESUMO
OBJECTIVES: Domatinostat (4SC-202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. METHODS: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1-14 with 7 days off or continuously days 1-21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty-four patients were treated with domatinostat. RESULTS: No formal maximum tolerated dose (MTD) was determined. One dose-limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment-related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. CONCLUSION: Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy.
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Benzamidas/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Feminino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/mortalidade , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Solute carrier membrane transporters (SLCs) control cell exposure to small-molecule drugs, thereby contributing to drug efficacy and failure and/or adverse effects. Moreover, SLCs are genetically linked to various diseases. Hence, in-depth knowledge of SLC function is fundamental for a better understanding of disease pathophysiology and the drug development process. Given that the model organism Drosophila melanogaster (fruit fly) expresses SLCs, such as for the excretion of endogenous and toxic compounds by the hindgut and Malpighian tubules, equivalent to human intestine and kidney, this system appears to be a promising preclinical model to use to study human SLCs. Here, we systematically compare current knowledge of SLCs in Drosophila and humans and describe the Drosophila model as an innovative tool for drug development.
Assuntos
Drosophila melanogaster/metabolismo , Desenvolvimento de Medicamentos/métodos , Proteínas Carreadoras de Solutos/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Modelos Animais , Especificidade da EspécieRESUMO
BACKGROUND/AIM: In this retrospective study, we compared breast cancer patients treated with and without mistletoe lectin I (ML-I) in addition to standard breast cancer treatment in order to determine a possible effect of this complementary treatment. PATIENTS AND METHODS: This study included 18,528 patients with invasive breast cancer. Data on additional ML-I treatments were reported for 164 patients. We developed a "similar case" method with a distance measure retrieved from the beta variable in Cox regression to compare these patients, after stage adjustment, with their non-ML-1 treated counterparts in order to answer three hypotheses concerning overall survival, recurrence free survival and life quality. RESULTS: Raw data analysis of an additional ML-I treatment yielded a worse outcome (p=0.02) for patients with ML treatment, possibly due to a bias inherent in the ML-I-treated patients. Using the "similar case" method (a case-based reasoning approach) we could not confirm this harm for patients using ML-I. Analysis of life quality data did not demonstrate reliable differences between patients treated with ML-I treatment and those without proven ML-I treatment. CONCLUSION: Based on a "similar case" model we did not observe any differences in the overall survival (OS), recurrence-free survival (RFS), and quality of life data between breast cancer patients with standard treatment and those who in addition to standard treatment received ML-I treatment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Proteínas Inativadoras de Ribossomos Tipo 2/uso terapêutico , Toxinas Biológicas/uso terapêutico , Idoso , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Qualidade de Vida , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15-guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15-/- mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15-/- mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15-/- mice also showed excessive accumulation of a thiopurine active metabolite (ie, DNA-incorporated thioguanine nucleotides [DNA-TG]) in an MP dose-dependent fashion, as a plausible cause of increased toxicity. MP dose reduction effectively normalized systemic exposure to DNA-TG in Nudt15-/- mice and largely eliminated Nudt15 deficiency-mediated toxicity. In 95 children with acute lymphoblastic leukemia, MP dose adjustment also directly led to alteration in DNA-TG levels, the effects of which were proportional to the degree of NUDT15 deficiency. Using leukemia-bearing mice with concordant Nudt15 genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in Nudt15-/- mice receiving a reduced MP dose compared with Nudt15+/+ counterparts exposed to a standard dose. In conclusion, we demonstrated that NUDT15 genotype-guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Leucemia/tratamento farmacológico , Mercaptopurina/uso terapêutico , Diester Fosfórico Hidrolases/genética , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/toxicidade , Sistemas CRISPR-Cas , Criança , Cálculos da Dosagem de Medicamento , Avaliação Pré-Clínica de Medicamentos , Deleção de Genes , Edição de Genes , Genótipo , Humanos , Leucemia/genética , Leucemia/patologia , Mercaptopurina/administração & dosagem , Mercaptopurina/toxicidade , Camundongos , Camundongos Knockout , Pirofosfatases/genéticaRESUMO
Although hyperthermia offers clinical appeal to sensitize cells to chemotherapy, this approach has been limited in terms of long-term outcome as well as economic and technical burden. Thus, a more detailed knowledge about how hyperthermia exerts its effects on chemotherapy may illuminate ways to improve the approach. Here, we asked whether hyperthermia alters the response to chemotherapy-induced DNA damage and whether this mechanism is involved in its sensitizing effect in BRCA-competent models of ovarian and colon cancer. Notably, we found that hyperthermia delayed the repair of DNA damage caused by cisplatin or doxorubicin, acting upstream of different repair pathways to block histone polyADP-ribosylation (PARylation), a known effect of chemotherapy. Furthermore, hyperthermia blocked this histone modification as efficiently as pharmacologic inhibitors of PARP (PARPi), producing comparable delay in DNA repair, induction of double-strand breaks (DSB), and cell cytotoxicity after chemotherapy. Mechanistic investigations indicated that inhibiting PARylation by either hyperthermia or PARPi induced lethal DSB upon chemotherapy treatment not only by reducing DNA repair but also by preventing replication fork slowing. Overall, our work reveals how PARP blockade, either by hyperthermia or small-molecule inhibition, can increase chemotherapy-induced damage in BRCA-competent cells. Cancer Res; 76(10); 2868-75. ©2016 AACR.
Assuntos
Cisplatino/farmacologia , Neoplasias do Colo/terapia , Replicação do DNA , Doxorrubicina/farmacologia , Hipertermia Induzida , Neoplasias Ovarianas/terapia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Terapia Combinada , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Feminino , Imunofluorescência , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/terapia , Poli(ADP-Ribose) Polimerase-1/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
The local renin-angiotensin system (RAS) in the brain is a multitasking system controlling a plethora of essential functions such as neurogenic hypertension, baroreflexes, and sympathetic activity. Aside from its vasoactive actions, brain angiotensin II (AT-II) has also been implicated in the pathogenesis of cognitive decline, and beneficial effects of angiotensin receptor blockers (ARBs) in Alzheimer (AD) and Parkinson diseases (PD) are suggested. However, the use of ARBs at antihypertensive dosages would lead to unwanted hypotensive reactions in AD patients. Here we treated the APP/PS1 transgenic mouse model of AD with the ARB losartan (10 mg/kg body weight) to determine whether blockade of the AT-II receptor subtype 1 (AT1-R) with intranasal losartan, using at a dosage far below its systemic antihypertensive dose, could maintain its neuroprotective effects independent of its systemic vasoactive action. Intranasal losartan treatment (10 mg/kg every other day for 2 months) of APP/PS1 mice decreased amyloid beta (Abeta) plaques 3.7-fold. Blood serum levels of interleukin-12 (IL-12)p40/p70, IL-1beta, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were increased in the vehicle-treated APP/PS1 mice. Intranasal losartan not only decreased IL-12p40/p70, IL-1beta, and GM-CSF, but also increased IL-10, which suppresses inflammation. Furthermore, losartan markedly increased tyrosine hydroxylase expression in the striatum and locus coeruleus. In conclusion, losartan exerts direct neuroprotective effects via its Abeta-reducing and antiinflammatory effects in the central nervous system (CNS). Therefore, intranasal losartan and potentially other ARBs, at concentrations below their threshold for altering systemic blood pressure, offer a new approach for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Citoproteção , Modelos Animais de Doenças , Losartan/administração & dosagem , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Administração Intranasal , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Losartan/farmacologia , Camundongos , Neurônios/patologia , Neurônios/fisiologia , Placa Amiloide/efeitos dos fármacos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Presenilina-1/genéticaRESUMO
OBJECTIVES: The Crohn's disease (CD) susceptibility gene, nucleotide-binding oligomerizetion domain 2 (NOD2)/caspase recruitment domain 15 (CARD15), is linked to the innate immune response associated with altered epithelial bacterial defense. Its relevance in antibiotic therapy of perianal fistulating CD remains elusive. The aim of the study was to explore systematically the association between NOD2/CARD15 variants and clinical response of perianal fistulas in patients using antibiotic therapy. METHODS: Fifty-two patients (median age 36 yr) with draining perianal fistulas were treated with ciprofloxacin (N = 49) or metronidazole (N = 3) for a median duration of 7 wk. Complete response was defined as the absence of any draining fistula despite gentle finger compression. Genotyping for NOD2/CARD15 variants and human beta (beta)-defensin 2 (HBD-2) copies was performed by 5' nuclease assays (Applied Biosystems, Foster City, CA). The examiners and laboratory investigators were blinded. The Fisher exact test and Wilcoxon signed rank test were used for statistical analysis. RESULTS: Ciprofloxacin was discontinued in one patient due to diarrhea after 2 wk. Complete fistula response was observed in 13 of 39 patients with NOD2/CARD15 wild-type (33.3%) compared with none in patients carrying NOD2/CARD15 variants (0%, P= 0.02). The median number of HBD-2 gene copies between responders and partial/nonresponders was similar. CONCLUSIONS: The study result suggests a substantial contribution of NOD2/CARD15 to the antibiotic treatment outcome of perianal fistulating CD. NOD2/CARD15 variants may predispose to an altered intestinal microflora in perianal fistulas that is less responsive to antibiotic treatment.
Assuntos
Anti-Infecciosos/uso terapêutico , Ciprofloxacina/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Predisposição Genética para Doença/genética , Genótipo , Metronidazol/uso terapêutico , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único/genética , Fístula Retal/tratamento farmacológico , Fístula Retal/genética , Adulto , Alelos , Anti-Infecciosos/efeitos adversos , Ciprofloxacina/efeitos adversos , Doença de Crohn/diagnóstico , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Metronidazol/efeitos adversos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Falha de Tratamento , beta-Defensinas/genéticaRESUMO
OBJECTIVES: Outcome and survival in anthracycline-based and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer are unpredictable. Insights into treatment prediction are expected from studies searching for an association between genetic polymorphisms and treatment outcome effects. A common feature of treatment with chemoreagents is therapeutically induced DNA damage. Therefore, we tested the hypothesis of a relationship between event-free survival and genotype distributions of seven polymorphic DNA repair enzymes and four cell cycle regulators. BASIC METHODS: This case-case comparison included 180 patients with primary invasive breast cancer diagnosed between 1986 and 2000 and subjected to adjuvant chemotherapy (anthracycline/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil). Ninety-two patients were reported without recurrence and 88 were reported with recurrences or dead. Median clinical follow-up was 61.7 months. Constitutional DNA isolated from archived tissues was genotyped at 19 loci by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Statistical analyses included adjusted risk estimates, Kaplan-Meier analyses, Cox proportional hazard model, and permutation testing. MAIN RESULTS: Carriers of the XRCC1_1196_AA genotype had a reduced risk for recurrence/death (odds ratio adjusted 0.19; 95% confidence interval: 0.06-0.61), which was observed in survival analyses of all patients (P=0.003) and patients treated with chemotherapy but not radiotherapy (P=0.006). Multivariate analysis confirmed XRCC1 as a potential treatment predictor (hazard ratio 0.62; 95% confidence interval: 0.43-0.89). The result was stable upon permutation testing. No other significant associations were observed. CONCLUSION: The DNA repair enzyme XRCC1 is a potential treatment predictor for the outcome and survival of anthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Antraciclinas/uso terapêutico , Neoplasias da Mama/enzimologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Haplótipos , Humanos , Metotrexato/uso terapêutico , Farmacogenética , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
OBJECTIVE: 6-thioguanine (6-TG) has emerged as a promising therapeutic alternative in patients with Crohn's disease intolerant or resistant to azathioprine (AZA) and/or 6-mercaptopurine (6-MP). The aim of the present study was to evaluate the safety and efficacy of 6-TG in patients with ulcerative colitis (UC) or indeterminate colitis (IC) intolerant or resistant to AZA/6-MP. MATERIAL AND METHODS: Twenty patients with an acute flare, steroid-dependent or steroid-refractory disease attending our outpatient department were included in the study. Measurement of 6-TG nucleotide levels was done to check compliance. Complete, partial and non-response were defined by means of the clinical activity index and the daily steroid demand. Secondary outcome parameters included changes in cumulative steroid doses, C-reactive protein (CRP) levels, and an endoscopic score. RESULTS: Out of 20 patients 4 were excluded owing to noncompliance; 2/16 compliant patients (13%) had to be prematurely withdrawn because of adverse events, which ceased upon drug discontinuation. By per-protocol analysis, 5/14 patients (36%) were complete, 6/14 (43%) partial and 3/14 (21%) non-responders. In addition to the reduction of the cumulative steroid dose over 3 months, CRP decreased in the study population and the endoscopic score decreased in treatment responders. CONCLUSIONS: Treatment with 6-TG was effective in patients with UC or IC previously intolerant or resistant to AZA/6-MP. Future work is needed to define a subpopulation of patients at low risk for its potential hepatotoxicity, which we assume will benefit from 6-TG.
Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Tioguanina/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Azatioprina/efeitos adversos , Azatioprina/metabolismo , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Colite Ulcerativa/sangue , Colite Ulcerativa/metabolismo , Relação Dose-Resposta a Droga , Endoscopia Gastrointestinal , Feminino , Genótipo , Nucleotídeos de Guanina/sangue , Humanos , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/metabolismo , Metiltioinosina/sangue , Metiltransferases/genética , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Orosomucoide/metabolismo , Cooperação do Paciente , Estudos Prospectivos , Qualidade de Vida , Tioguanina/administração & dosagem , Tioguanina/efeitos adversos , Tionucleotídeos/sangue , Resultado do TratamentoRESUMO
For targeting local and systemic inflammatory processes in inflammatory bowel disease (IBD) therapeutic agents of first choice (e.g. aminosalicylates, corticosteroids) have been developed in special galenic forms to accomplish the topical delivery of the active compounds to the terminal ileum (Crohn's disease) and/or the colon (Crohn's disease and ulcerative colitis). However, it has to be realized that intestinal physiology (e.g. motility, intraluminal pH profiles), extent and pattern of IBD as well as drug disposition demonstrate large interindividual differences resulting in variable clinical response rates between about 35% and 75%. 5-Aminosalicylate (5-AS) can be delivered to the colon either by azo-prodrugs (e.g. sulfasalazine, olsalazine or balsalazide) or by direct rectal administration of 5-AS in form of enemas, foam or suppositories. Such formulations will be only effective in patients with ulcerative colitis (UC). Various slow/controlled release preparations of 5-AS have been developed for oral use. Some of them (e.g. Pentasa, Salofalk) release sufficient 5-AS already in the small bowel which could provide some additional benefit in Crohn's disease (CD). As urinary and faecal recoveries of total 5-AS are similar for all oral formulations, no major clinical differences can be expected. Extent of the disease, profile of adverse effects and patient's acceptance provide some guidance for selection of the particular agent. Rectal installation of several glucocorticosteroids has been employed for many years. More recently scientific and clinical interest has been focused on budesonide which is extensively presystemically metabolized in the intestinal wall and the liver. Therefore, its systemic availability is low (10-15%) independent whether budesonide is administered orally as controlled release formulation in patients with CD or rectally as enema in patients with UC. Numerous pharmacokinetic and clinical studies have documented the anticipated topical delivery and clinical efficacy of this corticosteroid without serious side effects such as cushingoid features. It can be assumed that for any novel therapeutic principle in IBD the approach of topical delivery will be also tried.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Fármacos Gastrointestinais/administração & dosagem , Doenças Inflamatórias Intestinais/tratamento farmacológico , Administração Tópica , Animais , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/farmacocinética , Humanos , Doenças Inflamatórias Intestinais/metabolismoRESUMO
The chloride channel ClC-Kb is expressed in the basolateral cell membrane of the distal nephron and participates in renal NaCl reabsorption. Loss-of-function mutations of ClC-Kb lead to classic Bartter syndrome, a rare salt-wasting disorder. Recently, we identified the ClC-Kb(T481S) polymorphism, which confers a strong gain-of-function effect on the ClC-Kb chloride channel. The present study has been performed to explore the prevalence of the mutation and its functional significance in renal salt handling and blood pressure regulation. As evident from electrophysiological analysis with the 2-electrode voltage-clamp technique, heterologous expression of ClC-Kb(T481S) in Xenopus oocytes gave rise to a current that was 7-fold larger than the current produced by wild-type ClC-Kb. The prevalence of the mutant allele was significantly higher in an African population from Ghana (22%) than in whites (12%). As tested in 1 white population, carriers of ClC-Kb(T481S) were associated with significantly higher systolic (by approximately 6.0 mm Hg) and diastolic (by approximately 4.2 mm Hg) blood pressures and significantly higher prevalence (45% versus 25%) of hypertensive (> or =140/90 mm Hg) blood pressure levels. Individuals carrying ClC-Kb(T481S) had significantly higher plasma Na+ concentrations and significantly decreased glomerular filtration rate. In conclusion, the mutation ClC-Kb(T481S) of the renal epithelial Cl- channel ClC-Kb strongly activates ClC-Kb chloride channel function in vitro and may predispose to the development of essential hypertension in vivo.