RESUMO
In the era of precision medicine, there is increasing evidence that conventional cytotoxic agents may be suitable candidates for therapeutic drug monitoring (TDM)- guided drug dosage adjustments and patient's tailored personalization of non-selective chemotherapies. To that end, many liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assays have been developed for the quantification of conventional cytotoxic anticancer chemotherapies, that have been comprehensively and critically reviewed. The use of stable isotopically labelled internal standards (IS) of cytotoxic drugs was strikingly uncommon, accounting for only 48 % of the methods found, although their use could possible to suitably circumvent patients' samples matrix effects variability. Furthermore, this approach would increase the reliability of cytotoxic drug quantification in highly multi-mediated cancer patients with complex fluctuating pathophysiological and clinical conditions. LC-MS/MS assays can accommodate multiplexed analyses of cytotoxic drugs with optimal selectivity and specificity as well as short analytical times and, when using stable-isotopically labelled IS for quantification, provide concentrations measurements with a high degree of certainty. However, there are still organisational, pharmacological, and medical constraints to tackle before TDM of cytotoxic drugs can be more largely adopted in the clinics for contributing to our ever-lasting quest to improve cancer treatment outcomes.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos/métodos , Reprodutibilidade dos Testes , Espectrometria de Massa com Cromatografia Líquida , Neoplasias/tratamento farmacológico , Cromatografia Líquida de Alta PressãoRESUMO
BACKGROUND: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. DESIGN: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. RESULTS: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. CONCLUSION: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.
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Oncologia/tendências , Neoplasias/epidemiologia , Neoplasias/terapia , Caracteres Sexuais , Composição Corporal , Tomada de Decisões , Feminino , Humanos , Masculino , Neoplasias/genética , Neoplasias/patologia , Médicos , Resultado do TratamentoRESUMO
AIMS: Calcium sulphate (CaSO4) is a resorbable material that can be used simultaneously as filler of a dead space and as a carrier for the local application of antibiotics. Our aim was to describe the systemic exposure and the wound fluid concentrations of vancomycin in patients treated with vancomycin-loaded CaSO4 as an adjunct to the routine therapy of bone and joint infections. PATIENTS AND METHODS: A total of 680 post-operative blood and 233 wound fluid samples were available for analysis from 94 implantations performed in 87 patients for various infective indications. Up to 6 g of vancomycin were used. Non-compartmental pharmacokinetic analysis was performed on the data from 37 patients treated for an infection of the hip. RESULTS: The overall systemic exposure remained within a safe range, even in patients with post-operative renal failure, none requiring removal of the pellets. Local concentrations were approximately ten times higher than with polymethylmethacrylate (PMMA) as a carrier, but remained below reported cell toxicity thresholds. Decreasing concentrations in wound fluid were observed over several weeks, but remained above the common minimum inhibitory concentrations for Staphylococcus up to three months post-operatively. CONCLUSION: This study provides the first pharmacokinetic description of the local application of vancomycin with CaSO4 as a carrier, documenting slow release, systemic safety and a release profile far more interesting than from PMMA. In particular, considering in vitro data, concentrations of vancomycin active against staphylococcal biofilm were seen for several weeks. Cite this article: Bone Joint J 2017;99-B:1537-44.
Assuntos
Antibacterianos/farmacocinética , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Osteomielite/tratamento farmacológico , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Vancomicina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/metabolismo , Antibacterianos/uso terapêutico , Sulfato de Cálcio , Portadores de Fármacos , Feminino , Infecções por Bactérias Gram-Negativas/metabolismo , Infecções por Bactérias Gram-Positivas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Ortopédicos/instrumentação , Osteomielite/metabolismo , Estudos Prospectivos , Infecções Relacionadas à Prótese/metabolismo , Infecções dos Tecidos Moles/metabolismo , Vancomicina/metabolismo , Vancomicina/uso terapêuticoRESUMO
PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.
Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Monitoramento de Medicamentos/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Medicina de Precisão/métodos , Estudos Prospectivos , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
Main pharmacovigilance updates in 2011 are reviewed. Dronedarone: Serious cardio-vascular and hepatic adverse reactions for a questionable efficacy. Long-term proton pump inhibitors: A cause of hypomagnesemia. Bisphosphonates: A risk of atypical femoral fractures. Dasatinib: Cases of pulmonary arterial hypertension reported. Lenalidomide: A risk of second primary malignancies. Daptomycine: Cases of eosinophilic pneumonia reported. Tigecycline: Inferior to comparators. Drotrecogin alfa: Market withdrawal due to lack of efficacy. Nimesulide: More hepatotoxic than other NSAIDs. Topiramate: Evidence of teratogenicity (oral clefts). Valproate: Impaired cognitive development in addition to well-known teratogenicity. Antipsychotics in late pregnancy: A risk of neonatal complications.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Farmacovigilância , Feminino , Hospitais Universitários , Humanos , SuíçaRESUMO
There is increasing evidence that the clinical efficacy of tamoxifen, the first and most widely used targeted therapy for estrogen-sensitive breast cancer, depends on the formation of the active metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Large inter-individual variability in endoxifen plasma concentrations has been observed and related both to genetic and environmental (i.e. drug-induced) factors altering CYP450s metabolizing enzymes activity. In this context, we have developed an ultra performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) requiring 100 µL of plasma for the quantification of tamoxifen and three of its major metabolites in breast cancer patients. Plasma is purified by a combination of protein precipitation, evaporation at room temperature under nitrogen, and reconstitution in methanol/20 mM ammonium formate 1:1 (v/v), adjusted to pH 2.9 with formic acid. Reverse-phase chromatographic separation of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen is performed within 13 min using elution with a gradient of 10 mM ammonium formate and acetonitrile, both containing 0.1% formic acid. Analytes quantification, using matrix-matched calibration samples spiked with their respective deuterated internal standards, is performed by electrospray ionization-triple quadrupole mass spectrometry using selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of relative matrix effects variability, as well as tamoxifen and metabolites short-term stability in plasma and whole blood. The method is precise (inter-day CV%: 2.5-7.8%), accurate (-1.4 to +5.8%) and sensitive (lower limits of quantification comprised between 0.4 and 2.0 ng/mL). Application of this method to patients' samples has made possible the identification of two further metabolites, 4'-hydroxy-tamoxifen and 4'-hydroxy-N-desmethyl-tamoxifen, described for the first time in breast cancer patients. This UPLC-MS/MS assay is currently applied for monitoring plasma levels of tamoxifen and its metabolites in breast cancer patients within the frame of a clinical trial aiming to assess the impact of dose increase on tamoxifen and endoxifen exposure.
Assuntos
Antineoplásicos Hormonais/sangue , Neoplasias da Mama/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Tamoxifeno/análogos & derivados , Tamoxifeno/sangue , Espectrometria de Massas em Tandem/métodos , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Calibragem , Estabilidade de Medicamentos , Feminino , Humanos , Hidroxilação , Modelos Logísticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tamoxifeno/uso terapêuticoRESUMO
High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.
Assuntos
Cefalosporinas/uso terapêutico , Neutropenia/tratamento farmacológico , Adulto , Idoso , Cefepima , Cefalosporinas/efeitos adversos , Cefalosporinas/sangue , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Alucinações/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Nervoso/efeitos dos fármacos , Neutropenia/sangue , Estudos RetrospectivosRESUMO
Main pharmacovigilance signals and alerts issued in 2009 are reviewed. Efalizumab was withdrawn from the market due to increased risks, including progressive multifocal leukoencephalopathy (PML) and questionable efficacy. New cases of PML are still being reported with rituximab and natalizumab. Rare cases of pure red cell aplasia have been observed with mycophenate. Gastrointestinal perforation, severe skin rashes and various ocular disorders have been reported during erlotinib use. Severe skin rashes have been related to etravirine. Acute renal failure and pancreatitis can occur with exenatide. A link between sitagliptin and pancreatitis is suspected. Raised concerns of causality between insuline glargine and malignant tumors are not supported by strong evidence. Proton pump inhibitors seem to blunt clopidogrel benefit. Aliskiren can cause angioedema.
Assuntos
Retirada de Medicamento Baseada em Segurança , HumanosAssuntos
Antineoplásicos/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperazinas/sangue , Pirimidinas/sangue , Albuminas/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzamidas , Relação Dose-Resposta a Droga , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Genótipo , Glicoproteínas/metabolismo , Humanos , Mesilato de Imatinib , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Resultado do TratamentoRESUMO
Besides CYP2B6, other polymorphic enzymes contribute to efavirenz (EFV) interindividual variability. This study was aimed at quantifying the impact of multiple alleles on EFV disposition. Plasma samples from 169 human immunodeficiency virus (HIV) patients characterized for CYP2B6, CYP2A6, and CYP3A4/5 allelic diversity were used to build up a population pharmacokinetic model using NONMEM (non-linear mixed effects modeling), the aim being to seek a general approach combining genetic and demographic covariates. Average clearance (CL) was 11.3 l/h with a 65% interindividual variability that was explained largely by CYP2B6 genetic variation (31%). CYP2A6 and CYP3A4 had a prominent influence on CL, mostly when CYP2B6 was impaired. Pharmacogenetics fully accounted for ethnicity, leaving body weight as the only significant demographic factor influencing CL. Square roots of the numbers of functional alleles best described the influence of each gene, without interaction. Functional genetic variations in both principal and accessory metabolic pathways demonstrate a joint impact on EFV disposition. Therefore, dosage adjustment in accordance with the type of polymorphism (CYP2B6, CYP2A6, or CYP3A4) is required in order to maintain EFV within the therapeutic target levels.
Assuntos
Fármacos Anti-HIV/farmacocinética , Benzoxazinas/farmacocinética , Infecções por HIV/genética , Farmacogenética , Polimorfismo Genético , Adulto , Idoso , Alcinos , Alelos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzoxazinas/administração & dosagem , Benzoxazinas/uso terapêutico , Peso Corporal , Ciclopropanos , Citocromo P-450 CYP2A6 , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Dinâmica não Linear , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismoRESUMO
Imipenem plasma concentrations were analyzed in 57 febrile neutropenic patients using the NONMEM program. The recommended 2-g/day regimen achieved coverage of the most common bacteria (MIC(90) = 1 mg/liter) during the whole dosing interval in only 53% of patients. This goal was achieved in 90% of patients with 3 g/day.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Neoplasias Hematológicas/complicações , Imipenem/administração & dosagem , Imipenem/uso terapêutico , Neutropenia/induzido quimicamente , Neutropenia/complicações , Adolescente , Adulto , Idoso , Antibacterianos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Guias como Assunto , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imipenem/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Adulto JovemRESUMO
Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha(1)-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7+/-0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6+/-1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration-response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualizing imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.
Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/sangue , Piperazinas/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/sangue , Pirimidinas/farmacologia , Adulto , Idoso , Antineoplásicos/efeitos adversos , Área Sob a Curva , Benzamidas , Feminino , Tumores do Estroma Gastrointestinal/sangue , Genótipo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: To determine whether valganciclovir 450 mg every 48 h for cytomegalovirus (CMV) prophylaxis provides appropriate ganciclovir exposure in solid organ transplant recipients during continuous renal replacement therapy (CRRT). PATIENTS AND METHODS: Ganciclovir pharmacokinetics was intensively studied in two lung transplant recipients under valganciclovir 450 mg every 48 h over one dosing interval. In vitro experiments using blank whole blood spiked with ganciclovir further investigated exchanges between plasma and erythrocytes. RESULTS: Ganciclovir disposition was characterized by apparent total body clearance of 3.3 and 5.8 L/h, terminal half-life of 16.9 and 14.1 h, and apparent volume of distribution of 60.3 and 104.9 L in Patients 1 and 2, respectively. The observed sieving coefficient was 1.05 and 0.96, and the haemofiltration clearance was 3.3 and 3.1 L/h. In vitro experiments confirmed rapid efflux of ganciclovir from red blood cells into plasma, increasing the apparent efficacy of haemofiltration. CONCLUSIONS: A valganciclovir dosage of 450 mg every 48 h appears adequate for patients under CRRT requiring prophylaxis for CMV infection, providing concentration levels in the range reported for 900 mg once daily dosing outside renal failure.
Assuntos
Quimioprevenção/métodos , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Terapia de Substituição Renal , Ganciclovir/administração & dosagem , Ganciclovir/farmacocinética , Meia-Vida , Humanos , Transplante de Pulmão , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , ValganciclovirAssuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , RNA Interferente Pequeno/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Benzamidas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inativação Gênica , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologiaRESUMO
AIMS: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations. METHODS: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. RESULTS: A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. CONCLUSION: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations.
Assuntos
Antineoplásicos/farmacocinética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Orosomucoide/metabolismo , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Administração Oral , Adulto , Fatores Etários , Idoso , Antineoplásicos/administração & dosagem , Benzamidas , Peso Corporal , Feminino , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Mesilato de Imatinib , Absorção Intestinal , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Fatores SexuaisRESUMO
Two retrospective epidemiologic studies have shown that cannabis is the main psychoactive substance detected in the blood of drivers suspected of driving under the influence of psychotropic drugs. An oral administration double-blind crossover study was carried out with eight healthy male subjects, aged 22 to 30 years, all occasional cannabis smokers. Three treatments and one placebo were administered to all participants at a two week interval: 20 mg dronabinol, 16.5 mg D9-tétrahydrocannabinol (THC) and 45.7 mg THC as a cannabis milk decoction. Participants were asked to report the subjective drug effects and their willingness to drive under various circumstances on a visual analog scale. Clinical observations, a psychomotor test and a tracking test on a driving simulator were also carried out. Compared to cannabis smoking, THC, 11-OH-THC and THC-COOH blood concentrations remained low through the whole study (<13.1 ng THC/mL,<24.7 ng 11-OH-THC/mL and<99.9 ng THC-COOH/mL). Two subjects experienced deep anxiety symptoms suggesting that this unwanted side-effect may occur when driving under the influence of cannabis or when driving and smoking a joint. No clear association could be found between these adverse reactions and a susceptibility gene to propensity to anxiety and psychotic symptoms (genetic polymorphism of the catechol-O-methyltransferase). The questionnaires have shown that the willingness to drive was lower when the drivers were assigned an insignificant task and was higher when the mission was of crucial importance. The subjects were aware of the effects of cannabis and their performances on the road sign and tracking test were greatly impaired, especially after ingestion of the strongest dose. The Cannabis Influence Factor (CIF) which relies on the molar ratio of active and inactive cannabinoids in blood provided a good estimate of the fitness to drive.
Assuntos
Condução de Veículo , Cannabis/efeitos adversos , Dronabinol/efeitos adversos , Alucinógenos/efeitos adversos , Adulto , Método Duplo-Cego , Humanos , Masculino , Desempenho Psicomotor/efeitos dos fármacosRESUMO
Overtreatment (unnecessary treatment, excessive drug dosages, unjustified polypharmacy) alters the risk-benefit ratio. Its prevention requires the recognition of the situations and the understanding of the mechanisms leading to it. The pharmacological treatment of epilepsy exposes to such a risk and serves as an example for its detection and correction.
Assuntos
Anticonvulsivantes , Epilepsia/tratamento farmacológico , Quimioterapia Combinada , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , RiscoRESUMO
This article reviews some recent aspects of pharmacovigilance, of interest to the practitioner: biphosphonates and osteonecrosis of the jaw, antidepressants and suicide, antipsychotics and increased mortality risk and cerebrovascular events, withdrawal syndrome after in utero exposure to antidepressants SSRI, NSAIDs and increased cardiovascular events, cancer and topical immunosuppressants, visual loss and treatment of erectile dysfunction, valvulopathy and dopaminergic agonists. Risk-benefit assessment of drugs is a dynamic process. One must keep in mind that the data on the relationship between drugs and the clinical picture are of variable quality and that the size of the risk is often difficult to assess.
Assuntos
Tratamento Farmacológico/tendências , HumanosRESUMO
Studies are demonstrating additional benefits of multiple drug treatment in specific diseases. However, when a patient suffers multiple diseases, the lack of adequate clinical data on which to base a therapeutic attitude is baffling. The practitioner is forced to prescribe without a strong evidence base or to withhold medications for fear of doing more harm than good. In such circumstances, a prudent and drug sparing approach is to be preferred: a patient, not disease, oriented approach, using a few principles of rational prescribing: clear therapeutic objectives, prioritisation according to the severity of diseases, efficacy and safety of available therapies, therapeutic individualisation and monitoring, patient implication and attention to his/her desires and expectations.