scholarly journals Systemic and presystemic conversion of carbamazepine to carbamazepine-10,11-epoxide during long term treatment

2006 ◽  
Vol 12 (1) ◽  
pp. 13-16 ◽  
Author(s):  
Pietro Fagiolino ◽  
Marta Vázquez ◽  
Ivette Olano ◽  
Aurora Delfino
Keyword(s):  
Plasma Concentrations ◽  
Chronic Administration ◽  
Hplc Method ◽  
Term Treatment ◽  
Published Data ◽  
Long Term Treatment ◽  
Important Pathway ◽  
Kinetics Of ◽  
Dose Dependent

INTRODUCTION: Carbamazepine (CBZ) undergoes biotransformation, being CYP3A4 the major cytocrome P450 (CYP) enzyme catalyzing the carbamazepine-10,11-epoxide (EPOX) formation, which is quantitatively the most important pathway in CBZ metabolism. There is evidence of dose-dependent elimination of this drug due to its autoinduction capacity. Moreover, published data showed an incomplete bioavailability of CBZ since its absorption increases when grapefruit juice was administered. Both CYP3A4 and MRP2 (located in the enterocyte) are autoinduced during long term use of CBZ. As the other enzymes involved in CBZ metabolism are negligible in the gut, presystemic biotransformation through CYP3A4 could be responsible for the bioavailability of the drug as well as EPOX formation. OBJECTIVE: The purpose of our study was to assess the importance of presystemic formation of EPOX during the autoinduction of CBZ versus the daily administered dose. PATIENTS AND METHODS: 40 adults (average age: 28 years) and 29 children (average age: 9 years) receiving CBZ as monotherapy were included in the study. CBZ and EPOX plasma concentrations were analyzed by a previous validated HPLC method. RESULTS AND CONCLUSION: The results obtained confirmed the metabolic induction after chronic administration and provided new elements to suggest a strong contribution of dose-dependent bioavailability in the non linear kinetics of CBZ.

Secondary myelodysplastic syndrome following long-term treatment with azathioprine in patients with multiple sclerosis

2006 ◽  
Vol 12 (3) ◽  
pp. 363-366 ◽  
Author(s):  
Norman Putzki ◽  
Sabine Knipp ◽  
T im Ramczykowski ◽  
Susanne Vago ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Term Treatment ◽  
Immunosuppressive Drug ◽  
Term Therapy ◽  
Secondary Myelodysplastic Syndrome ◽  
Long Term Treatment ◽  
Complete Blood Counts ◽  
Long Term Therapy ◽  
Dose Dependent

Azathioprine (Aza) is a widely used immunosuppressive drug in multiple sclerosis (MS) treatment. Recently, the incidence of secondary myelodysplastic syndromes (sMDS) associated with a poor prognosis was found to be elevated in patients treated with Aza for non-malign disorders. Three hundred and seventeen MS patients were retrospectively analysed and complete blood counts were examined for those exposed to Aza. We identified one case of sMDS (cumulative dose 627 g) in a young patient and two further malignancies (cumulative doses 27 g and 54 g) in the Aza group ( n=81; 3.7%). In the non-Aza ( n=236) group, five malignancies (2.1%, P=0.419) were identified. Including our patient, four cases of sMDS after long-term Aza therapy in MS have been reported so far. Cases suggest a time- and dose-dependent risk of sMDS in long-term therapy of MS with Aza. Long-term Aza therapy needs careful monitoring.

Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 306-306
Author(s):  
Y. Kang ◽  
C. Yoo ◽  
B. Ryoo ◽  
H. Chang ◽  
J. Lee ◽  
...  
Keyword(s):  
Plasma Level ◽  
Gastrointestinal Stromal Tumors ◽  
Plasma Concentrations ◽  
Term Treatment ◽  
Albumin Concentration ◽  
Stromal Tumors ◽  
Long Term Treatment ◽  
The Mean ◽  
Median Interval

306 Background: Pharmacokinetic study in patients with gastrointestinal stromal tumors (GISTs) suggested that plasma concentrations of imatinib decrease following long-term exposure. We therefore measured changes in imatinib plasma trough levels (Cmin) after long-term exposure. Methods: Between November 2009 and May 2010, follow-up (FU) imatinib Cmin was measured in 65 patients who received the same dose of imatinib for at least 9 months after a previous baseline (BL) measurement. Total 244 blood samples were obtained (127 at BL and 117 at FU) and plasma level was measured by liquid chromatography-tandem mass spectrometry. Results: Median patient age was 54 years (range, 28–76 years) and 42 (64.6%) patients were male. Sixty-one (93.8%) patients were treated with 400 mg/day imatinib and 4 (6.2%) with 300 mg/day. The median interval from initiation of imatinib to BL test was 6.4 months (range, 0.5–66.6 months), and the median interval between BL and FU test was 13.1 months (range, 9.6–18.4 months). The mean ± standard deviation imatinib Cmin was significantly higher at FU than at BL (1442 ± 693 ng/mL vs 1221 ± 624 ng/mL, p<0.001). The mean inter- and intra-subject variabilities were 49.2% and 25.5%, respectively, at BL, and 44.2% and 20.4%, respectively, at FU. Multivariate analysis showed a significant correlation between the ratio of FU to BL imatinib Cmin and that of albumin (r=-0.397, p=0.001). In per-sample analysis, imatinib Cmin was significantly correlated with age, hemoglobin, albumin, creatinine clearance, previous major gastrectomy and time between initiation of imatinib and plasma level tests. Conclusions: Steady-state imatinib Cmin did not decrease but remained stable in most GIST patients during long-term treatment. Changes in imatinib Cmin were associated with changes in albumin concentration. Monitoring of imatinib Cmin only for concerns about time-dependent decreases in imatinib exposure is not necessary. [Table: see text]

scholarly journals Endothelin research and the discovery of macitentan for the treatment of pulmonary arterial hypertension

2016 ◽  
Vol 311 (4) ◽  
pp. R721-R726 ◽  
Author(s):  
Martine Clozel
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
Term Treatment ◽  
Vasopressin Release ◽  
Long Term Treatment ◽  
Pulmonary Arterial ◽  
Kinetics Of

Endothelin receptor antagonists (ERAs) are used for the treatment of pulmonary arterial hypertension (PAH). Macitentan, a dual (ETA+ETB) ERA approved for the long-term treatment of PAH, was discovered through a tailored research program aimed at improving efficacy and safety over the existing ERAs. The goal of improved efficacy was based on the understanding that not only the ETA receptor but also the ETB receptor contributed to the hemodynamic and structural changes induced by endothelin-1 (ET-1) in pathological conditions and on the predefined requirements for optimal tissue penetration and binding kinetics of the antagonist. The goal of improved safety was based on the discovery of the role of ETB receptors in vascular permeability and vasopressin release and on the elucidation of the mechanism by which bosentan (the first approved oral dual ETA/ETB ERA) caused liver enzyme changes. Our intention was to design a molecule that would block ETA and ETB receptors optimally and would not interfere with bile salt elimination. This review takes us through the drug discovery journey that led to the discovery, development, and registration of macitentan.

scholarly journals Long-term treatment with subcutaneous immunoglobulin in multifocal motor neuropathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luca Gentile ◽  
Massimo Russo ◽  
Carmelo Rodolico ◽  
Ilenia Arimatea ◽  
Giuseppe Vita ◽  
...  
Keyword(s):  
Life Quality ◽  
Ivig Therapy ◽  
Multifocal Motor Neuropathy ◽  
Term Treatment ◽  
Published Data ◽  
Motor Neuropathy ◽  
Subcutaneous Immunoglobulin ◽  
Long Term Treatment

AbstractMultifocal motor neuropathy (MMN) is a rare disease with a prevalence of less than 1 per 100,000 people. Intravenous immunoglobulin (IVIG) therapy, performed for a long-term period, has been demonstrated able to improve the clinical picture of MMN patients, ameliorating motor symptoms and/or preventing disease progression. Treatment with subcutaneous immunoglobulin (SCIg) has been shown to be as effective as IVIG. However, previously published data showed that follow-up of MMN patients in treatment with SCIg lasted no more than 56 months. We report herein the results of a long-term SCIg treatment follow up (up to 96 months) in a group of 8 MMN patients (6 M; 2F), previously stabilized with IVIG therapy. Clinical follow-up included the administration of Medical Research Council (MRC) sum-score, the Overall Neuropathy Limitation Scale (ONLS) and the Life Quality Index questionnaire (LQI) at baseline and then every 6 months. Once converted to SCIg, patients’ responsiveness was quite good. Strength and motor functions remained stable or even improved during this long-term follow-up with benefits on walking capability, resistance to physical efforts and ability in hand fine movements.

scholarly journals A review study of targeting of AAK1 and JAK1/2 using baricitinib in COVID-19 infected human cells

2020 ◽  
Vol 16 (supplement) ◽  
pp. 9-15
Author(s):  
Abeer M Al-Humaidhi
Keyword(s):  
Side Effects ◽  
Inhibitory Effect ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Pros And Cons ◽  
Experimental Trials ◽  
Pharmaceutical Agents ◽  
Dose Dependent ◽  
A Current

     The outbreak of a current public health coronavirus 2019 disease is a causative agent of a serious acute respiratory syndrome and even death. COVID-19 has exposed to multi-suggested pharmaceutical agents to control this global disease. Baricitinib, a well-known antirheumatic agent, was one of them. This article reviews the likely pros and cons of baricitinib in attenuation of COVID-19 based on the mechanism of drug action as well as its pharmacokinetics. The inhibitory effect of baricitinib on receptor mediated endocytosis promoter, AKK1, and on JAK-STAT signaling pathway is benefacial in inhibition of both viral assembling and inflammation. Also, its pharmacokinetic has encouraged the physicians toward the drug selection for COVID-19 treatment. On the other hand, most of baricitinib side effects are dose-dependent. In conclusion, targeting of AAK1 and JAK1/2 using baricitinib has predicted to be potential and effective with minimal side effects in management COVID-19 infected patients for a short therapeutic dosing period. Laboratory monitoring should be considered for some parameters. However, experimental trials are mandatory for a long-term treatment with a lower dose of baricitinib to evaluate its effectiveness and safety in patients with moderate COVID-19 infection.

Proactive therapeutic drug monitoring (TDM) may be helpful in managing long-term treatment with linezolid safely: findings from a monocentric, prospective, open-label, interventional study

2019 ◽  
Vol 74 (12) ◽  
pp. 3588-3595 ◽  
Author(s):  
Pier Giorgio Cojutti ◽  
Maria Merelli ◽  
Matteo Bassetti ◽  
Federico Pea
Keyword(s):  
Trough Level ◽  
Term Treatment ◽  
Therapeutic Drug ◽  
Interventional Study ◽  
Open Label ◽  
Long Term Treatment ◽  
Group A ◽  
Linezolid Therapy ◽  
Dose Dependent

Abstract Background Thrombocytopenia may be a dose-dependent adverse effect of linezolid therapy. Objectives To assess whether proactive therapeutic drug monitoring (TDM) could be helpful in preventing and/or in recovering from the occurrence of linezolid-induced thrombocytopenia during long-term treatment. Methods This was a monocentric, prospective, open-label, interventional study conducted between June 2015 and December 2017 among adult patients receiving >10 days of linezolid therapy and undergoing proactive TDM (desired trough level 2–8 mg/L) and platelet count assessment at day 3–5 and then once weekly up to the end of treatment. Results Sixty-one patients were included. Twenty-eight (45.9%) always had desired trough level (group A) and 33 (54.1%) experienced linezolid overexposure (group B) [29/33 transiently (subgroup B1) and 4/33 persistently (subgroup B2)]. No patient experienced linezolid underexposure. Median duration of treatment for the different groups ranged between 19 and 54 days. Thrombocytopenia occurred overall in 14.8% of cases (9/61). The incidence rate of thrombocytopenia was significantly lower (P=0.012) in both group A (10.7%; 3/28) and subgroup B1 (10.3%; 3/29) than in subgroup B2 (75.0%; 3/4). Thrombocytopenic patients belonging to both group A and group B1 recovered from thrombocytopenia without the need for discontinuing therapy. Multivariate linear regression analysis revealed that thrombocytopenia was independently associated with baseline platelet count and with median linezolid trough concentrations. Conclusions Proactive TDM of linezolid may be beneficial either in preventing or in recovering from dose-dependent thrombocytopenia, even when treatment lasts for more than 28 days. Larger prospective studies are warranted to confirm our findings.

scholarly journals EC313-a tissue selective SPRM reduces the growth and proliferation of uterine fibroids in a human uterine fibroid tissue xenograft model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hareesh B. Nair ◽  
Bindu Santhamma ◽  
Kalarickal V. Dileep ◽  
Peter Binkley ◽  
Kirk Acosta ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
Uterine Fibroids ◽  
Xenograft Model ◽  
Docking Studies ◽  
Term Treatment ◽  
Uterine Bleeding ◽  
Long Term Treatment ◽  
Scid Mouse Model ◽  
Dose Dependent

AbstractUterine fibroids (UFs) are associated with irregular or excessive uterine bleeding, pelvic pain or pressure, or infertility. Ovarian steroid hormones support the growth and maintenance of UFs. Ulipristal acetate (UPA) a selective progesterone receptor (PR) modulator (SPRM) reduce the size of UFs, inhibit ovulation and lead to amenorrhea. Recent liver toxicity concerns with UPA, diminished enthusiasm for its use and reinstate the critical need for a safe, efficacious SPRM to treat UFs. In the current study, we evaluated the efficacy of new SPRM, EC313, for the treatment for UFs using a NOD-SCID mouse model. EC313 treatment resulted in a dose-dependent reduction in the fibroid xenograft weight (p < 0.01). Estradiol (E2) induced proliferation was blocked significantly in EC313-treated xenograft fibroids (p < 0.0001). Uterine weight was reduced by EC313 treatment compared to UPA treatment. ER and PR were reduced in EC313-treated groups compared to controls (p < 0.001) and UPA treatments (p < 0.01). UF specific desmin and collagen were markedly reduced with EC313 treatment. The partial PR agonism and no signs of unopposed estrogenicity makes EC313 a candidate for the long-term treatment for UFs. Docking studies have provided a structure based explanation for the SPRM activity of EC313.

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