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1.
Mult Scler ; 30(7): 833-842, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38619037

ABSTRACT

BACKGROUND: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. METHODS: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. RESULTS: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. CONCLUSION: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108.


Subject(s)
Crotonates , Hydroxybutyrates , Multiple Sclerosis, Relapsing-Remitting , Nitriles , Toluidines , Humans , Toluidines/adverse effects , Toluidines/therapeutic use , Toluidines/administration & dosage , Toluidines/pharmacology , Crotonates/adverse effects , Crotonates/therapeutic use , Nitriles/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Female , Male , Double-Blind Method , Adolescent , Child , Treatment Outcome , Magnetic Resonance Imaging
2.
Mult Scler Relat Disord ; 85: 105539, 2024 May.
Article in English | MEDLINE | ID: mdl-38574721

ABSTRACT

BACKGROUND: Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. OBJECTIVES: This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. METHODS: This retrospective observational cohort study based on the 2015-2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18-64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. RESULTS: The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1-2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. CONCLUSIONS: Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.


Subject(s)
Crotonates , Dimethyl Fumarate , Fingolimod Hydrochloride , Hydroxybutyrates , Medication Adherence , Nitriles , Recurrence , Toluidines , Humans , Adult , Female , Male , Medication Adherence/statistics & numerical data , Middle Aged , Crotonates/administration & dosage , Crotonates/therapeutic use , Retrospective Studies , Toluidines/administration & dosage , Toluidines/therapeutic use , Young Adult , Dimethyl Fumarate/administration & dosage , Dimethyl Fumarate/therapeutic use , Fingolimod Hydrochloride/therapeutic use , Fingolimod Hydrochloride/administration & dosage , Adolescent , Multiple Sclerosis/drug therapy , Administration, Oral , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Immunologic Factors/administration & dosage
3.
J Neurol ; 271(6): 3142-3152, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38430270

ABSTRACT

OBJECTIVES: To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with relapsing-remitting multiple sclerosis (RRMS). MATERIALS AND METHODS: The EIT cohort started with alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR), or ozanimod (OZA); whereas, the ESC cohort was escalated from dimethylfumarate (DMF) or teriflunomide (TERI) to AZM, CLAD, FTY, NTZ, OCR, or OZA within the Austrian MS Treatment Registry. Patients had to stay on therapy for at least 3 months and up to 16 years. The EIT cohort included 743 and the ESC cohort 227 RRMS patients. We used multinomial propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for the bias of this non-randomized registry study. RESULTS: Estimated mean annualized relapse rates (ARR) were 0.09 for EIT and 0.4 for ESC patients. The incidence rate ratio (IRR) in the GLM model for relapses showed a decreased relapse probability of 78% for the EIT versus ESC cohort [IRR = 0.22, 95% CI (0.16-0.30), p < 0.001]. Analyzing the time to the first relapse by Cox regression, a hazard ratio (HR) of 0.17 [95% CI (0.13-0.22), p < 0.001] revealed a decreased risk of 83% for the EIT group. Regarding sustained Expanded Disability Status Scale (EDSS) progression for 12 weeks, a HR of 0.55 [95% CI (0.40-0.76), p < 0.001] showed a decreased probability of 45% for the EIT cohort. CONCLUSIONS: ESC treatment after DMF and TERI revealed a higher relapse and EDSS progression probability compared to EIT in Austrian RRMS patients. Therefore, an early intensive treatment should be started in patients with an active or highly active disease course.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Humans , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Male , Austria/epidemiology , Female , Adult , Immunosuppressive Agents/administration & dosage , Registries , Cohort Studies , Middle Aged , Immunologic Factors/administration & dosage , Dimethyl Fumarate/administration & dosage , Toluidines/administration & dosage
4.
Mult Scler ; 30(7): 820-832, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38551315

ABSTRACT

BACKGROUND: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS). OBJECTIVES: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing-remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials. METHODS: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis. RESULTS: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [0.7-5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder. CONCLUSION: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully.


Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Treatment Failure , Humans , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Female , Adult , Male , Retrospective Studies , Administration, Oral , Middle Aged , Fingolimod Hydrochloride/administration & dosage , Dimethyl Fumarate/administration & dosage , Crotonates/administration & dosage , Hydroxybutyrates , Toluidines/administration & dosage , Immunosuppressive Agents/administration & dosage , Nitriles/administration & dosage , Prognosis , Immunologic Factors/administration & dosage
5.
Article in English | MEDLINE | ID: mdl-34642237

ABSTRACT

BACKGROUND AND OBJECTIVES: To test whether low concentrations of teriflunomide (TF) could promote remyelination, we investigate the effect of TF on oligodendrocyte in culture and on remyelination in vivo in 2 demyelinating models. METHODS: The effect of TF on oligodendrocyte precursor cell (OPC) proliferation and differentiation was assessed in vitro in glial cultures derived from neonatal mice and confirmed on fluorescence-activated cell sorting-sorted adult OPCs. The levels of the 8,9-unsaturated sterols lanosterol and zymosterol were quantified in TF- and sham-treated cultures. In vivo, TF was administered orally, and remyelination was assessed both in myelin basic protein-GFP-nitroreductase (Mbp:GFP-NTR) transgenic Xenopus laevis demyelinated by metronidazole and in adult mice demyelinated by lysolecithin. RESULTS: In cultures, low concentrations of TF down to 10 nM decreased OPC proliferation and increased their differentiation, an effect that was also detected on adult OPCs. Oligodendrocyte differentiation induced by TF was abrogated by the oxidosqualene cyclase inhibitor Ro 48-8071 and was mediated by the accumulation of zymosterol. In the demyelinated tadpole, TF enhanced the regeneration of mature oligodendrocytes up to 2.5-fold. In the mouse demyelinated spinal cord, TF promoted the differentiation of newly generated oligodendrocytes by a factor of 1.7-fold and significantly increased remyelination. DISCUSSION: TF enhances zymosterol accumulation in oligodendrocytes and CNS myelin repair, a beneficial off-target effect that should be investigated in patients with multiple sclerosis.


Subject(s)
Central Nervous System Diseases/drug therapy , Cholesterol/metabolism , Crotonates/pharmacology , Demyelinating Diseases/drug therapy , Hydroxybutyrates/pharmacology , Immunosuppressive Agents/pharmacology , Nitriles/pharmacology , Oligodendrocyte Precursor Cells/drug effects , Oligodendroglia/drug effects , Remyelination/drug effects , Toluidines/pharmacology , Animals , Animals, Newborn , Cells, Cultured , Central Nervous System Diseases/metabolism , Crotonates/administration & dosage , Disease Models, Animal , Hydroxybutyrates/administration & dosage , Immunosuppressive Agents/administration & dosage , Larva , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nitriles/administration & dosage , Oligodendrocyte Precursor Cells/metabolism , Oligodendroglia/metabolism , Toluidines/administration & dosage , Xenopus laevis
6.
Drug Deliv ; 28(1): 1972-1981, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34565260

ABSTRACT

Crotamiton (CRT) is a commonly approved drug prescribed for the scabies treatment in many countries across the globe. However, poor aqueous solubility and low bioavailability, and side effects restrict its use. To avoid such issues, an appropriate carrier system is necessary which can address the aforementioned challenges for attaining enhanced biopharmaceutical attributes. The current study intends to provide a detailed account on the development and evaluation of CRT-loaded microemulsion (ME) hydrogel formulation containing tea tree oil (TTO) for improved drug delivery for scabies treatment in a safe and effective manner. Pseudo-ternary phase diagrams were constructed with TTO as the oily phase, and Cremophor®EL was used as the surfactant in a mass ratio 2:1 with co-surfactants (mixture of phospholipid 90G and Transcutol®P), and aqueous solution as the external phase. The optimized drug-loaded ME formulation was evaluated for skin penetration, retention, compliance, and dermatokinetics. The nonirritant behavior of the formulation was revealed by skin histopathology, which showed no changes in normal skin histology. In comparison to the conventional product, dermatokinetic experiments revealed that CRT has greater penetration and distribution in the epidermis of the mice skin. The findings imply that the proposed lipid-based ME hydrogel can aid in the resolution of CRT issues by providing a better and safer delivery option to epidermis and deeper epidermis in substantial quantities.


Subject(s)
Emulsions/chemistry , Hydrogels/chemistry , Scabies/drug therapy , Tea Tree Oil/chemistry , Toluidines/pharmacokinetics , Animals , Chemistry, Pharmaceutical , Drug Carriers , Drug Stability , Hydrogen-Ion Concentration , Mice , Surface Properties , Surface-Active Agents/chemistry , Toluidines/administration & dosage
7.
Int J Biol Macromol ; 171: 502-513, 2021 Feb 28.
Article in English | MEDLINE | ID: mdl-33422513

ABSTRACT

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.


Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Experimental/drug therapy , Arthritis, Rheumatoid/drug therapy , Crotonates/administration & dosage , Drug Carriers/administration & dosage , Durapatite/chemistry , Hyaluronic Acid/chemistry , Methotrexate/administration & dosage , Nanoparticles/administration & dosage , Toluidines/administration & dosage , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/toxicity , Arthritis, Experimental/pathology , Crotonates/pharmacokinetics , Crotonates/therapeutic use , Crotonates/toxicity , Cytokines/blood , Drug Carriers/pharmacokinetics , Drug Carriers/toxicity , Drug Evaluation, Preclinical , Drug Liberation , Hydroxybutyrates , Liver/drug effects , Liver/enzymology , Liver/pathology , Methotrexate/pharmacokinetics , Methotrexate/therapeutic use , Methotrexate/toxicity , Mice , Nanoparticles/toxicity , Nitriles , RAW 264.7 Cells , Rats , Rats, Wistar , Spectroscopy, Fourier Transform Infrared , Tissue Distribution , Toluidines/pharmacokinetics , Toluidines/therapeutic use , Toluidines/toxicity
8.
Mult Scler Relat Disord ; 48: 102734, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33429305

ABSTRACT

BACKGROUND: . Teriflunomide is an immunomodulatory drug approved for Multiple Sclerosis (MS) treatment that inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in the de novo pyrimidine synthesis pathway. This mechanism can produce antiviral effects, thus teriflunomide has gained attention during COVID-19 pandemic. Moreover, in the last months, some case-reports have been published describing MS patients treated with teriflunomide who developed mild and self-limiting forms of COVID-19. METHODS: Here, we describe the case of a 57-year-old man affected by MS, and treated with teriflunomide, who developed a mild form of SARS-CoV-2 infection. Moreover, we provide a detailed literature review about the available cases of COVID-19 in MS patients treated with teriflunomide. We report clinical features, disease course and outcome, and we discuss similarities and differences among patients. RESULTS: Apart from the present report, since February 2020, five papers have been published describing 14 MS patients who developed SARS-CoV-2 infection during teriflunomide treatment. Patients were mostly female (53%), with an average age of 50.5 (±11.3) years. Median EDSS was 2.25 (range 0-6). The average time on treatment with teriflunomide was 3.7 (± 1.6) years. Relevant comorbidities were present in 4 patients (27%). Regarding SARS-CoV-2 infection, the most common symptom was fever (100%) followed by gastrointestinal disturbances (67%), fatigue (55%) and cough (55%). 5 patients were hospitalized and 2 required oxygen support. In patient hospitalized (n=5) compared to the others (n=10), age was significantly higher (59.6 vs 45.9 years, p=0.025) while gender, EDSS, duration of teriflunomide therapy and comorbidities were not significantly different. Outcome was good for all patients with a variable recovery time, ranging from few days to some weeks. Teriflunomide was continued during the entire course of SARS-CoV-2 infection in all patients except for two. Compared to the patients already described, our patient was 7 years older, average time on teriflunomide treatment was about 2.5 years shorter, and median EDSS was 1.5 point lower. Despite significant comorbidities, the outcome was good since our patient was hospitalized but he did not require oxygen supplementation nor intensive care and was able to return at home after only 10 days. Teriflunomide therapy was continued throughout the period. CONCLUSION: Available data suggest that teriflunomide therapy should not be discontinued in MS patients who develop SARS-CoV-2 infection, also in presence of significant comorbidities or clinical conditions requiring hospitalization. Additional studies are necessary to assess if the drug can also have a protective role against SARS-CoV-2.


Subject(s)
COVID-19/therapy , Crotonates/administration & dosage , Immunologic Factors/administration & dosage , Multiple Sclerosis/drug therapy , Toluidines/administration & dosage , COVID-19/epidemiology , Comorbidity , Humans , Hydroxybutyrates , Male , Middle Aged , Multiple Sclerosis/epidemiology , Nitriles
9.
Expert Opin Drug Saf ; 20(4): 481-487, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33342303

ABSTRACT

BACKGROUND: Real-world safety data for the oral multiple sclerosis (MS) disease-modifying therapies (DMTs), dimethyl fumarate (DMF), fingolimod, and teriflunomide are important. We examined laboratory test abnormalities and adverse health conditions in new users. METHODS: Linked laboratory and administrative health data were accessed for all persons with MS (PwMS) filling their first oral DMT prescription in two Canadian provinces. PwMS were followed from first prescription fill until discontinuation, death, emigration or study end. Proportions of PwMS, and incidence rates (IR)/100 person-years, were calculated for ≥1 event of elevated alanine aminotransferase (ALT) (>the upper limit of normal [ULN]; all DMTs), liver toxicity (ALT>3xULN; fingolimod); lymphopenia and proteinuria (DMF), and cardiac arrhythmia, hypertension and pneumonia (all DMTs). RESULTS: Overall, 1,140 PwMS were followed for up to 2 years. De novo elevated alanine aminotransferase affected 13.2% (DMF), 12.4% (teriflunomide), and 30.0% (fingolimod) of users. Liver toxicity affected 2.8% of fingolimod, lymphopenia 3.1% of DMF, and proteinuria 2.9% of DMF users. The incidences of cardiac arrhythmia, pneumonia and hypertension ranged from <1 to 1.86/100 person-years depending on the DMT. CONCLUSIONS: The short-term, real-world incidences of abnormal laboratory results or adverse events were consistent with the pivotal clinical trial findings. Longer-term safety data are still needed.


Subject(s)
Crotonates/adverse effects , Dimethyl Fumarate/adverse effects , Fingolimod Hydrochloride/adverse effects , Multiple Sclerosis/drug therapy , Toluidines/adverse effects , Administration, Oral , Adult , Crotonates/administration & dosage , Databases, Factual , Dimethyl Fumarate/administration & dosage , Female , Fingolimod Hydrochloride/administration & dosage , Follow-Up Studies , Humans , Hydroxybutyrates , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Nitriles , Prospective Studies , Toluidines/administration & dosage
10.
Immunol Invest ; 50(6): 671-684, 2021 Aug.
Article in English | MEDLINE | ID: mdl-32597289

ABSTRACT

Antigen-specific immune responses are crucially involved in both multiple sclerosis (MS) and myasthenia gravis (MG). Teriflunomide is an immunomodulatory agent approved for treatment of MS through inhibition of lymphocyte proliferation. MG associated with muscle-specific tyrosine kinase (MuSK) antibodies often manifests with a severe disease course, prompting development of effective treatment methods. To evaluate whether teriflunomide treatment may ameliorate MuSK-autoimmunity, experimental autoimmune MG (EAMG) was induced by immunizing C57BL/6 (B6) mice three times with MuSK in complete Freund's adjuvant (CFA) (n = 17). MuSK-immunized mice were treated daily with teriflunomide (n = 8) or PBS (n = 9) starting from the third immunization (week 8) to termination (week 14). Clinical severity of EAMG was monitored. Immunological alterations were evaluated by measurement of anti-MuSK IgG, neuromuscular junction deposits, and flow cytometric analysis of lymph node cells. In MS patients under teriflunomide treatment, the peripheral blood B cell subset profile was analyzed. B6 mice treated with teriflunomide displayed relatively preserved body weight, lower EAMG prevalence, reduced average clinical grades, higher inverted screen scores, diminished anti-MuSK antibody and NMJ deposit levels. Amelioration of EAMG findings was associated with reduced memory B cell ratios in the lymph nodes. Similarly, MS patients under teriflunomide treatment showed reduced memory B cell, plasma cell, and plasmablast ratios. Teriflunomide treatment has effectively ameliorated MuSK-autoimmunity and thus may putatively be used in long-term management of MuSK-MG as an auxiliary treatment method. Teriflunomide appears to exert beneficial effects through inhibition of effector B cells.


Subject(s)
B-Lymphocyte Subsets/drug effects , Crotonates/administration & dosage , Hydroxybutyrates/administration & dosage , Multiple Sclerosis/drug therapy , Myasthenia Gravis, Autoimmune, Experimental/drug therapy , Nitriles/administration & dosage , Receptor Protein-Tyrosine Kinases/immunology , Receptors, Cholinergic/immunology , Toluidines/administration & dosage , Adult , Animals , B-Lymphocyte Subsets/immunology , Female , Humans , Male , Mice , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/diagnosis , Multiple Sclerosis/immunology , Myasthenia Gravis, Autoimmune, Experimental/blood , Myasthenia Gravis, Autoimmune, Experimental/diagnosis , Myasthenia Gravis, Autoimmune, Experimental/immunology , Receptor Protein-Tyrosine Kinases/administration & dosage , Receptors, Cholinergic/administration & dosage , Treatment Outcome
11.
Int J Biol Macromol ; 167: 906-920, 2021 Jan 15.
Article in English | MEDLINE | ID: mdl-33186648

ABSTRACT

The research work was intended to formulate teriflunomide (TFM) loaded nano lipid-based (TNLC) carbopol-gellan gum in situ gel (TNLCGHG) and to investigate its therapeutic efficacy against glioma, a brain and spine tumor. Nanoformulation was developed using gellan gum and carbopol 974P as gelling and mucoadhesive agents, respectively, Glyceryl di-behenate and Glyceryl mono-linoleate blend as lipids, and Gelucire 44/14: water blend as surfactant system. Globule size, PDI, zeta potential, encapsulation efficiency, mucoadhesive strength, and nasal permeation were found to be 117.80 nm, 0.56, -21.86 mV, 81.16%, 4.80 g, and 904 µg/cm2, respectively. Anticancer efficacy of TFM-loaded nano lipid-based carbopol-gellan gum in situ gel (TNLCGHG) was determined in human U-87MG glioma cell line. IC50 was found 7.0 µg/mL for TNLCGHG, 4.8 µg/mL for pure TFM, and 78.5 µg/mL for TNLC, which approve the superiority of surfactant along with gellan gum as permeation enhancer. Brain Cmax for technetium (99mTC) labeled intranasal (i.n.) 99mTC-TNLCGHG was found 2-folds higher than 99mTC-TNLC (i.n.) and 99mTC-TNLC intravenous (i.v.) because the TNLCGHG formulation contains surfactant with natural gelling polymers, which promisingly improved drug permeability. Finally, this research revealed encouraging outcomes and successfully developed intranasal TNLCGHG nanoformulation as a novel tool for safe delivery of TFM in glioma patients.


Subject(s)
Acrylic Resins/chemistry , Crotonates/administration & dosage , Drug Carriers/chemistry , Drug Delivery Systems , Lipids/chemistry , Nanogels/chemistry , Polysaccharides, Bacterial/chemistry , Toluidines/administration & dosage , Administration, Intranasal , Animals , Brain/drug effects , Brain/metabolism , Calorimetry, Differential Scanning , Cell Line, Tumor , Chemical Phenomena , Chromatography, High Pressure Liquid , Glioma/drug therapy , Hydroxybutyrates , Nanoparticles/chemistry , Nitriles , Particle Size , X-Ray Diffraction
12.
N Z Vet J ; 69(2): 121-126, 2021 Mar.
Article in English | MEDLINE | ID: mdl-32814497

ABSTRACT

Clinical history: An outbreak of intense pruritus and weight loss in a herd of 40 alpacas (Vicugna pacos) in the south-west of France was investigated after the death of 14 adults. One alpaca was referred to a veterinary teaching hospital for diagnosis and treatment but died soon after and one of the dead alpacas was submitted for necropsy. Clinical findings: The remaining alpacas were intensely pruritic with variably severe and extensive alopecia, erythema, lichenification and crusting on the face, ventral abdomen and distal limbs. Superficial skin scrapes from five animals revealed large numbers of Sarcoptes scabiei mites, and less frequent and numerous Chorioptes bovis mites. Coproscopic examinations revealed a median of 1,350 (min 500, max 8800) strongyle epg. The alpaca admitted for treatment was anaemic and hypoalbuminaemic. Skin scrapes revealed copious S. scabiei and C. bovis mites. The two alpacas examined post-mortem had similar skin lesions to those examined on-farm and were cachexic. One had lung lesions attributed to protostrongylid infestation and its liver contained numerous Dicrocoelium spp. adults. Diagnosis: Sarcoptic and chorioptic mange with secondary superficial bacterial skin infection, associated with severe internal parasitism and underfeeding. Treatment and outcome: All 25 alpacas were treated topically with a 3% chlorhexidine shampoo followed by a 0.025% amitraz wash at the initial visit and then 1, 2, 3, 7 and 9 weeks later. A systemic treatment with S/C 500 µg/kg ivermectin was administered at the initial visit and then 2, 7 and 9 weeks later. The alpacas were treated orally with 50 mg/kg praziquantel to control dicrocoeliosis. Nutritional measures, including increased pasture area and supplemental feeding were simultaneously implemented. Pruritus was reduced 1 week after the start of treatment and had resolved after 2 weeks. After 9 weeks, skin lesions were markedly improved. Six months after the initial visit, skin lesions entirely resolved and superficial skin scrapes, taken from half of the animals, were negative for mites. Clinical relevance: This is the first report of the use of two acaricides combined with a chlorhexidine shampoo to successfully treat simultaneous sarcoptic and chorioptic mange in alpacas.


Subject(s)
Camelids, New World/parasitology , Insecticides/therapeutic use , Ivermectin/therapeutic use , Scabies/veterinary , Toluidines/therapeutic use , Administration, Topical , Animals , Anthelmintics/therapeutic use , Anti-Infective Agents, Local/therapeutic use , Chlorhexidine/administration & dosage , Chlorhexidine/therapeutic use , Dicrocoeliasis/drug therapy , Dicrocoeliasis/veterinary , Drug Therapy, Combination , Female , Injections, Subcutaneous/veterinary , Insecticides/administration & dosage , Ivermectin/administration & dosage , Male , Praziquantel/therapeutic use , Scabies/drug therapy , Scabies/parasitology , Toluidines/administration & dosage
13.
Regul Toxicol Pharmacol ; 117: 104758, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32798612

ABSTRACT

Benfluralin, an herbicide of the dinitroaniline class used in weed control, was first registered in the United States in 1970. Increased incidence of liver tumors was observed in the 2 year dietary carcinogenicity studies. A review of the toxicology database provides evidence that the mode of action (MOA) of benfluralin responsible for hepatocellular adenoma and carcinoma in rodents depends on activation of the constitutive androstane (CAR)/pregnane X (PXR) receptors, that triggers enzyme induction and altered gene expression leading to hepatocyte proliferation. After prolonged exposures at high dose levels, altered hepatic foci and liver tumors are observed. This hepatocarcinogenic MOA has been described in rodents following long-term dietary exposures to other CAR/PXR activator chemicals, such as phenobarbital, and is generally considered as non-relevant in humans due to differences between human and rodent responses. We analyzed the existing and newly acquired toxicology data to establish that the hepatocarcinogenic MOA of benfluralin in rodents includes the same key events previously described in the rodent MOA of phenobarbital. A weight of evidence approach was taken to establish temporal and dose-related concordance of the causal key events supporting the conclusion that rodent liver carcinogenicity of benfluralin is unlikely to be relevant for human cancer risk.


Subject(s)
Liver Neoplasms/chemically induced , Mutagenicity Tests/methods , Toluidines/toxicity , Toxicity Tests, Chronic/methods , Toxicity Tests, Subchronic/methods , Animals , Dose-Response Relationship, Drug , Female , Humans , Liver Neoplasms/pathology , Male , Mice , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Rats, Transgenic , Risk Assessment , Rodentia , Toluidines/administration & dosage
14.
J Neurol ; 267(7): 2090-2100, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32246251

ABSTRACT

OBJECTIVES: To compare the efficacies, frequencies and reasons for treatment interruption of fingolimod (FTY), dimethyl fumarate (DMF) or teriflunomide (TERI) in a nationwide observational cohort. MATERIALS AND METHODS: Two cohorts of patients with relapsing-remitting multiple sclerosis (RRMS) having started treatment with FTY, DMF or TERI documented in the Austrian MS Treatment Registry (AMSTR) since 2014 and either staying on therapy for at least 24 months (24 m cohort) or with at least one follow-up visit after start of treatment (total cohort). The 24 m cohort included 629 RRMS patients: 295 in the FTY, 227 in the DMF and 107 in the TERI group. We used multinomial propensity scores for inverse probability weighting in generalized linear and Cox proportional hazards models to correct for the bias of this non-randomised registry study. RESULTS: Estimated mean annualized relapse rates (ARR) over 24 months were 0.13 for FTY, 0.09 for DMF and 0.11 for TERI treatment. For TERI in comparison with DMF, we observed higher probability for treatment interruption (p = 0.023) and reduced sustained EDSS regression for 12 (p = 0.016) and 24 weeks (p = 0.031) and, for the comparison of DMF versus FTY, a reduced sustained EDSS progression for 12 weeks (p = 0.02). CONCLUSIONS: Relapse rates with treatment with FTY, DMF and TERI were similar. Patients treated with DMF showed less sustained disability progression for 12 weeks than FTY-treated patients. However, FTY and DMF treatment was associated with more likely EDSS regression for 12 and 24 weeks and a lower probability for treatment interruption as compared to TERI-treated patients.


Subject(s)
Crotonates/pharmacology , Dimethyl Fumarate/pharmacology , Disease Progression , Fingolimod Hydrochloride/pharmacology , Immunosuppressive Agents/pharmacology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Outcome Assessment, Health Care/methods , Registries , Toluidines/pharmacology , Administration, Oral , Adult , Austria , Crotonates/administration & dosage , Dimethyl Fumarate/administration & dosage , Female , Fingolimod Hydrochloride/administration & dosage , Follow-Up Studies , Humans , Hydroxybutyrates , Immunosuppressive Agents/administration & dosage , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Nitriles , Severity of Illness Index , Toluidines/administration & dosage
15.
Mult Scler Relat Disord ; 40: 101954, 2020 May.
Article in English | MEDLINE | ID: mdl-32078948

ABSTRACT

BACKGROUND: Peginterferon beta-1a and teriflunomide are both first-line disease-modifying therapies (DMTs) approved for the treatment of relapsing multiple sclerosis (RMS); however, no head-to-head trials have directly compared their clinical efficacy. We performed a matching-adjusted comparison of individual patient data from the peginterferon beta-1a pivotal phase 3 study, ADVANCE, and its extension study, ATTAIN, with pooled aggregated data from the teriflunomide pivotal phase 3 studies, TEMSO and TOWER. METHODS: A total of 512 patients randomized to subcutaneous (SC) peginterferon beta-1a 125 mcg every 2 weeks in ADVANCE and 731 patients randomized to teriflunomide 14 mg daily (359 from TEMSO and 372 from TOWER) were matched on key baseline characteristics. After matching, weighted annualized relapse rate (ARR) and 24-week confirmed disability worsening (CDW) were calculated and compared for peginterferon beta-1a- and teriflunomide-treated patients. A subset analysis comparing weighted ARR in patients who were newly diagnosed with RMS (diagnosis ≤1 year before study enrollment and disease-modifying therapy naïve) was also performed. RESULTS: After matching, the peginterferon beta-1a and teriflunomide treatment groups were identically matched across baseline characteristics. The proportion of patients in the overall study populations with 24-week CDW at 108 weeks was significantly lower in the peginterferon beta-1a group than the teriflunomide group both before matching (8.5% vs 12.6%; P = 0.0249) and after matching (8.4% vs 12.6%; P = 0.0323). ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide both before matching (0.278 vs 0.354; P = 0.1326) and after matching (0.257 vs 0.354; P = 0.0510). Newly diagnosed patients treated with peginterferon beta-1a had numerically lower ARR than patients treated with teriflunomide both at 108 weeks (before matching: 0.225 vs 0.270; P = 0.587; after matching: 0.201 vs 0.270; P = 0.384) and at 5 years (before matching: 0.150 vs 0.196; after matching: 0.142 vs 0.196). CONCLUSIONS: In this matching-adjusted comparison of patients with RMS from three phase 3 trials, a significantly lower proportion of patients treated with SC peginterferon beta-1a 125 mcg every 2 weeks than with oral teriflunomide 14 mg once daily had 24-week CDW at 108 weeks. In addition, in both the overall population and newly diagnosed patient subgroups, ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide. The numerically lower ARR in newly diagnosed patients treated with peginterferon beta-1a compared with those treated with teriflunomide was sustained through up to 5 years of treatment.


Subject(s)
Crotonates/pharmacology , Disease Progression , Immunologic Factors/pharmacology , Interferon-beta/pharmacology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Outcome Assessment, Health Care , Polyethylene Glycols/pharmacology , Toluidines/pharmacology , Adult , Crotonates/administration & dosage , Female , Humans , Hydroxybutyrates , Immunologic Factors/administration & dosage , Interferon-beta/administration & dosage , Male , Middle Aged , Nitriles , Polyethylene Glycols/administration & dosage , Recurrence , Toluidines/administration & dosage
16.
Acta Pharmacol Sin ; 41(1): 129-137, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31341258

ABSTRACT

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 µmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 µmol/L. TER (5 µmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.


Subject(s)
Acyclovir/pharmacokinetics , Kidney/metabolism , Leflunomide/pharmacology , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Organic Anion Transport Protein 1/antagonists & inhibitors , Organic Anion Transporters, Sodium-Independent/antagonists & inhibitors , Acyclovir/administration & dosage , Acyclovir/metabolism , Administration, Intravenous , Animals , Cells, Cultured , Crotonates/administration & dosage , Crotonates/metabolism , Crotonates/pharmacology , Dogs , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Hydroxybutyrates , Leflunomide/administration & dosage , Leflunomide/metabolism , Madin Darby Canine Kidney Cells/drug effects , Madin Darby Canine Kidney Cells/metabolism , Male , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/metabolism , Nitriles , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Probenecid/administration & dosage , Probenecid/metabolism , Probenecid/pharmacology , Propionates/administration & dosage , Propionates/metabolism , Propionates/pharmacology , Quinolines/administration & dosage , Quinolines/metabolism , Quinolines/pharmacology , Rats , Rats, Sprague-Dawley , Tissue Distribution , Toluidines/administration & dosage , Toluidines/metabolism , Toluidines/pharmacology
17.
Clin Pharmacol Drug Dev ; 9(3): 341-345, 2020 04.
Article in English | MEDLINE | ID: mdl-31379101

ABSTRACT

Multiple sclerosis, which is characterized by inflammation and neurodegeneration, is considered a chronic disease of the central nervous system. Given the lack of pharmacokinetic evaluation of teriflunomide in the Iranian context, the present 2-way crossover study aimed to assess the pharmacokinetic properties and bioequivalence of 2 teriflunomide formulations. To this end, 2 single-dose generic and branded teriflunomide formulations were orally administered to 14 healthy Iranian male volunteers. A washout period of 21 days was allowed between the treatments. The plasma samples containing teriflunomide were analyzed by a simple and sensitive high-performance liquid chromatography method using standard ultraviolet detection. In addition, the pharmacokinetic parameters were calculated for bioequivalence evaluation. The peak area ratio between the teriflunomide and the internal standard was the source of calibration curves, which were linear over the range of 20-40,000 ng/mL (R2 = 0.9994). The results indicated that the 2 formulations had similar pharmacokinetics. Further, the 90%CI of the mean ratios of the test versus the reference formulations of log-transformed area under the concentration-time curve over 72 hours (93% to 107%) and peak concentration (92% to 108%) were within the acceptable range of 80% to 125%. Based on the obtained results, the test formulation of teriflunomide could be similar to that of the reference formulation.


Subject(s)
Crotonates/administration & dosage , Drugs, Generic/administration & dosage , Toluidines/administration & dosage , Administration, Oral , Adult , Area Under Curve , Chromatography, High Pressure Liquid , Cross-Over Studies , Crotonates/pharmacokinetics , Drugs, Generic/pharmacokinetics , Humans , Hydroxybutyrates , Iran , Male , Middle Aged , Nitriles , Therapeutic Equivalency , Toluidines/pharmacokinetics , Young Adult
18.
J Neurol ; 267(3): 694-702, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31720848

ABSTRACT

Patients with multiple sclerosis on long-term injectable therapies may suffer from the so-called "needle fatigue", i.e., a waning commitment to continue with the prescribed injectable treatment. Therefore, alternative treatment strategies to enhance patients' adherence are warranted. In this independent, multicentre post-marketing study, we sought to directly compare switching to either teriflunomide (TFN), dimethyl fumarate (DMF), or pegylated interferon (PEG) on treatment persistence and time to first relapse over a 12-month follow-up. We analyzed a total of 621 patients who were free of relapses and gadolinium-enhancing lesions in the year prior to switching to DMF (n = 265), TFN (n = 160), or PEG (n = 196). Time to discontinuation and time to first relapse were explored in the whole population by Cox regression models adjusted for baseline variables and after a 1:1:1 ratio propensity score (PS)-based matching procedure. Treatment discontinuation was more frequent after switching to PEG (28.6%) than DMF (14.7%; hazard ratio [HR] = 0.25, p < 0.001) and TFN (16.9%; HR = 0.27, p < 0.001). We found similar results even in the re-sampled cohort of 222 patients (74 per group) derived by the PS-based matching procedure. The highest discontinuation rate observed in PEG recipient was mainly due to poor tolerability (p = 0.005) and pregnancy planning (p = 0.04). The low number of patients who relapsed over the 12-month follow-up (25 out of 621, approximately 4%) prevented any analysis on the short-term risk of relapse. This real-world study suggests that oral drugs are a better switching option than low-frequency interferon for promoting the short-term treatment persistence in stable patients who do not tolerate injectable drugs.


Subject(s)
Drug Substitution , Immunosuppressive Agents/administration & dosage , Medication Adherence , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Administration, Oral , Adult , Crotonates/administration & dosage , Dimethyl Fumarate/administration & dosage , Female , Humans , Hydroxybutyrates , Injections, Subcutaneous , Interferon alpha-2/administration & dosage , Interferon-alpha/administration & dosage , Male , Middle Aged , Nitriles , Polyethylene Glycols/administration & dosage , Product Surveillance, Postmarketing , Propensity Score , Recombinant Proteins/administration & dosage , Retrospective Studies , Toluidines/administration & dosage , Young Adult
19.
Int J Pharm ; 572: 118800, 2019 Dec 15.
Article in English | MEDLINE | ID: mdl-31678378

ABSTRACT

The aim of the present work was to develop compound transdermal patch containing teriflunomide (TEF) and ketoprofen (KTP) using permeation enhancement strategy; reveal the molecular mechanism by which Azone (AZ) promoted transdermal absorption of compound patch through the enhancement of drug-drug intermolecular interaction. The formulation was optimized using in vitro skin permeation study and confirmed with pharmacodynamics study, anti-inflammatory study and analgesics study. Enhanced drug-drug interaction by AZ was characterized using FT-IR, 13C NMR, molecular modeling and thermal analysis. The optimized formulation was composed of TEF (3%), KTP (2%), AZ (10%) and DURO-TAK® 87-4098 as adhesive matrix. The skin permeation amount of TEF-KTP combination was promoted by AZ about 1.9 times (594.2 ±â€¯46.8 µg/cm2) and 1.2 times (502.92 ±â€¯24.0 µg/cm2) compared with TEF-AZ and KTP-AZ individual patch. It was proved that the interaction between TEF and KTP via hydrogen bonding was further enhanced by AZ due to the increased molecular mobility of acrylate polymer (ΔTg = -17.7 °C), which was proved by FTIR and 13C NMR spectra. The enhanced drug-drug intermolecular interaction increased drug dispersed status and decreased the quantity of drug's hydrogen bonding site, thus increasing the drug release amount significantly. In conclusion, a compound transdermal patch containing KTP and TEF was developed successfully and a novel enhancement mechanism was clarified at molecular level, which provided reference for the development of novel compound transdermal patch.


Subject(s)
Analgesics/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Arthritis, Experimental/prevention & control , Azepines/administration & dosage , Crotonates/administration & dosage , Ketoprofen/administration & dosage , Pain/prevention & control , Skin Absorption/drug effects , Toluidines/administration & dosage , Transdermal Patch , Acetic Acid , Administration, Cutaneous , Analgesics/chemistry , Analgesics/pharmacokinetics , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Arthritis, Experimental/chemically induced , Azepines/chemistry , Crotonates/chemistry , Crotonates/pharmacokinetics , Drug Combinations , Drug Compounding , Drug Interactions , Drug Liberation , Freund's Adjuvant , Hydrogen Bonding , Hydroxybutyrates , Ketoprofen/chemistry , Ketoprofen/pharmacokinetics , Male , Mice , Nitriles , Pain/chemically induced , Permeability , Rabbits , Rats , Toluidines/chemistry , Toluidines/pharmacokinetics
20.
Dermatol Ther ; 32(6): e13103, 2019 11.
Article in English | MEDLINE | ID: mdl-31583801

ABSTRACT

Bacterial folliculitis, rosacea, and other common skin conditions have been linked to infestation by Demodex mites (human demodicosis). Currently, there is little guidance for treatment of inflammatory conditions associated with demodicosis. Thus, the objective of this review is to evaluate the efficacy and safety of treatments utilized for Demodex infestation. PubMed (1946 to January 2019) and Embase (1947 to January 2019) were searched with the following term combinations: Demodex mites, Demodex folliculitis, demodicosis, Demodex folliculorum, or Demodex brevis and articles evaluating treatment of body surface colonization with Demodex mites were included. Common interventions used for Demodex infestation include metronidazole-based therapies, permethrin, benzoyl benzoate, crotamiton, lindane, and sulfur. Short courses of metronidazole taken orally have shown efficacy in reducing Demodex density. Additionally, topical administration of permethrin daily or twice daily was shown to be efficacious across multiple studies. Crotamiton and benzyl benzoate were also efficacious treatments. Several therapies were associated with mild-to-moderate skin irritation. Due to limited data, no standard of care can be identified at this time. Efficacious treatment options may include permethrin, crotamiton, benzyl benzoate, and oral metronidazole; however, long-term efficacy has not been established.


Subject(s)
Mite Infestations/drug therapy , Administration, Topical , Benzoates/administration & dosage , Folliculitis/drug therapy , Humans , Metronidazole/administration & dosage , Permethrin/administration & dosage , Rosacea/drug therapy , Toluidines/administration & dosage
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