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2.
BMC Neurol ; 20(1): 357, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967641

RESUMO

BACKGROUND: Identifying causes of alemtuzumab induced respiratory symptoms in Multiple Sclerosis (MS) patients is crucial. CASE PRESENTATION: We report a case of diffuse alveolar damage (DAD) in a patient with MS after the first course of alemtuzumab treatment. A 42-year-old female developed progressive non-productive cough and exertional dyspnea 2 months after alemtuzumab treatment. DAD was diagnosed histopathologically by lung biopsy. The patient recovered completely, alemtuzumab was not continued. CONCLUSIONS: Our case highlights another pathomechanism for non-infective lung-disorders in alemtuzumab treated MS patients. DAD is a potential, albeit rare side effect of alemtuzumab, broadening the spectrum of non-infective lung disorders that should be considered in the diagnostic work-up.


Assuntos
Alemtuzumab/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Alvéolos Pulmonares/patologia , Adulto , Feminino , Humanos
3.
Kidney Int ; 93(1): 159-172, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29042083

RESUMO

Volume retention in nephrotic syndrome has been linked to activation of the epithelial sodium channel (ENaC) by proteolysis of its γ-subunit following urinary excretion of serine proteases such as plasmin. Here we tested whether pharmacological inhibition of urinary serine protease activity might protect from ENaC activation and volume retention in nephrotic syndrome. Urine from both nephrotic mice (induced by doxorubicin injection) and nephrotic patients exhibited high aprotinin-sensitive serine protease activity. Treatment of nephrotic mice with the serine protease inhibitor aprotinin by means of subcutaneous sustained-release pellets normalized urinary serine protease activity and prevented sodium retention, as did treatment with the ENaC inhibitor amiloride. In the kidney cortex from nephrotic mice, immunofluorescence revealed increased apical γ-ENaC staining, normalized by aprotinin treatment. In Xenopus laevis oocytes heterologously expressing murine ENaC, aprotinin had no direct inhibitory effect on channel activity but prevented proteolytic channel activation. Thus, our study shows that volume retention in experimental nephrotic syndrome is related to proteolytic ENaC activation by proteasuria and can be prevented by treatment with aprotinin. Hence, inhibition of urinary serine protease activity might become a therapeutic approach to treat patients with nephrotic-range proteinuria.


Assuntos
Aprotinina/farmacologia , Edema/tratamento farmacológico , Canais Epiteliais de Sódio/efeitos dos fármacos , Rim/efeitos dos fármacos , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/enzimologia , Serina Proteases/urina , Inibidores de Serina Proteinase/farmacologia , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Doxorrubicina , Edema/enzimologia , Edema/etiologia , Edema/fisiopatologia , Canais Epiteliais de Sódio/genética , Canais Epiteliais de Sódio/metabolismo , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos da Linhagem 129 , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/fisiopatologia , Proteólise , Transdução de Sinais/efeitos dos fármacos , Xenopus laevis
5.
Neurol Res Pract ; 4(1): 55, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36336685

RESUMO

BACKGROUND: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing-remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. METHODS: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. RESULTS: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. CONCLUSION: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE.

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