601 research outputs found
Long-term therapy of interferon-alpha induced pulmonary arterial hypertension with different PDE-5 inhibitors: a case report
BACKGROUND: Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare. CASE PRESENTATION: We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy. CONCLUSION: This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach
MYASTHENIA GRAVIS IN IRANIAN CHILDREN
ObjectiveThis study was undertaken to evaluate the clinical spectrum of myasthenia gravis in children and determine factors that help the clinician in his/her diagnosis and management.Materials & MethodsA retrospective review was performed on all pediatric patients suffering from myasthenia gravis (M.G) admitted in the department of pediatric neurology of the Mofid Hospital of the Shaheed Beheshti University, between 1994 and 2002.ResultsOf the thirty-two children with M.G. enrolled in our study, seven were suffering from the congenital type while the remaining (25 cases) had the juvenile M.G. Initial symptoms of congenital M.G were ptosis (7/7), limitation of eye movement (2/7) and mild generalized weakness (6/7). Although the Tensilon test was positive in 85% of congenital M.G cases, no myasthenia crisis or spontaneous remission was observed in any of them. In children with juvenile M.G, the age of presentation was 1.2 to 12.5 years, mean age 5.7+4.2 years (15 girls and 10 boys). The most common presenting symptoms in juvenile group were ptosis in 96% and generalized weakness in 76%. Eight of them (32%) had had at least one myasthenia crisis. EMG was diagnostic in 83% and one case the tensilon test was positive in 84%. One patient had hyperthyroidism and had already been diagnosed with hypothyroidism; two of them were epileptics. Eight patients underwent thymectomy microscopically; in specimens examined, five (62%) showed thymic follicular hyperplasia while in remaining three results were normal. One patient (12.5%) recovered completely after thymectomy with no need for medication during the follow up. Four patients (50%) showed relative improvement and in three cases (37%) improvement was negligible.ConclusionThe results showed a female to male ratio of 1.5/1 which was correlated to adult M.G. The most common presenting symptoms consisted of ophtalmoplegia, with bilateral ptosis being the most significant. Although this study revealed that thymectomy lacks any remarkable prognostic influence, all patients had thymectomy after two years of disease onset. Some reports have indicated positive results if surgery was performed within two years of onset of disease.Key words: Myasthenia gravis, Children, Thymectomy, Congenita
Intractable Seizure Disorders: Efficacy of The Classic Ketogenic Diet
ObjectiveThe ketogenic diet is a high-fat, low carbohydrate, adequate protein diet,developed in the 1920s for the management of intractable seizure disorders in children. To evaluate efficacy and tolerability of the classic ketogenic diet, we analyzed records of the children started on the diet from 1999 to 2006 at the Mofid children's hospital.Materials & Methods The subjects were 87 children, mean age 55 months. Before initiation of the diet, 55% of the patients had seizures, at least 1-4 times per day, 36% - 5 or more per day and 9% - 2 to 4 times per week. Mean number of Anti Epileptic Drugs (AEDs) tried for them was 8 and 67% were receiving three or more drugs.Results The ketogenic diet showed drastic improvement, with at least 50% reduction in seizure frequency in 87% of our patients, 39% of whom showed complete seizure control in the third month. After one year, in 80% of the patients who returned, improvement continued, with 26% of them being seizure free; besides, 23% had one AED decreased, 36% had two or three AEDs decreased, and 25% (one child) had all AEDs discontinued. Of the 30 improved cases, 20%, at the end of the first year, had improved behavior as well, and 23% of them had become more alert. The median diet duration of the improved group was 15 months.Conclusion The improvement in our patients, low side effects, and the duration of diet by families reveal that the ketogenic diet can still be a very useful alternative therapy in certain epileptic children.
Current and future treatments of pulmonary arterial hypertension
Therapeutic options for pulmonary arterial hypertension (PAH) have increased over the last decades. The advent of pharmacological therapies targeting the prostacyclin, endothelin, and NO pathways has significantly improved outcomes. However, for the vast majority of patients, PAH remains a life‐limiting illness with no prospect of cure. PAH is characterised by pulmonary vascular remodelling. Current research focusses on targeting the underlying pathways of aberrant proliferation, migration, and apoptosis. Despite success in preclinical models, using a plethora of novel approaches targeting cellular GPCRs, ion channels, metabolism, epigenetics, growth factor receptors, transcription factors, and inflammation, successful transfer to human disease with positive outcomes in clinical trials is limited. This review provides an overview of novel targets addressed by clinical trials and gives an outlook on novel preclinical perspectives in PAH
Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors
Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 μg/kg × min 8-Methoxymethyl-IBMX, 1 μg/kg × min sildenafil, 5 μg/kg × min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of P(PA )reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor
No pharmacodynamic (PD) and pharmacokinetic (PK) interaction of riociguat (BAY 63-2521) and aspirin
Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration
BACKGROUND: The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. METHODS: CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. RESULTS: Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. CONCLUSION: In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics
Multi tyrosine kinase inhibitor dasatinib as novel cause of severe pre-capillary pulmonary hypertension?
<p>Abstract</p> <p>Background</p> <p>Pulmonary hypertension (PH) is a life-threatening disease with poor prognosis. Encouraging efforts have been made to target the main vasoproliferative aspects of the disease. Promising emerging therapeutics are tyrosine kinase inhibitors such as imatinib.</p> <p>Case presentation</p> <p>Here, we discuss the relevance of previously published cases and add another well-characterised patient who developed pre-capillary PH under long-term therapy with the multi-tyrosine kinase inhibitor dasatinib approved for therapy of chronic myeloic leukaemia (CML) and Philadelphia chromosome positive acute lymphocytic leukaemia (mean time of all patients on dasatinib: 26 months). Hence, we discuss the possibility of dasatinib itself causing PH after long-term therapy and turn specialist's attention to this possible severe side effect.</p> <p>At present, the true incidence of dasatinib-associated PH remains illusive and systematic data regarding haemodynamics are missing.</p> <p>Conclusion</p> <p>We therefore recommend systematic screening of dasatinib-treated patients for pulmonary hypertension and subsequent collection of haemodynamic data.</p
A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension
Copyright The Author(s) 2016. This article is published with open access at Springerlink.com. Open Access - This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were madePulmonary arterial hypertension (PAH) is a chronic and progressive disease which continues to carry an unacceptably high mortality and morbidity. The nitric oxide (NO) pathway has been implicated in the pathophysiology and progression of the disease. Its extremely short half-life and systemic effects have hampered the clinical use of NO in PAH. In an attempt to circumvent these major limitations, we have developed a new NO-nanomedicine formulation. The formulation was based on hydrogel-like polymeric composite NO-releasing nanoparticles (NO-RP). The kinetics of NO release from the NO-RP showed a peak at about 120 min followed by a sustained release for over 8 h. The NO-RP did not affect the viability or inflammation responses of endothelial cells. The NO-RP produced concentration-dependent relaxations of pulmonary arteries in mice with PAH induced by hypoxia. In conclusion, NO-RP drugs could considerably enhance the therapeutic potential of NO therapy for PAH.Peer reviewedFinal Published versio
Identification of splice defects due to noncanonical splice site or deep‐intronic variants in ABCA4
Pathogenic variants in the ATP-binding cassette transporter A4 (ABCA4) gene cause a continuum of retinal disease phenotypes, including Stargardt disease. Noncanonical splice site (NCSS) and deep-intronic variants constitute a large fraction of disease-causing alleles, defining the functional consequences of which remains a challenge. We aimed to determine the effect on splicing of nine previously reported or unpublished NCSS variants, one near exon splice variant and nine deep-intronic variants in ABCA4, using in vitro splice assays in human embryonic kidney 293T cells. Reverse transcription-polymerase chain reaction and Sanger sequence analysis revealed splicing defects for 12 out of 19 variants. Four deep-intronic variants create pseudoexons or elongate the upstream exon. Furthermore, eight NCSS variants cause a partial deletion or skipping of one or more exons in messenger RNAs. Among the 12 variants, nine lead to premature stop codons and predicted truncated ABCA4 proteins. At least two deep-intronic variants affect splice enhancer and silencer motifs and, therefore, these conserved sequences should be carefully evaluated when predicting the outcome of NCSS and deep-intronic variants
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