A comparison between the effects of two liposome-encapsulated bevacizumab formulations on ocular neovascularization inhibition.

Bevacizumab (BVZ), an anti-VEGF antibody, has demonstrated reliable outcomes in the treatment of irritating ocular neovascularization. Frequent intravitreal injections are necessitated due to rapid clearance and short local accessibility. We recruited liposome as a highly prevailing drug delivery system to enhance drug availability. Two liposome formulations were characterized and their in vitro stability was analyzed. The toxicity of the formulations on some ocular cell lines was also evaluated. In addition, the anti-angiogenic effects of formulations were examined. Drug permeation was measured across ARPE-19 and HCE cell lines as in vitro cellular barrier models. Results revealed that NLP-DOPE-BVZ acquired high stability at 4 °C, 24 °C, and 37 °C for 45 days. It also showed more capacity to entrap BVZ in NLP-DOPE-BVZ (DEE% 69.1 ± 1.4 and DLE% 55.66 ± 1.15) as compared to NLP-BVZ (DEE% 43.57 ± 14.64, and DLE% 37.72 ± 12.01). Although both formulations inhibited the migration and proliferation of HUVECs, NLP-DOPE-BVZ was more effective at inhibiting angiogenesis. Furthermore, NLP-DOPE-BVZ better crossed our established barrier cellular models. Based on the findings, the inclusion of DOPE in NLPs has significantly enhanced the features of drug carriers. This makes them a potential candidate for treating ocular neovascularization and other related ailments.

Formulation of nanoliposome-encapsulated bevacizumab (Avastin): Statistical optimization for enhanced drug encapsulation and properties evaluation.

Bevacizumab (Avastin®), an anti-vascular endothelial growth factor, is one of the most effective drugs widely used to inhibit ocular angiogenesis. Nanoliposomes were recruited to improve the accessibility of bevacizumab (BVZ) during treatment. To optimize drug entrapment efficiency (DEE %), the effect of some independent variables was evaluated utilizing response surface methodology. The optimized formulation containing BVZ (NLP-BVZ) was characterized, and its safety was assessed. Employingarising retinalpigment epithelial (ARPE) cells, the permeability of the nanoliposome was analyzed. Structural stability and integrity of NLP-BVZ were also estimated with different methods. Optimal condition for the maximum DEE (39.9%) was obtained with cholesterol/DPPC (1,2-Dipalimitoyl-Sn-glycero-3-phosphocholine) (%w/w) 13.64, BVZ/DPPC (%w/w) 83.78 and 9 freeze-thaw cycles. Neutral fabricated NLP-BVZ with an average size of 141.5 ±â€¯45.8 nm showed a smooth spherical structure and released the drug in a slow and sustained fashion. The formulation exhibited no obvious effect against human umbilical vein endothelial cells (HUVECs) and ARPEs. Additionally, the pattern of the circular dichroism (CD) and intrinsic fluorescence spectra confirmed the structural integrity of protein remained conserved after encapsulation. Taken together, the analysis indicated that the process of entrapment into nanoliposome meaningfully made the drug safer, more stable, and, therefore, appropriate for treating ocular disorders.

Mutations in C19orf12 and intronic repeat expansions in C9orf72 not observed in Iranian Parkinson's disease patients.

Various neurodegenerative disorders share some clinical features that sometimes renders differential diagnosis challenging. Genetic-based classification also has limitations as mutations in the same gene are sometimes associated with different clinically based diagnoses. In this light, we screened the C19orf12 neurodegeneration with brain iron accumulation (NBIA) causing gene and the C9orf72 intronic expansion mutation that is cause of amyotrophic lateral sclerosis in 186 Iranian Parkinson's disease (PD) patients. C19orf12 has previously been screened in PD patients in only one study, and to the best of our knowledge neither gene has ever been screened in a PD cohort from a Middle East population. The study was justified because mutations in C19orf12 had previously been shown to be common in Iranian neurodegeneration with brain iron accumulation patients and all the patients with mutations in this gene had exhibited Parkinsonism features. The C9orf72 intronic expansion mutation was screened because the mother of an Iranian amyotrophic lateral sclerosis patient with the expansion who had been diagnosed with PD also harbored the expansion. The screenings did not identify disease causing variations in either of the genes among the PD patients screened.

Identification of p.Gln858* in ATP13A2 in two EOPD patients and presentation of their clinical features.

We present results of homozygosity mapping in two siblings affected with early onset Parkinson's disease (EOPD) and mutation screening of ATP13A2 in these and other Iranian EOPD patients. Genome-wide SNP homozygosity analysis revealed linkage to a locus that included ATP13A2, and sequencing of the gene revealed a novel p.Gln858*-causing mutation in the homozygous state in the siblings. Sequencing of the gene in seven other unrelated EOPD patients previously shown not to have mutations in PRKN, DJ-1, PINK1, and LRRK2 identified the same homozygous p. Gln858*-causing mutation in another patient. Haplotype analysis revealed that two alleles harboring the mutation were not identical by decent. The variation identified represents the 13th known disease causing mutation in ATP13A2. The clinical features of the patients who harbored the mutation are compared to those of previously reported patients with mutations in ATP13A2. Bradykinesia and rigidity, but not tremor, were reported in nearly all the patients. l-dopa administration, though initially effective, usually caused dyskinesia upon prolonged usage. Eye movement abnormalities including saccades and supranuclear gaze palsy, were almost always observed. Dystonia and bulbar anomalies were common but more variable manifestations. Although a degree of cognitive decline was found in most of the patients, the decline was often mild and absent in one patient. Age at onset of symptoms was usually in the second decade of life, and sometimes in the third decade.

The novel mutation p.Asp251Asn in the ß-subunit of succinate-CoA ligase causes encephalomyopathy and elevated succinylcarnitine.

SUCLA2 is one of several nuclear-encoded genes that can cause encephalomyopathy accompanied by mitochondrial DNA depletion. The disorder usually manifests in early childhood and leads to early death. The gene encodes one of the subunits of succinyl-CoA synthase, the enzyme that catalyzes the reversible conversion of substrates succinyl-CoA and ADP to products succinate and ATP in the tricarboxylic acid pathway. Thirty-two individuals harboring mutations in SUCLA2 have so far been reported, and five different mutations were observed among these individuals. Here we report identification of a novel mutation in SUCLA2 in two cousins affected with encephalomyopathy. The novel mutation causes p.Asp251Asn; the affected amino acid is likely positioned within the ATP-grasp domain of the encoded protein. As previously reported in other patients, we did not observe elevation of methylmalonic acid, the biochemical hallmark of patients with mutations in SUCLA2. We instead found elevated levels of succinylcarnitine.