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Two decades of research on RNA interference (RNAi) have transformed a breakthrough discovery in biology into a robust platform for a new class of medicines that modulate mRNA expression. Here we provide an overview of the trajectory of small-interfering RNA (siRNA) drug development, including the first approval in 2018 of a liver-targeted siRNA interference (RNAi) therapeutic in lipid nanoparticles and subsequent approvals of five more RNAi drugs, which used metabolically stable siRNAs combined with N-acetylgalactosamine ligands for conjugate-based liver delivery. We also consider the remaining challenges in the field, such as delivery to muscle, brain and other extrahepatic organs. Today's RNAi therapeutics exhibit high specificity, potency and durability, and are transitioning from applications in rare diseases to widespread, chronic conditions. With six approved drugs, siRNA is now an established therapeutic modality poised for expansion. [ABSTRACT FROM AUTHOR]

Topical drug dosage forms such as ointments and creams can be easily removed through wetting, movement and contact. The new bioadhesive formulations with enhanced local anesthetic effects are needed for topical administration. The adhesive capacity of hydroxypropyl methylcellulose (HPMC) was determined by measuring the maximum detachment force and the adhesion work with an auto peeling tester. Topical delivery of Bupivacaine via various formulation approaches has been investigated in the present research work. Novel clear, stable, hydrogels, nanoemulsion based gels and metered dose film forming sprays of Bupivacaine base and its pharmaceutically acceptable HCl salt at 5% and 10% concentrations respectively for topical delivery has been developed and optimized. The formulations were developed to modulate the drug diffusion and accumulation at the intended site to exhibit the desired response. Topical hydrogels of Bupivacaine HCl were developed using co-solvents and penetration enhancers. The optimized hydrogels exhibited desired consistency, homogeneity, spreadabiltity and stability. Since, the polymers were water soluble; consequently, water washable gels were formed and offered benefits like ease of application and ease of removal. The bupivacaine gels containing both penetration enhancer and vasoconstrictor showed enhancement and prolonged efficacy compared to the control gel. To enhance the local anesthetic effects of bupivacaine, the transdermal bupivacaine gel formulation containing penetration enhancer and vasoconstrictor could be developed. [ABSTRACT FROM AUTHOR]

In this paper a hybrid genetic algorithmis used to study the employee scheduling problem in pharmaceutical industries. Scheduling is done based on the aspects of both management and employees. The management aspect is to reduce the total cost of the employee by minimizing the makes span. The employee aspects are a preferred number of shifts, shift types, days off, etc. In this scheduling an extra care is taken in not to assign a night shift on the day beforethe day off, because once a night shift assigned to the employee almost present in the next morning. A mathematical model is formed based on flexible working of the employees. In this model, 6 hour shifts isallotted to the employees, which reduces the total cost by 10.135% and the makes span by 4.145% compared to the other models. [ABSTRACT FROM AUTHOR]

Identifying genetic variants associated with lower waist-to-hip ratio can reveal new therapeutic targets for abdominal obesity. We use exome sequences from 362,679 individuals to identify genes associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI), a surrogate for abdominal fat that is causally linked to type 2 diabetes and coronary heart disease. Predicted loss of function (pLOF) variants in INHBE associate with lower WHRadjBMI and this association replicates in data from AMP-T2D-GENES. INHBE encodes a secreted protein, the hepatokine activin E. In vitro characterization of the most common INHBE pLOF variant in our study, indicates an in-frame deletion resulting in a 90% reduction in secreted protein levels. We detect associations with lower WHRadjBMI for variants in ACVR1C, encoding an activin receptor, further highlighting the involvement of activins in regulating fat distribution. These findings highlight activin E as a potential therapeutic target for abdominal obesity, a phenotype linked to cardiometabolic disease. Abdominal fat has been shown to increase cardiometabolic disease risk. In this study, the authors report that loss-of-function variants in the gene INHBE associate with lower BMI-adjusted waist-to-hip ratio, a surrogate measure of abdominal fat. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3–4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6–15.6, p = 4.2 × 10−5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2–2.4, p = 6.0 × 10–3) and Million Veteran Program (OR = 1.5, 95% CI 1.2–1.8, p = 1.8 × 10−4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7–4.5, p = 2.6 × 10−5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Vutrisiran (ALN‐TTRsc02) is a liver‐directed, investigational, small interfering ribonucleic acid drug for the treatment of transthyretin (TTR)‐mediated amyloidosis. This phase I, randomized, single‐blind, placebo‐controlled, single ascending dose study evaluated the pharmacodynamics, pharmacokinetics, and safety profile of subcutaneously administered vutrisiran (5–300 mg) in healthy subjects (n = 80). Vutrisiran treatment achieved potent and sustained TTR reduction in a dose‐dependent manner, with mean maximum TTR reduction of 57–97%, maintained for ≥ 90 days post dose. Vutrisiran was rapidly absorbed (peak plasma concentration 3–5 hours post dose), had a short plasma half‐life (4.2–7.5 hours), and plasma concentrations increased in a dose‐proportional manner. Pharmacodynamic and pharmacokinetic results were similar in Japanese and non‐Japanese subjects. Vutrisiran had an acceptable safety profile; the most common treatment‐related adverse event was mild, transient injection site reactions in four (6.7%) vutrisiran‐treated subjects. The favorable pharmacokinetic, pharmacodynamic, and safety results observed here support vutrisiran's continued clinical development. [ABSTRACT FROM AUTHOR]

Purpose: The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. Methods: Patients with hATTR amyloidosis with cardiomyopathy were randomized 2:1 to receive subcutaneous daily revusiran 500 mg (n = 140) or placebo (n = 66) for 5 days over a week followed by weekly doses. Co-primary endpoints were 6-min walk test distance and serum TTR reduction. Results: Revusiran treatment was stopped after a median of 6.71 months; the study Sponsor prematurely discontinued dosing due to an observed mortality imbalance between treatment arms. Eighteen (12.9%) patients on revusiran and 2 (3.0%) on placebo died during the on-treatment period. Most deaths in both treatment arms were adjudicated as cardiovascular due to heart failure (HF), consistent with the natural history of the disease. A post hoc safety investigation of patients treated with revusiran found that, at baseline, a greater proportion of those who died were ≥ 75 years and showed clinical evidence of more advanced HF compared with those who were alive throughout treatment. Revusiran pharmacokinetic exposures and TTR lowering did not show meaningful differences between patients who died and who were alive. Revusiran did not deleteriously affect echocardiographic parameters, cardiac biomarkers, or frequency of cardiovascular and HF hospitalization events. Conclusions: Causes for the observed mortality imbalance associated with revusiran were thoroughly investigated and no clear causative mechanism could be identified. Although the results suggest similar progression of cardiac parameters in both treatment arms, a role for revusiran cannot be excluded. Clinical Trial Registration: NCT02319005. [ABSTRACT FROM AUTHOR]

Introduction: Nutritional deficiency may result in adverse health consequences. Socio-cultural practices, financial condition, awareness of parents and local factors influence the nutritional status. Malnutrition is one of the leading health issues in India. Aim: To assess the nutritional status of school age children and the influence of socioeconomic status on nutrition. Materials and Methods: A community based cross-sectional study was conducted among 208 numbers of school children (4-14 years) in Guntur and Vijayawada slum areas during July and August 2018. Semi-structured questionnaire was used to collect anthropometric and general data. Anthropometric measurements such as weight in Kg and height in cm were recorded. Chi-square test, unpaired t-test and Multivariate analysis were used to assess nutritional status at 5% level of significance. Results: The prevalence of stunted children (low height for age), Wasted children (low BMI for age) were 46.63% and 48.08%, respectively. The percentage of children with underweight (low weight for age), overweight (high BMI for age) were 68.27% and 4.80%, respectively. 53.85% underweight children belonged to lower socioeconomic status. No difference in prevalence was observed among boys and girls for stunting and underweight (p>0.05). The mean heights of normal and stunted children were significantly different (p<0.01). The mean weights of normal and underweight were significantly different (p<0.01). The mean BMIs of normal and wasted children were significantly different (p<0.01). Conclusion: Both boys and girls had equal prevalence of malnutrition. Prevalence of stunting, underweight and wasting were more than that of national prevalence. Underweight are significantly high in low socio-economic status and nuclear family. [ABSTRACT FROM AUTHOR]

A Systematic scientific study of the subject of luminescence is of recent origin, from the middle of 19th century. Due to excellent photo-resistance and chemical stability, great brightness, long-lasting time, no radiation and environmental capability, which resulted in their wide applications in many fields, are more appropriately focused by scientists and engineers. From this literature review we got to know that the tetra strontium aluminate phosphors could be synthesized by solid state reaction method and combustion method. By doping different rare earth in a host matrix the emission color could be changed. [ABSTRACT FROM AUTHOR]

Short interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) are the most clinically advanced oligonucleotide-based platforms. A number of N-acetylgalactosamine (GalNAc)-conjugated siRNAs (GalNAc-siRNAs), also referred to as RNA interference (RNAi) therapeutics, are currently in various stages of development, though none is yet approved. While the safety of ASOs has been the subject of extensive review, the nonclinical safety profiles of GalNAc-siRNAs have not been reported. With the exception of sequence differences that confer target RNA specificity, GalNAc-siRNAs are largely chemically uniform, containing limited number of phosphorothioate linkages, and 2’-O-methyl and 2’-deoxy-2’-fluoro ribose modifications. Here, we present the outcomes of short-term (3–5 week) rat and monkey weekly repeat-dose toxicology studies of six Enhanced Stabilization Chemistry GalNAc-siRNAs currently in clinical development. In nonclinical studies at supratherapeutic doses, these molecules share similar safety signals, with histologic findings in the organ of pharmacodynamic effect (liver), the organ of elimination (kidney), and the reticuloendothelial system (lymph nodes). The majority of these changes are nonadverse, partially to completely reversible, correlate well with pharmacokinetic parameters and tissue distribution, and often reflect drug accumulation. Furthermore, all GalNAc-siRNAs tested to date have been negative in genotoxicity and safety pharmacology studies. [ABSTRACT FROM AUTHOR]

In this paper, an average informational parameter based approach for lung cancer detection and diagnosis has been proposed. Suggested methodology is established on average information parameters by utilizing image processing tools for lung cancer investigation. The real issue with the lung cancer diseases is the time constraint for physical diagnosis that expands the death possibilities. Henceforth essentially proposed technique is an approach that would help the medical practitioners for precise and superior decision against the lung cancer discovery. The crucial point in the proposed method is that it helps the doctors for taking a firm decision on lung cancer diagnosis. Microscopic lung images are taken for analysis and investigation by using digital image processing techniques which also recovers the quality of images that has been degraded by several reasons including random noise. The statistical parameters are implemented for lung cancer analysis. The statistical and mathematical parameters are implemented like Entropy, Standard Deviation, Mean, Variance and MSE under average information method. The statistical range of each parameter is calculated for number of iterations. The individual statistical parameter analysis with its impact on lung cancer images is carried out and finally the Artificial Neural Network is the final decision maker in lung cancer diagnosis. This paper also rejects the null hypothesis test by implementing one of the standard statistical methods. [ABSTRACT FROM AUTHOR]

We studied preexisting respiratory syncytial virus (RSV)-specific serum and nasal antibodies and their correlation with infectivity, viral dynamics, and disease severity in a human experimental infection model. Higher preinoculation serum neutralizing antibody titers and nasal immunoglobulin (Ig) A predicted lower infectivity and lower measures of viral replication. However, once individuals were infected, no significant protective effect of preexisting antibodies was seen. Lack of correlation between serum and mucosal antibodies was observed, implying that they are independent co-correlates of protection against RSV infection. We suggest that protection from RSV infection is a function of a complex interplay between mucosal and serum humoral immune responses. [ABSTRACT FROM AUTHOR]

Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. [ABSTRACT FROM AUTHOR]

Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n=4), 0.05 (n=3), 0.15 (n=3), or 0.3(n=7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. [ABSTRACT FROM AUTHOR]

Metformin hydrochloride is oral antidiabetic drug belonging to the biguanide class of drugs. Metformin hydrochloride is used to treat non-insulin dependent diabetes mellitus (NIDDM-Type II diabetes), alone or in combination with other hypoglycaemic agents. It is also used in the treatment of polycystic ovary syndrome. The objective of the study was to prepare the sodium alginate beads of antidiabetic drug Metformin hydrochloride to provide sustained release effect. Five batches (F1-F5) were formulated by using varying concentration of drug and polymer. In this method drugs were blended with biopolymer and sodium alginate in different ratio (1:1, 1:2, 1:3, 1:4 and 1:5) and calcium chloride was used as a cross-linking agent. Metformin loaded Alginate beads were formulated by ionotropic gelation and prepared beads were evaluated with respect to its particle size, surface characteristics, entrapment effiency, swelling index, loss on drying, total moisture content and in-vitro release of drug. From the above investigation it was found that the biopolymer will serve as a better alternative to develop the alginate bead. [ABSTRACT FROM AUTHOR]

Cefixime is an antibiotic useful for the treatment of a number of bacterial infections. It is a third generationcephalosporin. The bactericidal action of cephalosporin is due to the inhibition of cell wall synthesis. It binds to one of the penicillin binding proteins (PBPs) which inhibit the final transpeptidation step of the peptidoglycan synthesis in the bacterial cell wall, thus inhibiting biosynthesis and arresting cell wall assembly resulting in bacterial cell death. Recently biopolymer was used as material for conventional as well as novel dosage form development. The biopolymer was isolated from the seed of Glycine max (Soybean) by non solvent addition method. The merits of biopolymers have over synthetic polymers are low cost, natural origin, nontoxic, biocompatible, biodegradable, environmental friendly processing, local availability, better patient tolerance as well as public acceptance. The polymer were subjected to its physicochemical, phytochemical and micromeritic studies. [ABSTRACT FROM AUTHOR]

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RNA interference (RNAi) is a natural mechanism regulating protein expression that is mediated by small interfering RNA5 (siRNA). Harnessing RNAi has potential to treat human disease; however. clinical evidence for the effectiveness of this therapeutic approach is lacking. ALN-RSV01 is an siRNA directed against the mRNA of the respiratory syncytial virus (RSV) nucleocapsid (N) protein and has substantial antiviral activity in a murine model of RSV infection. We tested the antiviral activity of ALN-RSV01 in adults experimentally infected with wild-type RSV. Eighty-eight healthy subjects were enrolled into a randomized, double-blind, placebo-controlled trial. A nasal spray of ALN-RSV01 or saline placebo was administered daily for 2 days before and for 3 days after RSV inoculation. RSV was measured serially in nasal washes using several different viral assays. Intranasal ALN-RSV01 was well tolerated, exhibiting a safety profile similar to saline placebo. The proportion of culture-defined RSV infections was 71.4 and 44.2% in placebo and ALN-RSV01 recipients, respectively (P = 0.009), representing a 38% decrease in the number of infected and a 95% increase in the number of uninfected subjects. The acquisition of infection over time was significantly lower in ALN-RSV01 recipients (P = 0.007 and P = 0.03, viral culture and PCR, respectively). Multiple logistic regression analysis showed that the ALN-RSV01 antiviral effect was independent of other factors, including preexisting RSV antibody and intranasal proinflammatory cytokine concentrations. ALN-RSV01 has significant antiviral activity against human RSV infection, thus establishing a unique proof-of-concept for an RNAi therapeutic in humans and providing the basis for further evaluation in naturally infected children and adults. [ABSTRACT FROM AUTHOR]

Fire and Mello initiated the current explosion of interest in RNA interference (RNAi) biology with their seminal work in Caenorhabditis elegans. These observations were closely followed by the demonstration of RNAi in Drosophila melanogaster. However, the full potential of these new discoveries only became clear when Tuschl and colleagues showed that 21-22 bp RNA duplexes with 3" overhangs, termed small interfering (si)RNAs, could reliably execute RNAi in a range of mammalian cells. Soon afterwards, it became clear that many different human cell types had endogenous machinery, the RNA-induced silencing complex (RISC), which could be harnessed to silence any gene in the genome. Beyond the availability of a novel way to dissect biology, an important target validation tool was now available. More importantly, two key properties of the RNAi pathway - sequence-mediated specificity and potency - suggested that RNAi might be the most important pharmacological advance since the advent of protein therapeutics. The implications were profound. One could now envisage selecting disease-associated targets at will and expect to suppress proteins that had remained intractable to inhibition by conventional methods, such as small molecules. This review attempts to summarize the current understanding on siRNA lead discovery, the delivery of RNAi therapeutics, typical in vivo pharmacological profiles, preclinical safety evaluation and an overview of the 14 programs that have already entered clinical practice. [ABSTRACT FROM AUTHOR]

Examines the relationship between the pharmacodynamic and antipsoriatic effects of alefacept, a biologic agent that targets CD4+ and CD8+ memory T cells. Use of circulating lymphocyte levels and the psoriasis area severity index; Observation that one or two courses of alefacept reduced CD4+ and CD8+ memory T-cell counts; Finding that the reductions in memory T-cell counts were related to all measures of disease activity evaluated and the duration of response to therapy.

Alefacept, human LFA-3/IgGz[sub 1] fusion protein, is currently under clinical development for the treatment of chronic plaque psoriasis and other T cell mediated disorders. This recombinant protein binds CD2 on T cells and FcγRIII on accessory cells (e.g., natural killer cells, macrophages), inhibiting T cell activation/proliferation and inducing selective T cell apoptosis. These effects are associated with selective reductions in memory-effector (CD4[sup +]CD45RO[sup +] and CD8[sup +]CD45RO[sup +]) T cells. Two open-label studies were conducted in healthy male volunteers to evaluate the pharmacokinetics, biologic activity, and tolerability of a single dose of alefacept when administered as a 0.15 mg/kg 30-sec i.v. bolus (n=12), 0.04 mg/kg intramuscular (i.m.) injection (n=8), or 0.04mg/kg 30-min intravenous (i.v.) infusion (n=8). I.V. infusion produced a higher C[sub max] (0.96 ± 0.26 mcg/ml vs. 0.36 ± 0.19 mcg/ml) and a shorter T[sub max] (2.8 ± 1.9 hr vs. 86 ± 60 hr) when compared to i.m. injection. Based on A UC[sub 0-last] and A UC[sub 0-∞] values, the relative bioavailability of i.m. to i.v. infusion was approximately 60%. After absorption from the i.m. injection was complete, the rate of alefacept elimination from the serum appeared consistent with the i.v. infusion half-life (approximately 12 days). Biologic activity was demonstrated by transient reductions in absolute number of CD2[sup +] lymphocytes, with notable specificity for memory T-cell subsets. Alefacept was well tolerated; the most common adverse effects were headache, pharyngitis, rash, and myalgia. IM administration was not associated with significant local reactions. Results of these studies support i.v. bolus or i.m. administration of alefacept. An i.m. dose of approximately 150 to 200% of the i.v. dose is an appropriate and convenient alternative to i.v. administration. [ABSTRACT FROM AUTHOR]

Human complement component C4 is encoded by two structurally distinct loci in the major histocompatibility complex (MHC) class III region. The two isotypes, C4A and C4B, differ at only four residues in the C4d fragment, but C4 constitutes the most polymorphic of the complement components. It is not known, however, whether the regions involved in the regulation of C4 expression also display polymorphic variation. By using the technique of DNase I hypersensitivity mapping, we established that the only area of transcriptional activity for C4 in the hepatocyte cell line, HepG2, occurs approximately 500 base pairs upstream of the transcriptional start site. This region was found to be remarkably constant in sequence when analyzed in the context of differing MHC haplotypes including HLA B57, C4A6, C4B1, DR7, which has been correlated with reduced expression of the C4A isotpye. Similarly, polymerase chain reaction followed by single-strand conformation polymorphism analysis failed to demonstrate any promoter polymorphisms in 103 individuals comprising 52 systemic lupus erythematosus patients and 51 healthy controls. [ABSTRACT FROM AUTHOR]

The original article contained incorrect terminology for one of the cardiac measures; throughout the manuscript and supplementary information 'intraventricular septum wall thickness' should have been given as 'interventricular septum wall thickness'. Corrections should also be noted for Tables 1 and 4: in the Table 1 legend 'Low risk – Neither above at baseline' should read 'Low risk – Neither above threshold at baseline'; in Table 4, the rows 'Mild: eGFR > 60 to < 90 ml/min/1.73 m2' and 'Moderate: eGFR > 30 to < 60 ml/min/1.73 m2' should read 'Mild: eGFR ≥ 60 to < 90 ml/min/1.73 m2' and 'Moderate: eGFR ≥ 30 to < 60 ml/min/1.73 m2', respectively. The original article also contained a mistake in the text of the Pharmacokinetics sub-section of Results; 'There were no apparent differences in revusiran Cmaxbetween patients with mild (eGFR: 30 and < 60 ml/min/1.73 m2) or moderate (eGFR: 60 to < 90 ml/min/1.73 m2) renal impairment when compared with patients with normal (eGFR: ≥ 90 ml/min/1.73 m2) renal function at Weeks 0, 26, and 52 (p > 0.20) (Supplementary Fig. 6)' should read 'There were no apparent differences in revusiran Cmaxbetween patients with mild (eGFR: ≥ 60 to < 90 ml/min/1.73 m2) or moderate (eGFR: ≥ 30 and < 60 ml/min/1.73 m2) renal impairment when compared with patients with normal (eGFR: ≥ 90 ml/min/1.73 m2) renal function at Weeks 0, 26, and 52 (p > 0.20) (Supplementary Fig. 6)'. [ABSTRACT FROM AUTHOR]

Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP).Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W).Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis).Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development.Trial Registration Number: NCT01617967 . [ABSTRACT FROM AUTHOR]