The Great Masquerade: Varying Manifestations of Lysinuric Protein Intolerance.

Lysinuric protein intolerance (LPI) is an inborn metabolic error caused by cationic amino acid transport defects. The disease has a significant degree of phenotypic variation, with no confirmed genotype-phenotype correlation. Because it presents with symptoms similar to far more common diseases, the diagnosis is often missed, resulting in increased morbidity and mortality. This case series describes three examples of LPI with pulmonary, neurological, and immunological manifestations, emphasising the importance of keeping this disorder on the differential list. Appropriate metabolic and genetic testing is important in providing the correct diagnosis and timely care in such cases.

Hematopoietic Stem Cell Transplantation for Storage Disorders: Present Status.

Storage disorders are a group of inborn errors of metabolism caused by the defective activity of lysosomal enzymes or transporters. All of these disorders have multisystem involvement with variable degrees of neurological features. Neurological manifestations are one of the most difficult aspects of treatment concerning these diseases. The available treatment modalities for some of these disorders include enzyme replacement therapy, substrate reduction therapy, hematopoietic stem cell transplantation (HSCT) and the upcoming gene therapies. As a one-time intervention, the economic feasibility of HSCT makes it an attractive option for treating these disorders, especially in lower and middle-income countries. Further, improvements in peri-transplantation medical care, better conditioning regimens and better supportive care have improved the outcomes of patients undergoing HSCT. In this review, we discuss the current evidence for HSCT in various storage disorders and its suitability as a mode of therapy for the developing world.

Effect of Differential Surface Anisotropy on Dissolution Behavior of Fenofibrate Crystal Habits: Comparative Study using USP Type 2 and Type 4 Dissolution Apparatuses.

The solid-state properties of active pharmaceutical ingredient (API) have significant impact on its dissolution performance. In the present study, two different crystal habits viz. rod and plate shape of form I of FEN were evaluated for dissolution profile using USP Type 2 and Type 4 apparatuses. Molecular basis of differential dissolution performance of different crystal habits was investigated. Rod (FEN-R) and plate (FEN-P) shaped crystal habits of Form I of FEN were generated using anti-solvent crystallization method. Despite the same polymorphic form and similar particle size distribution, FEN-P demonstrated higher dissolution performance than FEN-R. Crystal face indexation and electrostatic potential (ESP) map provided information on differential relative abundance of various facets and their molecular environment. In FEN-R, the dominant facet (001) is hydrophobic due to the exposure of chlorophenyl moiety. Whereas, in FEN-P the dominant facet (01-1) was hydrophilic due to the presence of chlorine and ester carbonyl groups. Deeper insight on the impact of different facets on dissolution behavior was obtained by energy framework analysis by unveiling strength of intermolecular interactions along various crystallographic facets. Moreover, type 4 apparatus provided higher discriminatory ability over USP Type 2 apparatus, in probing the crystal habit induced differential dissolution performance of FEN. The findings of this study emphasize that crystal habit should be considered as an important critical material attribute (CMA) during formulation development of FEN and due considerations should be given to the selection of the appropriate dissolution testing set-up for establishing in vitro-in vivo correlation.

Back-Referral of Convalescing Neonates: Challenges and Strategies in India.

OBJECTIVES: To investigate the barriers and facilitators involved in the back-referral process of newborns from a tertiary care centre to district Special Newborn Care Units (SNCUs) for step-down care. METHODS: The study employed mixed methods, including feedback questionnaires for parents of back-referred neonates, in-depth interviews with doctors and nurses from six SNCUs, and focused group discussions with medical staff at a tertiary-level institute. The study was conducted over a period of seven and a half months in a north Indian tertiary care centre. RESULTS: The back-referral process received positive acceptance from parents and healthcare personnel. Notable barriers included the lack of Retinopathy of Prematurity (ROP) screening services in some SNCUs, inadequate free transport facilities for back-referral, and deficiencies in two-way communication. Parents provided valuable feedback for improvement, suggesting back-referral to the SNCU nearest to their home, daytime back-referral with adequate prior notice, and the availability of post-partum obstetric care at SNCUs for the mother. Inadequate environmental hygiene and limited availability of ROP services were identified as concerns. Facilitators included effective communication, proximity-based back-referral, and ongoing mentoring of SNCUs by tertiary centres. CONCLUSIONS: Establishing efficient two-way communication between tertiary centres and district SNCUs, provision of essential facilities at SNCUs, and ensuring a seamless continuum of care are pivotal for successful back-referral of convalescent neonates. Addressing these factors can contribute to improving the back-referral process, level 3 bed availability at the tertiary centres and neonatal health outcomes.

Study on Sulfamethoxazole-Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties.

Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.

Effect of Deep Eutectic System (DES) on Oral Bioavailability of Celecoxib: In Silico, In Vitro, and In Vivo Study.

Different deep eutectic systems (DES) of choline chloride (CC)-urea (UA) (1:2), CC-glycerol (GLY) (1:2), CC-malonic acid (MA) (1:1), and CC-ascorbic acid (AA) (2:1) were generated and characterized by polarized light microscope (PLM) and Fourier transform infrared spectroscope (FTIR). The equilibrium solubility of celecoxib (CLX) in DES was compared to that in deionized water. The CC-MA (1:1) system provided ~10,000 times improvement in the solubility of CLX (13,114.75 µg/g) and was used for the generation of the CLX-DES system. The latter was characterized by PLM and FTIR to study the microstructure and intermolecular interaction between the CLX and CC-MA (1:1) DES. FTIR demonstrated the retention of the chemical structure of CLX. In vitro drug release studies in FaSSIF initially demonstrated high supersaturation, which decreased by ~2 fold after 2 h. Density functional theory (DFT)-based calculations provided a molecular-level understanding of enhanced solubility. Gibbs free energy calculations established the role of the strongest binding of CLX with CC and MA. A phase solubility study highlighted the role of hydrotropy-induced solubilization of the CLX-DES system. Animal pharmacokinetic studies established 2.76 times improvement in Cmax, 1.52 times reduction in tmax, and 1.81 times improvement in AUC0-∞. The overall results demonstrated the potential of developing a DES-based supersaturating drug-delivery system for pharmaceutical loading of drugs having solubility and dissolution rate-limited oral bioavailability.

A report of 5 Indian families with multicentric carpotarsal osteolysis syndrome.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant skeletal dysplasia characterised by swelling and restriction of movement in the wrist and ankle joints, as well as osteolysis of the carpal and tarsal bones, that can be misdiagnosed as juvenile idiopathic arthritis. We describe five Indian families with heterozygous nonrecurrent missense pathogenic variants in exon 1 of MAF bZIP transcription factor B (MAFB).

The spectrum of neurological manifestations and genotype-phenotype correlation in Indian children with Gaucher disease.

Gaucher disease (GD), one of the most frequent autosomal recessive lysosomal storage disorders, occurs due to bi-allelic pathogenic variants in the GBA1. Worldwide, the c.1448T>C (L483P) homozygous pathogenic variant is reported to be associated with neurological GD phenotype. Clinical distinction between GD1 and GD3 may be challenging due to subtle neurological features. Objective methods to evaluate neurological signs and saccades may help in early diagnosis. This study was conducted to assess the neurological phenotype, and its severity using a modified severity scoring tool (mSST), and the genotype-phenotype correlation. A total of 45 children aged 2 years 6 months to 15 years with a confirmed enzymatic and molecular diagnosis of GD with or without therapy were recruited. mSST tool was used to assess the severity of the neurological phenotype. A digital eye movement tracker (View Point Tracker) was used to assess eye movements. Clinical and genetic findings were analyzed. Out of 45 patients, 39 (86.7%) had at least one neurological phenotype detected using the mSST tool, with impairment of cognitive function (68.8%, 31/45) being the commonest feature. Thirty-two of 45 (71%) were assessed for saccadic eye movements using the eye tracker. Of these, 62.5% (20/32) had absent saccades. Four children (8.9%, 4/32) without clinical oculomotor apraxia had absent saccades on the viewpoint eye tracker. Overall, 77.7% (35/45), had homozygosity for c.1448T>C in GBA1 of which 91.4% (32/35) had neurological manifestations. Other alleles associated with neurological phenotype included c.1603C>T(p.R535C), c.1184C>T (p.S395F), c.115+1G>A (g.4234G>A), c.260G>A (p.R87Q) and c.1352A>G (p.Y451C). To conclude, in India, the c.1448T>C pathogenic variant in GBA1 is the commonest  and is associated with neurological phenotype of GD. Therefore, every patient of GD should be assessed using the mSST scoring tool for an early pick up of neurological features. The routine use of a viewpoint eye tracker in children with GD would be useful for early recognition of saccadic abnormalities.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

Autosomal Recessive Congenital Ichthyosis and Steroid-Resistant Nephrotic Syndrome due to Homozygous Mutation in the ALOX12B gene: A Novel Association with Review of Literature.

Nephrotic syndrome (NS) associated with autosomal recessive congenital ichthyosis (ARCI) is a rare association. In this article, we described a 4-year-old boy with steroid-resistant NS (SRNS) who had a history of ichthyotic skin lesions since birth. Renal biopsy revealed focal segmental glomerulosclerosis (tip variant). The skin biopsy was consistent with the findings of ichthyosis. Next-generation sequencing revealed a homozygous pathogenic variant (c.1625_1626del) in the exon 12 of the ALOX12B gene, confirming the diagnosis of ARCI2. The ALOX12B gene belongs to the lipoxygenase family and has a pivotal role in the formation of lipid layers in the epidermis. Leukotrienes have a counter-regulatory effect within the inflamed glomeruli, which influences the vascular tone and glomerular basement membrane permeability, that can be implicated in the pathogenesis of the NS. This child is currently in remission, on tacrolimus and low-dose prednisolone, with emollients and is on regular follow-up. SRNS associated with congenital ichthyosis secondary to a mutation in the ALOX12B gene has never been reported so far. The knowledge regarding this novel association will help the treating physicians in diagnosing this condition early, which will enable proper genetic counseling and prognostication of the disease to the family.

Profile of Back-Referrals to Special Newborn Care Units.

OBJECTIVE: To study the outcomes of neonates back-referred from a tertiary care centre to special newborn care units (SNCUs) for step-down care. METHODS: This prospective cohort study was conducted at a tertiary care neonatal unit and SNCUs in neighbouring states. We studied preterm and term neonates back-referred to district SNCUs from September, 2018 to April, 2019. The infants were followed up till 3 months corrected age, for mortality, re-hospitalization, emergency visits and unscheduled outpatient visits. Preterm inborn neonates <32 weeks gestation discharged directly to home formed the controls. RESULTS: 201 back-referred neonates (study cohort) and 55 preterm neonates discharged to home (controls) were followed up till 3 months corrected age. Amongst the back-referred neonates, 5% died, 7% required re-hospitalization, 11% made emergency visits, and 24% made unscheduled outpatient visits. These outcomes were similar to the controls. CONCLUSION: Back-referral of convalescing neonates is a safe method of utilizing the limited healthcare resources in tertiary care centers in developing country settings.

Deep eutectic systems: An overview of fundamental aspects, current understanding and drug delivery applications.

The deep eutectic system (DES) is a relatively new concept in the field of drug delivery science. DES is a class of eutectic mixtures comprised of two or more components, with a eutectic point far below than the melting temperature of the pure components. The strong hydrogen bonding interactions between DES constituents are responsible for significant lowering of melting point in DES. A significant number of molecules cannot reach from drug discovery phase to drug development phase because of poor biopharmaceutical attributes, such as solubility and permeability. DES can be a novel alternative to overcome these issues. In last few years DESs have been widely used in different pharmaceutical and chemical processes. However, comprehensive information regarding their drug delivery potential is not available. This review deals with fundamental aspects such as types, preparation, thermodynamics, toxicity, biodegradability and their applications in the field of drug delivery. Current challenges, future prospects and translational aspects of DES as drug delivery system have also been discussed.

Ethosomes as Novel Vesicular Carrier: An Overview of the Principle, Preparation and its Applications.

BACKGROUND: In the study of lipid vesicular carriers in permeation enhancement of drug molecules across skin after the success story of liposomes, ethosomes are a recent addition. There are a number of published reviews but still, there is a lack of reviews representing various aspects in a systematic way with a detailed description of current research works. This review serves to fill this deficiency along with special emphasize on its preparation methods and applications. METHODS: Information was collected from previously published literatures which were represented after analysis in terms of various aspects such as principles, composition, preparation, mechanism of penetration, modified forms, characterization, marketed preparations and its applications. RESULT: This review is represented in an informative and easily understandable way. Basic principles and background were covered in the introduction section. Composition section contains the basic components of formulations along with the impact of various parameters on the characterization of the ethosome. A detailed discussion of all the methods along with their own utility is elaborately provided. Various aspects of characterization studies of ethosomes are also discussed. Therapeutic and cosmetic applications of ethosomes are also outlined here. CONCLUSION: In spite of having a excellent permeation-enhancing and targeted drug release profile, ethosome suffers from limited commercialization. Various challenges regarding their commercialization and product development are also discussed in this review with an objective of acting as a directional route for the researchers.