A Comprehensive Insight on Pharmaceutical Co-crystals for Improvement of Aqueous Solubility.

Various drugs are not able to reach the market due to their poor bioavailability and poor solubility in aqueous media. Hence, several approaches are used to enhance the solubility of poorly water-soluble drugs. Co-crystallization is one of the approaches used to enhance the solubility of poorly water-soluble drugs. Co-crystals are solid crystalline substances consisting of two or more ingredients in a stoichiometric ratio in which one of the ingredients is an active pharmaceutical ingredient (API) and the other is a co-former. API and co-former mix with one another in a co-crystal through intermolecular interactions. This review represents an overview of co-crystals, a comparison of co-crystals and other solid forms, mechanisms of solubility enhancement by co-crystals in brief, techniques of co-former selection, a list of co-formers used during various co-crystals formation and a list of marketed co-crystals formulation, method of co-crystals preparation and characterization techniques of co-crystals.

Evaluation of IFN-gamma response to rotavirus and non-structural protein NSP4 of rotavirus in children following severe rotavirus diarrhea.

BACKGROUND: Rotavirus (RV) is the commonest cause of severe gastroenteritis in young children worldwide. However the natural immune mechanisms controlling and preventing rotavirus disease in humans are not fully understood. OBJECTIVE: To examine cellular immune responses to whole rotavirus (vaccine strain, 116E) and non-structural protein-4 (116E-NSP4) in children during natural rotavirus-infection. STUDY DESIGN: Gamma-interferon (IFN-gamma) responses were evaluated by enzyme-linked immunospot assay in peripheral blood mononuclear cells from children with RV (n=26) or non-RV (n=10) gastroenteritis and from RV-exposed adults (n=10). Additionally, IL-4 responses were assessed in 5 of the 10 adults and 6 of 26 RV-infected children. RESULTS: IFN-gamma secreting cells specific to whole RV were detected in 68% of RV-positive children and to NSP4 in 43% of these children between 4 and 30 days of illness onset. IFN-gamma responses were transient and were found higher in RV-exposed adults than in children (P<0.05). Within the RV-positive group, IFN-gamma responses in children with prior RV-exposure were higher than children without prior exposure (P<0.05). The response to whole RV and NSP4 were positively correlated (P<0.01, r(s)=0.66). CONCLUSIONS: Significant IFN-gamma responses to rotavirus candidate vaccine strain 116E were detected in children during natural RV-infection and in RV-exposed adults. Significant IFN-gamma responses to NSP4 were also observed in these study groups.

Natural immunity to rotavirus infection in children.

Annual deaths in infants and young children due to rotavirus (RV) infection are around 100,000 in India and about 600,000 globally. Development of a vaccine for this disease is a high priority. The protective mechanisms for RV diarrhea in human are not fully understood, but it is known that children develop natural immunity against RV. Early exposure to RV results in most severe episode of diarrhea and subsequent infections are milder or asymptomatic. Of the immune responses measured during natural infection, RV-specific antibodies have been well documented, whereas data on cellular immunity in humans are sparse. It is generally thought that two outer capsid proteins VP4 and VP7 play a critical role in protective immunity by stimulating production of neutralizing antibodies. While serotype- specific protection mediated by antibodies directed against the outer capsid proteins may be a mechanism of protection, such a correlate for protection has been difficult to demonstrate in humans during clinical trials. Increasing evidences suggest that viral proteins that lack a capacity of eliciting neutralizing antibody response also induce protective immunity. Limited efforts have focused on the role of non-structural proteins in protective immunity. This review describes current understanding of antibody responses in children with focus on responses specific to viral antigens with their possible role in protective immunity. We have also briefly reviewed the responses elicited to non-antibody effectors during RV infection in human subjects.

Quantitative evaluation of rotaviral antigenemia in children with acute rotaviral diarrhea.

BACKGROUND: Rotaviral antigen and RNA have recently been identified in the serum of patients with rotaviral gastroenteritis, but the roles they play in disease remains undetermined. METHODS: Rotaviral antigen and RNA were quantified by enzyme-linked immunosorbant assay and by quantitative reverse-transcription polymerase chain reaction in stool and serum specimens from children with rotaviral diarrhea (n=102), children with nonrotaviral diarrhea (n=40), and nondiarrheal control children (n=30). RESULTS: Rotaviral antigenemia was detected in 64%, 3%, and 0% of the children with rotaviral diarrhea, the children with nonrotaviral diarrhea, and the nondiarrheal control children, respectively. The level of rotaviral antigen in serum was approximately 2x10(2) -fold lower than that in stool, and a moderate correlation was observed between the 2 levels. Rotaviral RNA was detected in 93% of the antigen-positive serum specimens. The median number of RNA copies in serum was approximately 1 x 10(5) -fold lower than that in stool, and no correlation was observed between the 2 levels. Serum levels of both antigen and RNA were inversely associated with baseline titers of rotaviral serum immunoglobulin G (P<.01). Antigenemia was also associated with G1 serotype. CONCLUSIONS: Rotaviral antigenemia and viremia were common in children with rotaviral diarrhea, but antigen and RNA levels in serum were substantially lower than those in stool. Antigenemia was associated with infection with G1 strains and with low baseline titers of rotaviral serum antibody.

Rotavirus nonstructural protein NSP4 induces heterotypic antibody responses during natural infection in children.

Seroconversion of immunoglobulin A (IgA) and immunoglobulin G (IgG) (> or =4-fold rise) to rotavirus nonstructural protein 4 (NSP4) was determined, by use of enzyme-linked immunosorbent assay with fusion proteins glutathione S-transferase (GST)-NSP4 from strains SA11 (A), 116E (B), and RRV (C), in 40 children with acute rotavirus gastroenteritis and in 30 with the same disease due to other pathogens. The IgG seroconversion rates in the rotavirus group were 67.5%, 70%, and 60% when recombinant (r) NSP4A, -B, and -C, respectively, were used as antigen in the assay, and, for rotavirus-uninfected children, rates were 10%, 13%, and 7%. IgA seroconversion occurred in 57%, 70%, and 50%, respectively, of children with rotavirus gastroenteritis; in rotavirus-uninfected children, 1 child each seroconverted to the different rNSP4s. Among 9 children infected with strain NSP4A, 7, 6, and 5 children showed IgG seroconversion, and, among 18 infected with NSP4A, -B, and -C, 16, 17, and 15, respectively, showed IgG seroconversion. Between NSP4A-infected and NSP4B-infected children, IgA responses were similar to IgG responses. In conclusion, significant NSP4-specific antibody response occurs in natural rotavirus infection, and the antibody response appears to be broad and heterotypic in nature.