An overview on in situ micronization technique – An emerging novel concept in advanced drug delivery

The use of drug powders containing micronized drug particles has been increasing in several pharmaceutical dosage forms to overcome the dissolution and bioavailability problems. Most of the newly developed drugs are poorly water soluble which limits dissolution rate and bioavailability. The dissolution rate can be enhanced by micronization of the drug particles. The properties of the micronized drug substance such as particle size, size distribution, shape, surface properties, and agglomeration behaviour and powder flow are affected by the type of micronization technique used. Mechanical communition, spray drying and supercritical fluid (SCF) technology are the most commonly employed techniques for production of micronized drug particles but the characteristics of the resulting drug product cannot be controlled using these techniques. Hence, a newer technique called in situ micronization is developed in order to overcome the limitations associated with the other techniques. This review summarizes the existing knowledge on in situ micronization techniques. The properties of the resulting drug substance obtained by in situ micronization were also compared.     

Evidence-based Clinical Practice Guidelines for Interventional Pain Management in Cancer Pain

Intractable cancer pain not amenable to standard oral or parenteral analgesics is a horrifying truth in 10–15% of patients. Interventional pain management techniques are an indispensable arsenal in pain physician''s armamentarium for severe, intractable pain and can be broadly classified into neuroablative and neuromodulation techniques. An array of neurolytic techniques (chemical, thermal, or surgical) can be employed for ablation of individual nerve fibers, plexuses, or intrathecalneurolysis in patients with resistant pain and short life-expectancy. Neuraxial administration of drugs and spinal cord stimulation to modulate or alter the pain perception constitutes the most frequently employed neuromodulation techniques. Lately, there is a rising call for early introduction of interventional techniques in carefully selected patients simultaneously or even before starting strong opioids. After decades of empirical use, it is the need of the hour to head towards professionalism and standardization in order to secure credibility of specialization and those practicing it. Even though the interventional management has found a definite place in cancer pain, there is a dearth of evidence-based practice guidelines for interventional therapies in cancer pain. This may be because of paucity of good quality randomized controlled trials (RCTs) evaluating their safety and efficacy in cancer pain. Laying standardized guidelines based on existing and emerging evidence will act as a foundation step towards strengthening, credentialing, and dissemination of the specialty of interventional cancer pain management. This will also ensure an improved decision-making and quality of life (QoL) of the suffering patients.     

Microscopic Agglutination Test Analysis Identifies Prevalence of Intermediate Species Serovars in Ruminants in Endemic States of India

Serological survey was carried out in order to investigate the seroprevalence of leptospirosis in ruminants in coastal regions (flood prone areas) of endemic states (Andhra Pradesh, Gujarat, Kerala, Maharashtra and Tamil Nadu) of India using non-purposive samples collected during the year 2011 and 2012. A total of 553 serum samples (Cattle-332; Buffaloes-85; Goats-107 and Sheep-29) collected randomly from twenty one coastal districts of five states were tested at 1:100 dilution in microscopic agglutination test using 14 reference leptospira serovars. The overall seroprevalence of 24.96 % (138/553) with 20.48 % in cattle, 20 % in buffaloes, 58.62 % in sheep and 38.3 % in goats was observed. The results of χ² tests revealed that the seroprevalance in cattle across different districts (regions) in each of the surveyed states are not associated except in Kerala (χ² = 33.98, p < 0.05). In other species (buffalo, sheep and goat) also there is no association of seroprevalance across different districts in each of the states. Among the targeted endemic states, high prevalence was observed in Maharashtra (19/53 = 35.85 %) followed by Kerala (52/165 = 31.51 %), Andhra Pradesh (16/50 = 32 %), Gujarat (48/212 = 22.64 %) and Tamil Nadu (3/72 = 4.17 %). Out of 138 reacted sera, 37 samples showed multiple reactivities with 26.81 % prevalence. The predominant leptospiral antibodies were determined against frequency of distribution of the serovars Hardjo (28.99 %) followed by Kaup (18.12 %), Pomona (15.94 %), Bankinang (14.49 %). This study supports that ruminants may have a role in maintaining intermediate species serovar Kaup apart from being a well-known reservoir for Hardjo serovar in endemic states of India.     

Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo

Results from retrospective studies on the relationship between cytochrome P450 (P450) 2B6 (CYP2B6) genotype and cyclophosphamide (CY) efficacy and toxicity in adult cancer patients have been conflicting. We evaluated this relationship in children, who have faster CY clearance and receive different CY-based regimens than adults. These factors may influence the P450s metabolizing CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Therefore, we sought to characterize the in vitro and in vivo roles of hepatic CYP2B6 and its main allelic variants in 4HCY formation. CYP2B6 is the major isozyme responsible for 4HCY formation in recombinant P450 Supersomes. In human liver microsomes (HLM), 4HCY formation correlated with known phenotypic markers of CYP2B6 activity, specifically formation of (S)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolidine and hydroxybupropion. However, in HLM, CYP3A4/5 also contributes to 4HCY formation at the CY concentrations similar to plasma concentrations achieved in children (0.1 mM). 4HCY formation was not associated with CYP2B6 genotype at low (0.1 mM) or high (1 mM) CY concentrations potentially because CYP3A4/5 and other isozymes also form 4HCY. To remove this confounder, 4HCY formation was evaluated in recombinant CYP2B6 enzymes, which demonstrated that 4HCY formation was lower for CYP2B6.4 and CYP2B6.5 compared with CYP2B6.1. In vivo, CYP2B6 genotype was not directly related to CY clearance or ratio of 4HCY/CY areas under the curve in 51 children receiving CY-based regimens. Concomitant chemotherapy agents did not influence 4HCY formation in vitro. We conclude that CYP2B6 genotype is not consistently related to 4HCY formation in vitro or in vivo.     

Participation in decision making regarding type of surgery and treatment-related satisfaction in North Indian women with early breast cancer

Introduction: Breast conserving surgery followed by radiotherapy is an established modality of treatment in early breast cancer patients since three decades, but yet it has not been adopted worldwide. Purpose: The aim of this study is to investigate the factors affecting decision making regarding type of surgery and satisfaction with type of surgery in North Indian women with early breast cancer. Materials and Methods: A questionnaire was prepared to assess the factors responsible for decision making regarding type of surgery (breast conserving surgery (BCS) versus modified radical mastectomy (MRM) and to evaluate involvement of patient in decision making regarding the type of surgery. 47 women with early breast cancer on radiotherapy or on follow-up were interviewed by the resident doctors. Results: Out of 47 patients, 28 underwent BCS and 19 MRM. Women undergoing BCS were younger, more literate than in those undergoing MRM. In the two arms (BCS versus MRM), decision for surgery was made by surgeon alone in 53% versus 73%, along with patient in 42% versus 6%, and only 10% women participated in decision making in each arm. Only 50% versus 30% patients had a clear understanding of the risks and benefits of both procedures in the two arms. Conclusion: North Indian women do not independently take decision regarding any type of surgery. The reason for opting for either kind of surgery was based on surgeon's recommendation or concern about recurrence. Body image was not an issue amongst majority.     

Identification of Setaria cervi heat shock protein70 by mass spectrometry and its evaluation as diagnostic marker for lymphatic filariasis

Using mass spectrometry and immunological approaches, a heat shock protein70 associated with lymphatic filariasis (LF) has been identified from a bovine filarial parasite Setaria cervi. A heat shock protein was detected in different life stages of S. cervi when exposed to an elevated temperature of 44 °C. A combination of ATP-agarose column chromatography and electro-elution was used for its purification from adult female extract. On closer examination, it migrated as a single band at 68 kDa on 10% SDS-PAGE. Peptide sequences TTPSYVAFTDTER, DSGAIAGLNVLR, IINEPTAAAIAYGLDK, NALESYAFNMK and LLSDFFSGK were obtained through MALDI-LC/MS analysis. Confirmation of peptides was accomplished by MASCOT database which showed substantial sequence homology with S. digitata, Wuchereria bancrofti, and Caenorhabditis elegans. Multiple sequence alignment using Clustal W showed 98% identity with W. bancrofti and only 28% with human HSP70. Furthermore, the antigenicity plot has shown that the highly antigenic amino acid residues are constituted within the conserved peptides. These observations suggest a plausible biological connection of ScHSP70 with the disease and its strong immunogenic nature. ScHSP70 showed antigenic cross-reactivity with IgG class of antibody in different categories of filarial sera. However, when IgG subclasses were tested, IgG4 showed high specificity and sensitivity with asymptomatic microfilaraemic sera.     

Management of pericatheter cerebrospinal fluid leak after intrathecal implantation of a drug delivery system

Persistent cerebrospinal fluid leak is a known complication of intrathecal pump system insertion for drug delivery. Various treatment modalities, such as an epidural blood patch, use of glue, removal of catheter, and surgical closure of dura and subdural blood patch, have been reported previously. This report presents a 35-year-old woman in whom an intrathecal pump system was inserted for cancer pain management with intrathecal morphine. This was complicated by a persistent cerebrospinal fluid leak that was successfully managed by purse-string sutures over the dura around the catheter, without removing the intrathecal implant. The cause of the cerebrospinal fluid leak and different treatment approaches are discussed.