Controlled porosity osmotic pump-based controlled release systems of pseudoephedrine. I. Cellulose acetate as a semipermeable membrane.

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions.     

The Caspase 1 Inhibitor VX-765 Protects the Isolated Rat Heart via the RISK Pathway

Purpose

Protecting the heart from ischaemia-reperfusion (IR) injury is a major goal in patients presenting with an acute myocardial infarction. Pyroptosis is a novel form of cell death in which caspase 1 is activated and cleaves interleukin 1β. VX-785 is a highly selective, prodrug caspase 1 inhibitor that is also clinically available. It has been shown to be protective against acute IR in vivo rat model, and therefore might be a promising possibility for future cardioprotective therapy. However, it is not known whether protection by VX-765 involves the reperfusion injury salvage kinase (RISK) pathway. We therefore investigated whether VX-765 protects the isolated, perfused rat heart via the PI3K/Akt pathway and whether protection was additive with ischaemic preconditioning (IPC).

Methods

Langendorff-perfused rat hearts were subject to ischaemia and reperfusion injury in the presence of 30 μM VX-765, with precedent IPC, or the combination of VX-765 and IPC.

Results

VX-765 reduced infarct size (28 vs 48% control; P?<?0.05) to a similar extent as IPC (30%; P?<?0.05). The PI3 kinase inhibitor, wortmannin, abolished the protective effect of VX-765. Importantly in the model used, we were unable to show additive protection with VX-765 + IPC.

Conclusions

The caspase 1 inhibitor, VX-765, was able to reduce myocardial infarction in a model of IR injury. However, the addition of IPC did not demonstrate any further protection.

     

Early predictors of severity in acute lower intestinal tract bleeding

BACKGROUND: Identification of high-risk patients with lower intestinal tract bleeding (LIB) is challenging, and prognostic factors have not been clearly defined. The aim of this study was to determine risk factors for severe acute LIB. METHODS: A total of 252 consecutive patients admitted with acute LIB were identified. Data were collected on 24 clinical factors available in the first 4 hours of evaluation. The outcome was severe bleeding, which was defined as continued bleeding within the first 24 hours of hospitalization (transfusion of > or = 2 units of blood and/or hematocrit decrease of > or = 20%) and/or recurrent bleeding after 24 hours of stability (additional transfusions, further hematocrit decrease of > or = 20%, or readmission for LIB within 1 week of discharge). RESULTS: Severe LIB occurred in 123 patients (49%). Independent correlates of severe bleeding were as follows: heart rate, > or = 100/min (odds ratio [OR], 3.67; 95% confidence interval [CI], 1.78-7.57); systolic blood pressure, < or = 115 mm Hg (OR, 3.45; 95% CI, 1.54-7.72); syncope (OR, 2.82; 95% CI, 1.06-7.46); nontender abdominal examination (OR, 2.43; 95% CI, 1.22-4.85); bleeding per rectum during the first 4 hours of evaluation (OR, 2.32; 95% CI, 1.28-4.20); aspirin use (OR, 2.07; 95% CI, 1.12-3.82); and more than 2 active comorbid conditions (OR, 1.93; 95% CI, 1.08-3.44). CONCLUSION: Clinical data available on initial evaluation can be used to identify patients at risk for severe LIB, who may benefit most from urgent intervention.     

The c.797 G>A (p.R266K) cystathionine β‐synthase mutation causes homocystinuria by affecting protein stability

Mutations in the cystathionine beta‐synthase (CBS) gene are the cause of classical homocystinuria, the most common inborn error in sulfur metabolism. The c.797 G>A (p.R266K) mutation in CBS was originally described in several Norwegian pyridoxine responsive CBS deficient patients, and heterologous gene expression studies have shown that the protein has near wild‐type levels of enzyme activity. Here, we characterize a transgenic mouse lacking endogenous Cbs and expressing p.R266K human CBS protein from a zinc inducible metallothionein promoter (Tg‐R266K Cbs^‐/‐). Unlike mice expressing other mutant CBS alleles, the Tg‐R266K transgene is unable to efficiently rescue neonatal lethality of Cbs^‐/‐ on a C57BL/6J background. On a C3H/HeJ background, zinc‐induced Tg‐R266K Cbs^‐/‐ mice express CBS mRNA, but have very low levels of CBS protein and enzyme activity, resulting in extreme elevations in serum total homocysteine (tHcy). Treatment with pyridoxine did not have any appreciable effect on tHcy, indicating this allele is not pyridoxine responsive in mice. However, treatment with the proteasome inhibitor bortezomib resulted in an 97% reduction in tHcy and a 2381% increase in liver CBS activity. These studies show that the p.R266K mutation causes increased proteasomal degradation in vivo, and that treatments that stabilize the protein can be used to reverse its effect.     

Physician assessment of family cancer history and referral for genetic evaluation in colorectal cancer patients.

BACKGROUND AND AIMS: An accurate family history is an essential component of cancer risk assessment. Our aim was to determine the concordance of family history assessments made by physicians with patients' self-reports and the frequency of referral for genetic evaluation in high-risk colorectal cancer (CRC) patients. METHODS: A self-administered family cancer history questionnaire was completed by 387 consecutive CRC patients at their first visit to a gastroenterology cancer clinic. Physician notes from the first visit were reviewed to determine the concordance of the family cancer history with patients' self-reported history. Prevalence of individuals that satisfied the Bethesda guidelines for hereditary colon cancer were compared with actual rates of referral. Regression analyses were used to determine factors associated with a comprehensive physician evaluation of family history. RESULTS: Oncologists documented a comprehensive family history in 59% (184 of 311) of patients with a first- or second-degree relative with cancer. Young age at diagnosis and a first-degree relative with CRC were not associated with a more comprehensive family history assessment. An increasing number of cancers per family was a strong predictor of a less comprehensive family history assessment (odds ratio = 0.63; P < 0.0001). Seventy-five of 387 (19%) CRC patients met Bethesda guidelines for genetics assessment, however, only 13 of 75 (17%) were referred. CONCLUSIONS: Increased complexity in family cancer history leads to a decrease in accuracy of family history, suggesting the need for systematic approaches to facilitate family history assessment. Familial cancer risk remains largely unrecognized and referral rates for genetic evaluation for CRC syndromes are low.     

BRAF mutation testing with a rapid,fully integrated molecular diagnostics system

Fast and accurate diagnostic systems are needed for further implementation of precision therapy of BRAF-mutant and other cancers. The novel Idylla^TM BRAF Mutation Test has high sensitivity and shorter turnaround times compared to other methods. We used Idylla to detect BRAF V600 mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples and compared these results with those obtained using the cobas 4800 BRAF V600 Mutation Test or MiSeq deep sequencing system and with those obtained by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory employing polymerase chain reaction–based sequencing, mass spectrometric detection, or next-generation sequencing. In one set of 60 FFPE tumor samples (15 with BRAF mutations per Idylla), the Idylla and cobas results had an agreement of 97%. Idylla detected BRAF V600 mutations in two additional samples. The Idylla and MiSeq results had 100% concordance. In a separate set of 100 FFPE tumor samples (64 with BRAF mutation per Idylla), the Idylla and CLIA-certified laboratory results demonstrated an agreement of 96% even though the tests were not performed simultaneously and different FFPE blocks had to be used for 9 cases. The Idylla^TM BRAF Mutation Test produced results quickly (sample to results time was about 90 minutes with about 2 minutes of hands on time) and the closed nature of the cartridge eliminates the risk of PCR contamination. In conclusion, our observations demonstrate that the Idylla test is rapid and has high concordance with other routinely used but more complex BRAF mutation–detecting tests.     

Concept,Design and Development of Innovative Endoscope Holder System for Endoscopic Otolaryngological Surgeries

Endoscopic surgeries have gained popularity not only in ENT but also in other surgical faculties. Endoscopic approach for sinus surgeries and otologic surgeries is well known. However, the major disadvantage of endoscopic aided surgeries as against microscope aided surgeries is thought to be the effective reduction in the working hands as the non-dominant hand of the surgeon is utilized for holding the endoscope. This urged the need for development of the endoscopic holder so as to allow both the hands of the surgeon for surgical manipulation.

Electronic supplementary material

The online version of this article (doi:10.1007/s12070-014-0738-y) contains supplementary material, which is available to authorized users.