Influence of menthol and pressure-sensitive adhesives on the in vivo performance of membrane-moderated transdermal therapeutic system of nicardipine hydrochloride in human volunteers.

A membrane-moderated transdermal therapeutic system of nicardipine hydrochloride was developed using 2% w/w hydroxypropylcellulose (HPC) gel as a reservoir system containing 5% w/w of menthol as a penetration enhancer. The permeability flux of nicardipine hydrochloride through the ethylene vinyl acetate (EVA) copolymer membrane was found to increase with an increase in vinyl acetate content in the copolymer. The effect of various pressure-sensitive adhesives (MA-31, MA-38 or TACKWHITE A 4MED on the permeability of nicardipine hydrochloride through EVA 2825 membrane (28% w/w vinyl acetate) or EVA 2825 membrane/skin composite was also studied. The results showed that nicardipine hydrochloride permeability through EVA 2825 membrane coated with TACKWHITE A 4MED/skin composite was higher than that coated with MA-31 or MA-38. Thus, a new transdermal therapeutic system for nicardipine hydrochloride was formulated using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE A 4MED, and 2% w/w HPC gel as reservoir containing 5% w/w of menthol as a penetration enhancer. In vivo studies in healthy human volunteers indicated that the TTS of nicardipine hydrochloride, designed in the present study, provided steady-state plasma concentration of the drug with minimal fluctuations for 26h with improved bioavailability in comparison with the immediate release capsule dosage form.     

Differential effects of route of T‐2 toxin exposure on hepatic oxidative damage in mice

T‐2 toxin is the most toxic among mycotoxins and poses a potential health hazard for both humans and animals. At high doses, T‐2 toxin can cause shock‐like syndrome that can result in death. We evaluated the effect of time course and route of exposure on hepatic oxidative damage in mice and it is only such study so far to compare the effects of dermal and subcutaneous exposure of T‐2 toxin. Mice were exposed to 1 LD50 of T‐2 toxin either by percutaneous (5.94 mg/kg body weight) or subcutaneous (1.54 mg/kg body weight) route and sacrificed at 0, 1, 3, and 7 days postexposure. Analysis of a number of serum biochemical variables, antioxidant enzymes activity, gene and protein expression by immunoblot assay showed time and route dependent effects of T‐2 induced hepatic oxidative damage. Time dependent increase in protein carbonyl content and protein oxidation was seen in serum and liver. Results of our study may provide possible mechanism for developing medical countermeasures against T‐2 toxin. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 64–73, 2015.     

Local RF capacitive hyperthermia: thermal profiles and tumour response

At the Cancer Institute we are using RF capacitive hyperthermia as an adjuvant to radiotherapy and/or chemotherapy in the local control of soft tissue sarcomas. We have studied the influence of bolus conductivity, electrode and phantom sizes on the rate of heating of agar phantoms. We have varied the bolus conductivity by varying the saline concentration in the bolus bags from zero to 2.0 per cent, during heating. We found that the rate of heating of phantoms increases and that of the bolus decreases with the increase in the saline concentration of bolus up to 1 per cent, irrespective of phantom and electrode sizes. However, for a given size of electrodes the rate of heating decreased with the increase in the phantom size. When the diameter and height of the phantom were equal to the diameters of electrodes the rate of heating of the phantom was nearly uniform. However, when the diameter of the phantom was larger than that of electrodes the rate of heating in the radial axis decreased with the increase in the radial distance. On the basis of this data we suggest the use of electrodes larger in size by 1.0-3.0 cm than the size of the tumour, where the size of the anatomical site to be heated is larger than the electrode size to be used. Phantom and clinical data have indicated that the presence of bone in the field of heating can lead to hot spots. Preliminary clinical results have shown that the response of sarcomas to thermo-chemo-radiotherapy was superior to that of either thermo-radiotherapy or radiotherapy alone.     

Evidence for a frontocortical-septal glutamatergic pathway and compensatory changes in septal glutamate uptake after cortical and fornix lesions in the rat

To determine the source of glutamatergic input to the septum and to the nucleus accumbens septi, glutamate uptake was assessed after transections of the frontal cortex and/or fornix. Uptake in the septum and accumbens was reduced by 25 and 30% respectively, 6 days after bilateral frontal cortex transections. Both indices returned to control levels 30 days postoperatively. In contrast, while unilateral fornix transection did not affect uptake in the accumbens at either day 6 or 30, uptake in the septum was significantly reduced (25–35%) at both times. When a unilateral transection of the fornix was performed in rats with a pre-existing bilateral ablation of the frontal cortex, a further reduction in uptake was observed in the septum (50–60% at both 6 and 30 days after the fornix transection). The data implicate glutamate as a neurotransmitter in frontocortico-septal projections and suggest that the contribution of the hippocampo-septal system to total glutamate uptake in the septum is increased following ablation of the frontocortico-septal system.     

Use and Effectiveness of Antimicrobial Intravesical Treatment for Prophylaxis and Treatment of Recurrent Urinary Tract Infections (UTIs): a Systematic Review

Purpose of Review

Intravesical antibiotics (IVA) has been used for prophylaxis and treatment of recurrent urinary tract infections (rUTIs). However, there is a lack of comprehensive evidence and consensus on its use. We conducted a systematic review to collect all available data about the effectiveness of IVA in prevention and treatment of rUTIs and to give an overview on the outcomes to date.

Methods

A systematic review was carried out for all English language articles from inception to August 2017, according to the Cochrane and PRISMA standards using MEDLINE, Scopus, Biomed Central, EMBASE, CINAHL, and Web of Science with references cross-checked and individual urology journals hand-searched.

Results

After an initial identification of 658 studies, we screened 37 abstracts and 18 full-text papers of which 11 were included in our final review. This included 285 patients with a mean age of 52 years and a female:male ratio of 129:117. The IVA used was gentamicin, neomycin/polymyxin, neomycin or colistin and IVA was used for rUTIs as prophylaxis in 5 studies (n?=?168) and treatment in 6 studies (n?=?117). Overall, a good reduction in symptomatic UTI was seen in 78%, with a short-term success rate and discontinuation rates of 71% (120/168) and 8% (14/168) in the prophylaxis group and 88% (103/117) and 5% (6/117) in the treatment groups respectively. There was a change in the sensitivity of organisms in 30% (50/168) and 23% (27/117) in the treatment and prophylaxis groups respectively. Twenty patients discontinued their IVA instillations which were higher for the non-gentamicin group (11%) compared to the gentamicin group (5%). The side effects were minor and included allergy, suprapubic discomfort, autonomic dysreflexia, urinary tract infections and diarrhoea.

Summary

Intravesical antimicrobial instillation seems to be a relatively safe and effective method for the prophylaxis and treatment of recurrent UTIs, especially in the short term. It gives clinicians an alternative treatment modality in high-risk patients predisposed to UTIs where all other forms of systemic treatments have failed.

     

Molecular Detection and Assessment of Hemato-Biochemistry,Oxidant/Antioxidant Status in Natural Canine Monocytic Ehrlichiosis Cases from Northern India

The present study was aimed at detecting natural cases of canine monocytic ehrlichiosis (CME) by molecular and cytological methods and assessment of clinico-patho-biochemical parameters among the affected population. Nested polymerase chain reaction was found to be highly sensitive (47.7 %) in detecting the acute cases, followed by buffy coat (29.5 %) and blood smear examination (22.7 %). CME incidence rate was found to be 8.4 %. Hemogram revealed significant (P < 0.01) depletion in the levels of hemoglobin, hematocrit, total erythrocyte count, monocyte and platelet count in diseased dogs as compared to healthy controls. Plasma biochemistry revealed hypoproteinemia, hypoalbuminemia and hyperglobulinemia along with significantly (P < 0.05) higher blood urea nitrogen and alanine aminotransferase values. CME revealed non-significant increase in the levels of erythrocytic lipid peroxides, reduced glutathione and activity of superoxide dismutase, whereas activities of glutathione-S-transferase and glutathione reductase showed significant (P < 0.05) increase and decrease, respectively as compared to healthy controls. Plasma levels of cortisol, insulin and blood level of copper showed non-significant (P > 0.05) reduction, whereas blood level of zinc showed significant (P < 0.05) reduction as compared to healthy controls. These findings revealed that changes in erythrocytic oxidant–antioxidant profile and blood mineral concentration in canine monocytic ehrlichiosis are largely non-significant and inconsistent. Hence, further study is required to elucidate their role in pathogenesis of canine monocytic ehrlichiosis.     

Evaluation of a combined therapeutic regimen of 8-OH-DPAT and environmental enrichment after experimental traumatic brain injury

When provided individually, both the serotonin (5-HT(1A))-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and environmental enrichment (EE) enhance behavioral outcome and reduce histopathology after experimental traumatic brain injury (TBI). The aim of this study was to determine whether combining these therapies would yield greater benefit than either used alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to enriched or standard (STD) housing, where either 8-OH-DPAT (0.1 mg/kg) or vehicle (1.0 mL/kg) was administered intraperitoneally once daily for 3 weeks. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. CA1/CA3 neurons and choline acetyltransferase-positive (ChAT(+)) medial septal cells were quantified at 3 weeks. 8-OH-DPAT and EE attenuated CA3 and ChAT(+) cell loss. Both therapies also enhanced motor recovery, acquisition of spatial learning, and memory retention, as verified by reduced times to traverse the beam and to locate an escape platform in the water maze, and a greater percentage of time spent searching in the target quadrant during a probe trial in the TBI + STD + 8-OH-DPAT, TBI + EE + 8-OH-DPAT, and TBI + EE + vehicle groups versus the TBI + STD + vehicle group (p ≤ 0.0016). No statistical distinctions were revealed between the TBI + EE + 8-OH-DPAT and TBI + EE + vehicle groups in functional outcome or CA1/CA3 cell survival, but there were significantly more ChAT(+) cells in the former (p = 0.003). These data suggest that a combined therapeutic regimen of 8-OH-DPAT and EE reduces TBI-induced ChAT(+) cell loss, but does not enhance hippocampal cell survival or neurobehavioral performance beyond that of either treatment alone. The findings underscore the complexity of combinational therapies and of elucidating potential targets for TBI.