Notes

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CNP-pGC activation to induce vascular relaxation.Muskoxen (Ovibos moschatus) are increasingly exposed to a broad diversity of stressors in their rapidly changing Arctic environment. There is an urgent need to develop validated tools to monitor the impact of these stressors on the hypothalamic-pituitary-adrenal (HPA) axis activity of muskoxen to help inform conservation actions. Here, we evaluated whether muskox qiviut (dense wooly undercoat) cortisol accurately reflects changes in HPA axis activity. Two repeated pharmacological challenges, involving weekly administrations of saline (control group) or adrenocorticotropic hormone (ACTH) during five consecutive weeks, were done on captive muskoxen, in winter (no hair growth) and summer (maximum hair growth). Pre-challenge qiviut cortisol levels were significantly higher in the shoulder than in the neck, but neither differed from rump concentrations. Qiviut cortisol levels significantly increased (p less then 0.001) in response to the administration of ACTH during the hair growth phase, but not in the absence of growth (p = 0.84). Cortisol levels in the qiviut segment grown during the summer challenge increased significantly over a six-month period in the ACTH-injected muskoxen with a similar trend occurring in the control animals. Finally, cortisol levels in shed qiviut were significantly higher and not correlated to those of fully grown qiviut shaved three months earlier. Our results show that cortisol is deposited in qiviut during its growth and that qiviut cortisol can thus be used as an integrated measure of HPA axis activity over the period of the hair's growth. Differences in qiviut cortisol across body regions, significant differences in qiviut segments over time, and differences between shed qiviut versus unshed qiviut, highlight the importance of consistent design and methodology for sample collection and analyses in order to account for sources of variation when using qiviut cortisol as a biomarker of HPA axis activity in muskoxen.Regulation of energy allocation and metabolic rate plays an important role in determining behavior and fitness in wild animals, calling for the validation of non-invasive markers of energetic condition. Recently, the thyroid hormone triiodothyronine (T3) has emerged as a promising marker as concentrations decrease to lower the metabolic rate during energetically challenging periods. However, it remains largely unclear whether T3 merely represents an alternative or provides additional information compared to other compounds involved in the regulation of energy acquisition and allocation, like cortisol and C-peptide, as few joint measurements have been conducted to date in non-invasively collected samples. We aimed to validate the non-invasive measurement of immunoreactive urinary total T3 (uTT3), in comparison to urinary cortisol (uCort) and urinary C-peptide (uCP), as a marker of metabolic response to variation in food intake in macaques, and to address a number of issues regarding the collection, storage andht led to a decrease in uTT3. uTT3 was largely unaffected by repeated freeze-thaw cycles and by refrigeration for medium-term storage (2 days) but degraded substantially when stored at ambient temperature for the same period. In conclusion, uTT3 measurements inform on the effect of food intake and its associated metabolic response to variation in energetic status. Since uTT3 is reasonably robust to many issues associated with collection and storage of urine samples under field conditions, it is a promising biomarker for studies of energetic condition and basal metabolic rate in wild macaques.Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered "highly soluble" across the range of pH values usually encountered in the upper gastrointestinal tract. Furthermore, evidence in the open literature suggests that carbamazepine is a BCS Class 2 drug. Nevertheless, the oral absolute bioavailability of carbamazepine lies between 70 and 78% and both in vivo and in vitro data support the classification of carbamazepine as a highly permeable drug. Since the therapeutic and toxic plasma level ranges overlap, carbamazepine is considered to have a narrow therapeutic index. For these reasons, a BCS based biowaiver for IR tablets of carbamazepine cannot be recommended. Interestingly, in nine out of ten studies, USP dissolution conditions (900 mL water with 1% SLS, paddle, 75 rpm) appropriately discriminated among bioinequivalent products and this may be a way forward to predicting whether a given formulation will be bioequivalent to the comparator product.The main aim of the present investigation highlights the development of mannose appended rifampicin containing solid lipid nanoparticles (Mn-RIF-SLNs) for the management of pulmonary TB. The developed Mn-RIF-SLNs showed particle size of Mn-RIF-SLNs (479 ± 13 nm) which was found to be greater than that of unconjugated SLNs (456 ± 11 nm), with marginal reduction in percentage entrapment efficiency (79.41 ± 2.42%). The in vitro dissolution studies depicted an initial burst release followed by sustained release profile indicating biphasic release pattern, close-fitting Weibull model having least F-value. The cytotoxicity studies using J774A.1 cell line represented that the developed SLNs were non-toxic and safe as compared to free drug. Fluorescence imaging and flow cytometric (FACS) analysis depicted significant (1.79-folds) intracellular uptake of coumarin-6 (fluorescent marker) loaded Mn-C6-SLNs. CDDO-Im Nrf2 activator The in vivo pharmacokinetic studies in sprague-dawley rats were performed and Mn-RIF-SLNs showed remarkable enhancement in terms of relative bioavailability (~17-folds) as compared to its drug solution via oral administration. The biodistribution studies revealed higher lung accumulation (1.8-folds) of Mn-RIF-SLNs as compared to the Un-RIF-SLNs. In conclusion, the developed Mn-RIF-SLNs could serve as a promising tool for delivering the drug cargo to the site of infection (lungs) in the treatment of TB.
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