Aqueous Stability and Oral Pharmacokinetics of Meloxicam and Carprofen in Male C57BL/6 Mice

We found that carprofen and meloxicam under 3 environmental conditions (ambient dark, ambient light, and 4 °C) remained stable for at least 7 d. We then evaluated the oral pharmacokinetics of meloxicam (20 mg/kg) and carprofen (10 mg/kg) in male C57BL/6 mice after oral gavage or administration in the drinking water. Mice did not drink meloxicam-medicated water but readily consumed carprofen-medicated water, consuming an average of 14.19 mL carprofen-medicated water per 100 g body weight daily; mice drank more during the dark phase than during the light phase. Plasma analyzed by HPLC (meloxicam) and tandem mass spectrometry (carprofen) revealed that the peak meloxicam and carprofen concentrations were 16.7 and 20.3 μg/mL and occurred at 4 and 2 h after oral gavage, respectively. Similar blood levels were achieved after 12 h access to the carprofen-medicated water bottle. At 24 h after oral gavage, the drugs were not detectable in plasma. Meloxicam plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.4 mg/L × h, 7.4 h, 0.36 L/kg, and 0.125 mL/h × kg, respectively. Carprofen plasma AUC, elimination half-life, apparent volume of distribution, and apparent oral clearance were 160.8 mg/L × h, 7.4 h, 0.42 L/kg, and 0.062 mL/h × kg, respectively. No gross or microscopic evidence of toxicity was seen in any mouse. Our findings indicate that carprofen can be administered in drinking water to mice and that medicated water bottles should be placed 12 to 24 h prior to painful procedures.Abbreviation: COX, cyclooxygenaseThe provision of appropriate and effective analgesia for research rodents is a constant challenge for veterinary care personnel.^1,22,53,54 Several barriers exist that may hinder the administration of sufficient analgesia, including appropriate training for administering analgesics, the possibility for inducing handling stress, interstrain and interindividual variability in response to and metabolism of a given analgesic substance, and the different levels of analgesic required after any one of the numerous procedures or experimental conditions that any given research mouse may undergo.¹⁴ Furthermore, little information is available in the literature regarding the pharmacokinetics of commonly used NSAID in laboratory mice or after alternative routes of administration. Information regarding method of administration, dose ranges, and dosing intervals is often extrapolated from other species; however, the extent of interspecies variability is often unknown.Carprofen is a NSAID that is derived from propionic acid and has antiinflammatory, antipyretic, and analgesic properties. The compound has a chiral center at the α-carbon position and exists as a racemic mixture composed of R (–) and S (+) enantiomers,⁴⁷ which is a complicating factor in pharmacokinetic investigations. In all species studied to date, the R enantiomer is less potent than is the S enantiomer, and there is minimal conversion between enantiomers in vivo.²⁶ As with other NSAID, the positive pharmacologic effects of carprofen arise through species-specific differential inhibition of cyclooxygenase (COX) isomers. The pharmacokinetics of carprofen have been evaluated in several mammalian species, including rats,^21,24 cows,^10,27 dogs,³³ cats,⁴⁸ sheep,^7,56 horses,^11,27,34,46 rabbits,¹⁸ and humans.⁴⁷ Most^{9,20,23,33,46,54} of these studies evaluated pharmacokinetic parameters after intravenous or subcutaneous administration; other studies^33,47 evaluated the pharmacokinetics of carprofen after oral administration. Evidence regarding the relative COX2 selectivity of carprofen is inconsistent throughout the literature,²³ and in vitro studies have suggested that carprofen is a nonselective inhibitor of COX2 in horses but a selective COX2 inhibitor in cats.³ These findings serve to further emphasize the potential for interspecies variability in the pharmacokinetics of carprofen and the need for species-specific dosage information.Meloxicam is an enolic acid NSAID derivative that has antiinflammatory, analgesic, and antipyretic properties.¹³ Its antiinflammatory action is achieved through preferential inhibition of COX2, which may contribute to reducing the gastrointestinal side effects that may be seen with other NSAID. Meloxicam has a long half-life in many species, thereby supporting once-daily administration and making the drug an attractive veterinary analgesic.¹³ The pharmacokinetics of meloxicam have been evaluated in several mammalian species, including rats,⁴³ horses,^45,52 cows,³⁷ goats,^20,44 sheep,⁴⁴ pigs,^15,16 dogs,^4,36,58 donkeys,²⁸ chickens,² humans,⁴² and some exotic and wild species (for example, camels,⁵⁵ iguanas,¹² vultures³⁸).Both carprofen and meloxicam typically are administered to mice subcutaneously, but there are anecdotal reports of the provision of NSAID in the drinking water. This method of administration is an attractive option, because it potentially could ensure that adequate and stable blood drug levels are achieved throughout a period of analgesic need and would remove the handling stress associated with subcutaneous injection or oral gavage.^8,19,35 To date, no data have been published to support this route of administration for NSAID to mice. Before adopting this practice, it is important to determine whether meloxicam and carprofen are stable when diluted in water, whether rodents consume medicated water, and whether blood drug levels obtained after this route of administration are comparable to those of other methods of administration. The current study evaluated the stability of carprofen and meloxicam in water under various environmental conditions and assessed the palatability and oral pharmacokinetics of both compounds when administered in the drinking water and by oral gavage. In addition, mice were evaluated for evidence of acute NSAID-related toxicity of gastrointestinal, hepatic, and renal tissues.     

Native American elders' health congruence: the role of gender and corresponding functional well-being, hospital admissions, and social engagement

Addressing the need to explore how Native American (NA) elders' subjective health (SH) compares to their objective health (OH; chronic disease conditions), we examined whether: congruence between 8191 NA elders' SH and OH parallels that of non-NA elders; health optimism (SH > OH) is protective and health pessimism (SH < OH), is detrimental; and whether gender moderates links between health congruence and health-related outcomes. Results comparing health optimists and pessimists to realists in functioning, hospitalizations, and social engagement showed optimists experienced better outcomes; pessimists had poorer outcomes; the role of health congruence differed by gender. Findings suggest implications for improving health-related outcomes among NA elders.     

Monitoring of Individual Needs in Diabetes (MIND)-2: Follow-up data from the cross-national Diabetes Attitudes,Wishes, and Needs (DAWN) MIND study

OBJECTIVE

To test the effects of implementing computer-assisted Monitoring of Individual Needs in Diabetes (MIND) in routine diabetes care on psychological status and glycemic control, identify predictors of poor psychological outcomes, and evaluate care providers’ experiences.

RESEARCH DESIGN AND METHODS

The MIND procedure was implemented as part of the annual review in diabetes clinics across eight countries in a prospective observational study with a 1-year follow-up. MIND encompasses well-being (World Health Organization Five Well-Being Index [WHO-5]), diabetes-related distress (Problem Areas in Diabetes [PAID]), a Life Event Inventory, and the patient’s agenda for their consultation. Medical data and agreed case-management actions were retrieved from the charts.

RESULTS

Of the total 1,567 patients, 891 patients (57%) were monitored at a 1-year follow-up. Twenty-eight percent of the patients screened positive for depression and/or diabetes distress at baseline and considered cases, 17% of whom were receiving psychological care. Cases were significantly more often female and had type 2 diabetes and worse glycemic control compared with noncases. Clinically relevant improvements in WHO-5 and PAID were observed over time in cases, irrespective of referral (effects sizes 0.59 and 0.48, respectively; P < 0.0001). Glycemic control did not change. Female sex, life events, and concomitant chronic diseases were predictors of poor psychological outcomes. MIND was well received by patients and staff.

CONCLUSIONS

MIND appears suitable for screening and discussion of emotional distress as part of the annual review. Broader dissemination in diabetes care is recommendable, but sustainability will depend on reimbursement and availability of support services.A relatively large proportion of people with diabetes suffer from psychological distress that often stays unrecognized and untreated (1,2). To improve recognition of the psychological needs of diabetic patients, routine monitoring of emotional well-being has been advocated, using validated screening tools (3,4). However, the act of screening by itself is unlikely to impact psychological outcomes, unless linked to discussion of outcomes with the patient, followed by a referral for those identified in need of additional psychological care (5,6). Previous studies have demonstrated that monitoring of well-being and discussing outcomes as part of routine consultation help to improve psychological well-being in both youth and adults with diabetes (7,8). Based on this work, we set out to test the effects of implementing the Monitoring of Individual Needs in Diabetes (MIND) procedure as part of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) program (9). Baseline data from this DAWN MIND study have been reported elsewhere (10).In this study, we present the 12-month follow-up results testing the impact of implementing MIND on emotional well-being, diabetes-related distress, and glycemic control in routine secondary diabetes care in eight countries. In addition, we sought to identify predictors of poor psychological functioning at follow-up and evaluate the care providers’ experience of implementing well-being monitoring as part of routine care.     

Attention and Memory Biases in Social Anxiety Disorder: The Role of Comorbid Depression

Cognitive biases play an important role in the onset and maintenance of Social Anxiety Disorder (SAD). Few studies, however, have examined the role of comorbid Major Depressive Disorder (MDD) in the processing of emotional material. In addition, little is known about the relation among different cognitive biases. In the current study, 73 participants (54.79% female) completed an emotion face dot-probe task followed by a recognition memory test. Compared to participants with SAD, participants with comorbid SAD and MDD oriented away from supraliminally presented angry faces. Subsequently, SAD participants with and without comorbidity recognized fewer angry faces than non-disordered controls. Furthermore, attention biases for subliminally presented stimuli predicted recognition accuracy only for comorbid participants. These results suggest that the presence of comorbid MDD affects attentional orienting in SAD participants. In addition, it highlights the interconnectedness of attention and memory biases for comorbid participants.     

Diabetes fatalism and its emotional distress subscale are independent predictors of glycemic control among Lebanese patients with type 2 diabetes

Background: Achieving and sustaining optimal glycemic control in type 2 diabetes (T2DM) is difficult because of socio-cultural and psychosocial factors including diabetes fatalism. Diabetes fatalism is ‘a complex psychological cycle characterized by perceptions of despair, hopelessness, and powerlessness’.

Purpose: The purpose of this paper is to explore whether diabetes fatalism and other psychosocial and socio-cultural variables are correlates of glycemic control in Lebanese population with T2DM.

Methods: A convenience sample of 280 adult participants with T2DM were recruited from a major hospital in greater Beirut-Lebanon area and from the community. Diabetes fatalism was assessed using the Arabic version of 12-item Diabetes Fatalism Scale. Multiple linear regression models were used to assess the relationship between HbA1c and psychosocial and socio-cultural characteristics including diabetes fatalism. Four models were run to examine the independent association between HbA1c and diabetes fatalism and to identify which of the 3 subscales (emotional distress, spiritual coping and perceived self-efficacy) were associated with HbA1c.

Results: The mean age of the participants was 58.24(SD?=?13.48) and the majority were females (53.76%), while 32.73% of the sample had diabetes for more than 10 years. Fully adjusted multiple linear regression models showed that higher scores on diabetes fatalism and the emotional distress subscale (P?=?0.018) were significantly associated with higher HbA1c values. In addition, having diabetes for more than 11 years (P?=?0.05) and a higher number of diabetes complications (P?<?0.001) were associated with higher HbA1c levels. However, advanced age (P?=?0.055), female gender (P?=?0.003), and diabetes education (P?=?0.011) were significantly associated with lower HbA1c levels.

Conclusion: This is the first study in the Arab region that identifies diabetes fatalism as an independent predictor of glycemic control among Lebanese. Future studies should further investigate this construct to guide interventions that can address it for better diabetes outcomes.     

IgG Fc membrane receptor on normal human glomerular visceral epithelial cells

Summary This study demonstrates that human glomerular epithelial cells are able to bind heat aggregated immunoglobulins and antigen-antibody complexes. This has been observed on kidney cryostat sections, on whole glomeruli and on cultured visceral epithelial cells. Binding depends on the presence of the Fc portion of IgG and occurs in the absence of complement, showing that the IgG Fc receptor is different from the C3b receptor. The use of heat aggregated anti-peroxidase IgG and of peroxidase anti-peroxidase complexes allowed us to demonstrate, at the ultrastructural level, that the binding of the reagents at the plasma membrane was followed by their internalization within coated pits of vesicles. These observations strongly suggest that glomerular visceral epithelial cells are capable of receptor mediated endocytosis. The role of this process in glomerular diseases remains to be established.     

Polyelectrolyte multilayers functionalized by a synthetic analogue of an anti-inflammatory peptide, alpha-MSH, for coating a tracheal prosthesis

Polyelectrolyte multilayer films made of poly (L-lysine) (PLL) and poly (L-glutamic acid) (PGA) have been functionalized by covalent binding of a synthetic analogue of the anti-inflammatory peptide, alpha-melanocyte-stimulating hormone (alpha-MSH) to PGA to create biologically active coatings for tracheal prostheses. The morphology and in vivo stability of the films were investigated by atomic force microscopy and confocal laser scanning microscopy, respectively. For the in vivo evaluation, 87 rats were implanted and examined for a period superior to 3 months. Histological analysis, performed 1 month after implantation, showed a fibroblast colonization of the periprosthetic side and a respiratory epithelium type on the endoluminal side of the implant for all the polyelectrolyte coatings tested. However, for prostheses modified by PGA ending multilayer films, a more regular and less obstructive cell layer was observed on the endoluminal side compared to those modified by PLL ending films. Systemic anti-inflammatory IL-10 production was only detected in rats implanted with prostheses functionalized by alpha-MSH, demonstrating, in vivo, the anti-inflammatory activity of the embedded peptide into multilayer architectures.