Cell therapies for acute and chronic traumatic brain injury.

Traumatic brain injury (TBI) is a global health problem, for which there are no approved therapies. Advances in acute clinical care have improved post-TBI survival, yet many patients are left with chronic TBI-related disabilities (i.e. chronic TBI). Existing treatments that focus on rehabilitation and symptom management do not modify the disease and have limited effectiveness. Consequently, chronic TBI-related disabilities remain a significant unmet medical need. Cell therapies have neuroprotective and neurorestorative effects which are believed to modify the disease. In this article, we review the safety and efficacy of cell therapies in early-phase clinical studies that have shown potential to improve outcomes in acute to chronic phases of TBI.

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Hyaluronic Acid Soft Tissue Filler for the Treatment of The Hypoplastic Chin: An Observational Study.

BACKGROUND: The hypoplastic chin is associated with facial unattractiveness. OBJECTIVE: To evaluate safety and efficacy of JUVÉDERM Voluma XC Injectable Gel (hyaluronic acid filler, HAF) for treatment of hypoplastic chin. METHODS: This was a one-year, open-label, single-center study. RESULTS: Thirty subjects received HAF injections of which 24 subjects (80%) completed the study. Mean facial angle significantly improved at all time points compared with baseline, improving by 1.83° (95% confidence interval, 0.91, 2.75; p < .001) at 12 months. Subject satisfaction with lower face and jawline increased significantly for all FACE-Q questions and time points compared with baseline (p < .05). Subject satisfaction with overall facial appearance, and percentage of subjects "not bothered" by area under chin increased significantly for most FACE-Q questions and time points compared with baseline (p < .05). CONCLUSION: In this completed one-year study, HAF injection for hypoplastic chin was safe and accompanied by significant improvement in facial angle, measures of subject satisfaction, and GAIS.

Facial treatment preferences in aesthetically aware women.

BACKGROUND: Individuals typically self-identify symptoms of facial aging that lead them to seek facial aesthetic treatments. No systematic data exist to describe preferences for facial areas requiring treatment. OBJECTIVE: To determine (1) the facial areas most likely to be treated first, (2) the relationship between the most bothersome facial area and the area first planned for treatment, and (3) differences between younger and older women. METHODS: A total of 603 women aged 30 to 65 years considering aesthetic treatments participated in an online research survey using Maximum Difference scaling. RESULTS: Maximum Difference analysis revealed that crow's feet lines (CFLs) were most likely to be treated first (82% of the first preferences), followed by oral commissures (74%) and tear troughs (72%). There was a strong correlation between the most bothersome facial area and the area first planned for treatment. In women younger than 45 years, features of the upper face were more likely to be treated first, whereas women aged 50 years or older had an increased preference for treating features of the lower face, with a reduction in preference for upper face treatment. CONCLUSION: This cross-sectional survey suggests that aesthetically oriented women have changing facial treatment preferences with age; however, CFLs are of most concern.

Incretin-based therapies.

Incretin-based therapies have established a foothold in the diabetes armamentarium through the introduction of oral dipeptidyl peptidase-4 inhibitors and the injectable class, the glucagon-like peptide-1 receptor agonists. In 2009, the American Diabetes Association and European Association for the Study of Diabetes authored a revised consensus algorithm for the initiation and adjustment of therapy in Type 2 diabetes (T2D). The revised algorithm accounts for the entry of incretin-based therapies into common clinical practice, especially where control of body weight and hypoglycemia are concerns. The gut-borne incretin hormones have powerful effects on glucose homeostasis, particularly in the postprandial period, when approximately two-thirds of the ß-cell response to a given meal is due to the incretin effect. There is also evidence that the incretin effect is attenuated in patients with T2D, whereby the ß-cell becomes less responsive to incretin signals. The foundation of incretin-based therapies is to target this previously unrecognized feature of diabetes pathophysiology, resulting in sustained improvements in glycemic control and improved body weight control. In addition, emerging evidence suggests that incretin-based therapies may have a positive impact on inflammation, cardiovascular and hepatic health, sleep, and the central nervous system. In the present article, we discuss the attributes of current and near-future incretin-based therapies.

Exenatide once-weekly clinical development: safety and efficacy across a range of background therapies.

In patients with type 2 diabetes mellitus (T2DM), the physiologic glucagon-like peptide-1 (GLP-1) response, which is involved in glucose regulation through several mechanisms, is dysfunctional. GLP-1 receptor agonists can fill an unmet therapeutic need in the treatment of T2DM: improving glycemic control without increasing the risk of hypoglycemia (except with concomitant sulfonylureas) and reducing weight in a substantial proportion of patients. GLP-1 receptor agonists have impacted established disease treatment algorithms for T2DM. For example, in 2009 the American Diabetes Association and European Association for the Study of Diabetes revised their consensus treatment algorithm to incorporate GLP-1 receptor agonists. GLP-1 receptor agonists were originally represented by exenatide BID (ExBID), a short-acting agent requiring twice-daily injections at mealtime. The longer-acting agent liraglutide, requiring once-daily injections, recently received regulatory approval. Several other long-acting agents are in clinical development, one of which is the once-weekly formulation of exenatide (exenatide once weekly [ExQW]). This article reviews the clinical development of ExQW in the DURATION program. Patients in theses clinical trials were receiving various background treatments, ranging from lifestyle therapy to combination oral therapy, although the majority (68%) received metformin monotherapy. Specifically, safety, glycemic control, and weight were compared in patients treated with ExQW versus ExBID, sitagliptin, pioglitazone, or insulin glargine. Moreover, measures of ß-cell function, cardiovascular risk, inflammation, and hepatic health were investigated. During ExQW clinical development, consistent clinical efficacy (glycosylated hemoglobin, -1.5% to -1.9%; weight, -2 kg to -4 kg) and safety data were observed in patients with T2DM treated with ExQW.

Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes.

BACKGROUND: The majority of patients with type 2 diabetes mellitus have blood pressure (BP) exceeding the recommended value of <130/80 mm Hg. Optimal control of hyperglycemia and hypertension has been shown to reduce the incidence of macrovascular and microvascular complications due to diabetes. Treatment with the GLP-1 receptor agonist exenatide, previously demonstrated to reduce hemoglobin A(1C) and weight in subjects with type 2 diabetes, was associated with BP reduction in several studies. METHODS: This analysis explored the effects of exenatide vs. placebo or insulin on BP measurements in pooled data from six trials including 2,171 subjects studied for at least 6 months. RESULTS: Overall, 6 months of exenatide treatment was associated with a significantly greater reduction in systolic BP (SBP) compared with placebo (least squares mean (s.e.): difference of -2.8 mm Hg (0.75); P = 0.0002) or insulin (difference of -3.7 mm Hg (0.85); P < 0.0001). No significant intergroup differences in diastolic BP (DBP) were observed. The majority of the intergroup difference was observed in subjects with SBP > or = 130 mm Hg (difference of -3.8 mm Hg (1.08) from placebo: P = 0.0004; difference of -4.0 mm Hg (1.01) from insulin; P < 0.0001). The largest intertreatment differences between exenatide and comparators were observed in subjects with SBP >/=150 mm Hg. Similar responses were observed in African-American subjects. A weak correlation between the amount of weight lost and reduction in SBP was found (r = 0.09, P = 0.002) for exenatide-treated subjects. CONCLUSIONS: These results support the need for a prospective, randomized, controlled study of BP changes during exenatide treatment in patients with hypertension and type 2 diabetes.

Exenatide improves hypertension in a rat model of the metabolic syndrome.

BACKGROUND: Exenatide is a peptide incretin mimetic that has glucoregulatory actions associated with weight reduction. Previous reports demonstrated acute increases in blood pressure after systemic or intracerebroventricular administration of exenatide or glucagon like peptide 1 (GLP 1) in rats. However, there are limited studies testing the chronic effects of these peptides on arterial pressure and no reports showing the effects of these peptides to reverse hypertension in the context of the metabolic syndrome. METHODS: Thus, we examined the response to peripheral exenatide using telemetry in conscious, unrestrained rats under normotensive conditions and in a model of hypertension/metabolic syndrome induced by corticosterone. Rats were implanted with either corticosterone or wax (control) pellets, followed 14 days later by the additional implantation of pumps to deliver exenatide (1 microg/kg per day) or vehicle for 7 days. RESULTS: The 21-day corticosterone treatment produced hypertriglyceridemia, visceral fat deposition, hyperglycemia, insulin resistance, and an elevation of mean arterial blood pressure (MAP) by 14 +/- 1 mmHg. Exenatide significantly reversed corticosterone-induced increases in blood pressure and this normalization occurred independently from change in body weight. Additionally, exenatide reduced MAP by 5 +/- 3 mmHg in normotensive control rats. CONCLUSIONS: These results are the first demonstration of a durable antihypertensive effect of exenatide in a glucocorticoid-induced model of the metabolic syndrome.

Caffeine stimulates cytochrome oxidase expression and activity in the striatum in a sexually dimorphic manner.

Epidemiological studies indicate that caffeine consumption reduces the risk of Parkinson's disease (PD) in men, and antagonists of the adenosine 2A receptor ameliorate the motor symptoms of PD. These findings motivated us to identify proteins whose expression is regulated by caffeine in a sexually dimorphic manner. Using mass spectroscopy, we found that Cox7c, a nuclear-encoded subunit of the mitochondrial enzyme cytochrome oxidase, is up-regulated in the striatum of male but not female mice after receiving a single dose of caffeine. The expression of two other Cox subunits, Cox1 and Cox4, was also stimulated by caffeine in a male-specific fashion. This up-regulation of Cox subunits by caffeine was accompanied by an increase in Cox enzyme activity in the male striatum. Caffeine-induced stimulation of Cox expression and activity were reproduced using the adenosine 2A receptor (A2AR)-specific antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261), and coadministration of the A2AR-specific agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) counteracted the elevation of Cox expression and activity by caffeine. Caffeine also increased Cox activity in PC-12 cells. In contrast, small interfering RNA (siRNA) knockdown of Cox7c expression in PC-12 cells blunted Cox activity, and this was counteracted by caffeine treatment. Caffeine was also found to increase Cox7c mRNA expression in the striatum and in PC-12 cells. This occurred at the level of transcription and was mediated by a segment of the Cox7c promoter. Overall, these findings indicate that cytochrome oxidase is a metabolic target of caffeine and that stimulation of Cox activity by caffeine via blockade of A2AR signaling may be an important mechanism underlying the therapeutic benefits of caffeine in PD.

Emerging incretin based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors.

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance. These strategies are typically used in a stepwise manner: employing oral glucose lowering agents, followed by insulin therapy. This traditional approach fails to address the progressive decline in beta cell function. Moreover, these therapies are often associated with weight gain in overweight or obese patients with type 2 diabetes. Both exogenous insulin and insulin secretagogues are associated with an increased risk of hypoglycemia. Recently, new treatments that leverage the glucoregulatory effects of incretin hormones, such as glucagon like peptide 1 have been introduced. Both incretin mimetics and DPP-4 inhibitors address both the underlying pathophysiology and overcome several of the limitations of established therapies by providing improvements in glycemia, and control of body weight with minimal risk of hypoglycemia.

Management of Type 2 diabetes: the role of incretin mimetics.

Type 2 diabetes is characterised by insulin resistance and progressive beta-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive beta-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in beta-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.

Bromocriptine and clozapine regulate dopamine 2 receptor gene expression in the mouse striatum.

In a previous study, we showed that the psychoactive drug caffeine alters the expression of the dopamine 2 receptor (D2R) gene in vitro and in vivo. Here, we report that acute administration of antipsychotic and anti-parkinsonian drugs also regulate D2R gene expression in PC12 cells and in the mouse striatum. Treatment of PC12 cells with the atypical antipsychotic and specific 5-HT antagonist clozapine (60 microM) reduced D2R/luciferase reporter expression by 46% after 24 h. However, male and female mice treated with a clinical dose of clozapine (10 mg/kg) showed no changes in striatal D2R mRNA expression when assayed by quantitative RT-PCR. Treatment of PC12 cells with the specific D2R agonist anti-parkinsonian drug, bromocriptine mesylate (BCM; 5 microM) also resulted in decreased D2R/luciferase reporter activity (27%). In contrast to clozapine, a clinical dose of BCM (16 mg/kg) led to a 21% decrease and a 45% increase in striatal D2R mRNA expression in male and female mice, respectively, after 24 h. Coadministration of clozapine and BCM in PC12 cells resulted in a synergistic decrease in D2R/luciferase reporter expression (68%), and coadministration of these drugs in vivo led to decreases in striatal D2R mRNA expression in both male and female mice (45% and 22%, respectively). Collectively, these results indicate that clozapine, BCM, or a combination of these drugs have differential effects on dopamine receptor gene expression and might also affect striatal physiology in a sexually dimorphic manner.

Caffeine regulates neuronal expression of the dopamine 2 receptor gene.

The psychoactive drug caffeine influences neuronal physiology; however, it is unknown whether it can dynamically alter the expression of genes that influence neurotransmission. Here, we report that caffeine stimulates transcription of the dopamine 2 receptor (D2R) gene in PC-12 cells and primary striatal cultures and increases D2R protein expression in the striatum. Physiological doses of caffeine and the specific adenosine 2A receptor antagonist 8-(3-chlorostyryl) caffeine both increased the activity of a D2R/luciferase reporter construct within 24 h, and simultaneous treatment with 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), a specific adenosine 2A receptor agonist, eliminated this effect. Tests of additional constructs revealed that specific regions of the D2R promoter (-117/-75) and 5'-untranslated region (+22/+317) were required for activation of D2R gene expression by caffeine. In primary striatal cultures, caffeine increased spontaneous firing of neurons between 12 and 80 min after treatment, whereas it increased D2R mRNA expression after only 4 h. These results indicate that regulation of D2R gene expression by caffeine occurs after the initial physiological response has subsided. In vivo, female mice treated with a dose of caffeine (50 mg/kg) showed 1.94- and 2.07-fold increases in D2R mRNA and protein expression, respectively. In contrast, male mice exhibited a 31% decrease in D2R mRNA expression and showed no changes in D2R protein expression. Collectively, these results demonstrate for the first time that caffeine alters D2R expression in neurons. They also suggest that caffeine consumption can lead to sexually dimorphic patterns of gene expression in the brain.

Nuclear immunostaining in rat neuronal cells using two anti-Kir2.2 ion channel polyclonal antibodies.

The inwardly rectifying potassium ion channel Kir2.2 has recently been demonstrated to have nuclear and plasma membrane subcellular localization. Nuclear expression of Kir2.2 is controversial, as a functional role for Kir2.0 potassium channels in the nucleus has not been investigated. However, in this report we have demonstrated Kir2.2 nuclear localization in sections of rat hindbrain and dorsal root ganglia tissue, using two anti- Kir2.2 polyclonal antisera with different epitope specificities. These data confirm nuclear localization and are suggestive of new functions of Kir2.0 potassium ion channels in the nucleus.