What restricts the clinical use of nicotinic acid?

Nicotinic acid is the oldest hypolipidemic agent in use, since 1955. It possesses broad-spectrum lipidmodifying properties including reduction of total cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides. In addition, nicotinic acid is the most potent available hypolipidemic agent for increasing plasma high density lipoprotein (HDL) cholesterol and decreasing lipoprotein (a) levels. Clinical trials have demonstrated that nicotinic acid can decrease cardiovascular morbidity and mortality. However, nicotinic acid is underused in the clinical setting due to its high rate of side effects, including flushing, gastrointestinal disorders, rash, hyperglycemia and hyperuricemia. The nicotinic acid-associated side effects and their management are the focus of this review.     

What is the impact of ethics on clinical trials?

Ethics has often been ignored or evaded in clinical trials, and the conditions under which global clinical trials are conducted make this problem likely to persist. Ethics can, however, have an impact at any of several stages of a trial when the individuals involved are committed. This editorial provides historical examples of ignoring, evading or, alternatively, using ethical help to improve clinical trials, and suggests that the actual role of ethics depends on the individuals involved.     

Lipoic acid - the drug of the future?

Numerous experimental and clinical studies proved efficiency of treatment with lipoic acid-containing drugs in diseases, in which pro- and antioxidant balance is disrupted (diabetes, neurodegenerative diseases, acquired immune deficiency syndrome (AIDS), tumors, etc.). Efficiency of lipoate has been attributed to unique antioxidant properties of lipoate/dihydrolipoate system, its reactive oxygen species (ROS) scavenging ability and significant effect on the tissue concentrations of reduced forms of other antioxidants, including one of the most powerful, glutathione (thus lipoate is called an antioxidant of antioxidants). Moreover, analysis of literature data suggests participation of lipoic acid in processes of cell growth and differentiation. This fact can be crucial to clinical practice, however, this problem requires further studies.     

What Is the Impact of Comorbid Depression on Adolescent Substance Abuse Treatment?

ABSTRACT. Background: Substance use disorders (SUDs) are among the most common psychiatric diagnoses in adolescents. Some research suggests that comorbid depression in adolescents with SUD is associated with increased likelihood of alcohol dependence, poorer social competence, and greater risk for suicide attempts. However, little is known about how depression influences adolescent substance abuse treatment retention and outcomes. Methods: This review aimed to summarize the effects of comorbid depression on treatment retention and outcomes across 13 adolescent SUD treatment studies. Results: Results indicated that depression has a mixed relationship with treatment retention and outcomes, exerting a negative, positive, or nonsignificant effect depending on aspects of the study. Conclusions: More research needs to be done, particularly addressing the potential mediators and moderators of the relationship between depression and SUD outcomes. Importantly, recognizing that the studies varied widely in hypotheses and research methods, the field needs to develop more standardized methods to allow for a clearer understanding of the role of comorbid depression.     

What is the future of PEGylated therapies?

The tremendous potential of biologic drugs is hampered by short half-lives in vivo, resulting in significantly lower potency than activity seen in vitro. These short-acting therapeutic agents require frequent dosing profiles that can reduce applicability to the clinic, particularly for chronic conditions. Therefore, half-life extension technologies are entering the clinic to enable improved or new biologic therapies. PEGylation is the first successful technology to improve pharmacokinetic (PK) profiles of therapeutic agents and has been applied in the clinic for over 25 years. Over 10 PEGylated therapeutics have entered the clinic since the early 1990s, and new PEGylated agents continue to expand clinical pipelines and drug patent life. PEGylation is the most established half-life extension technology in the clinic with proven safety in humans for over two decades. Still, it is one of the most evolving and emerging technologies that will be applied for the next two decades.     

Effects of the β-amino acid antagonist TAG on thalamocortical inhibition

Chemical transmission at inhibitory synapses in thalamus may involve receptor activation by β-amino acids and glycine, as well as GABA. Given their hypothesized roles, we investigated effects of the putative β-amino acid antagonist 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (TAG) on synaptic inhibition in dorsal thalamus. We performed whole-cell recordings in 200–250 μm sections and immunocytochemical (ICC) studies in ventrobasal thalamus of rat brain (P12-P14). Stimulation of medial lemniscus evoked inhibitory postsynaptic currents (IPSCs) which were purely glycinergic or GABA_Aergic, or most commonly mixed glycinergic and GABA_Aergic responses, based on abolition by strychnine, bicuculline, or combined antagonism. TAG antagonized mixed IPSCs (IC₅₀ ∼70 μM) in a manner distinguishable from classical glycine and GABA_A receptor antagonists. TAG (250 μM) reduced the amplitude of glycinergic components which had a decay time constant of ∼9 ms or ∼230 ms by 45–50%, and a GABA_Aergic component which had a decay time constant of ∼40 ms by ∼60%. As in the glycinergic component, TAG reduced the amplitude of infrequently occurring, pure glycinergic IPSCs. Surprisingly, TAG had no effect on pure GABA_Aergic IPSCs, with a decay time constant of ∼20 ms that correlated to kinetics of GABA-activated channels. ICC studies showed co-localization of α_1/2 glycine and α₄ GABA_A receptors at inhibitory synapses. Activation of α₄ receptors by β-amino acids may contribute to the GABA_Aergic component of mixed IPSCs. The short and long-duration glycinergic IPSCs had decay time constants that correlated to the burst durations of single channels opened by β-amino acids and glycine. Overall, the effects of TAG implicate β-amino acid involvement in GABA_Aergic and glycinergic transmission.     

Effects of sublethal copper exposure on two gammarid species: which is the best competitor?

Biomarker responses in organisms exposed to copper were examined by comparing two gammarid species, Gammarus roeseli and Dikerogammarus villosus, based on gender. G. roeseli specimens were exposed to 20 μg/L of copper for 6, 12, 24 and 48-h periods, while D. villosus were exposed to 20 and 30 μg/L of copper for 12, 48 and 72 h. Males and females of each species were exposed separately and biomarker measurements were performed for each species and gender. The selected biomarkers were antioxidant enzymes as total glutathione peroxidase (GPxtot), selenium-dependent glutathione peroxidase (SeGPx), and catalase activities. Malondialdehyde level (MDA) was measured as a biomarker of toxic effect. Energy reserves were evaluated by means of lipid, glycogen and protein levels. For both species and gender, antioxidant enzyme activities were weakly modified by copper exposure and differences were transient. MDA levels were increased in both species and genders in exposed animals compared to controls, when energy reserves were decreased. G. roeseli was more rapidly overwhelmed by copper toxicity while the first response of D. villosus was the mobilization of its energetic content. D. Villosus probably has specific physiological properties that enable it to cope with copper toxicity and thus become the best competitor.     

TNF-α modulates the immunosuppressive effects of MSCs on dendritic cells and T cells

Mesenchymal stem cells are progenitor cells that have capabilities to differentiate different cell types. Also, MSCs possess immune suppressive effects on DC differentiation and T cell activation through a wide range of soluble factors and receptors. The properties of MSCs change through activation of cytokines particularly IFN-γ and TNF-α. The DC phenotypes and functions including the expression of co-stimulatory and co-inhibitory molecules and capabilities of DCs to induce allogeneic activation of CFSE-labeled splenocytes as well as cytokine production when they were differentiated in the presence of MSCs, TNF-α activated MSCs, IFN-γ activated MSCs and IFN-γ & TNF-α activated MSCs were analyzed. Treg population and T cell polarization were investigated using flowcytometry and real-time PCR respectively. Here, we showed that IFN-γ slightly enhances immunosuppressive effects of MSCs on immune system through induction tolerogenic DCs with elevated expression of IDO and increasing Treg population. Conversely, TNF-α decreases immunomodulation properties of MSCs on immune cells through the enhancement of co-stimulatory molecules such as ICOSL and HLA-DR, reduction of PDL-1 and PDL-2 expression and decrease of TGF-β and IL-10 in DCs as well as inhibition of T cell polarization into T_H2 and Treg. Taken together, these data showed crucial effects of microenvironments on MSC behaviors indicating that functions of MSCs differentially altered in the presence of different cytokines.     

What is the pathophysiology of the septic host upon admission?

The enormous case-fatality rate of severe sepsis and septic shock has resulted in considerable efforts being made towards understanding their complex mechanisms of pathogenesis. This has been done with the hope that agents that interfere with the pathways of pathogenesis and modulate the immune response of the host may be candidates for therapy. Disappointing results from most trials of immunomodulators in sepsis have led to understanding that the progression of patients to multiple organ dysfunction syndrome involves blunting of the pro-inflammatory cytokine storm. Instead, the compensatory anti-inflammatory response syndrome (CARS) develops, which is characterised by immunoparalysis. Components of this syndrome are impaired phagocytosis by neutrophils, decreased expression of HLA-DR on monocytes, impairment of ex vivo cytokine stimulation of monocytes, CD4 lymphopenia due to apoptosis of lymphocytes and predominance of anti-inflammatory T(h)2 and regulatory T-cell responses over pro-inflammatory T(h)1 and T(17) responses. CARS is not the sole explanation for the failure of trials of immunomodulators in sepsis. Recent data from the Hellenic Sepsis Study Group demonstrate that components of CARS upon transition from sepsis to severe sepsis/shock differ in relation to the underlying type of infection. These data underscore that the pathogenesis of sepsis presents considerable heterogeneity from one patient to another. That heterogeneity should be taken into consideration when deciding to administer an immunomodulator.     

What has prevented the expansion of insulin sensitisers?

The ability to improve insulin sensitivity with synthetic compounds was uncovered by empirical discoveries by Takeda in the late 1970s. The potential of a class of thiazolidinediones for the treatment of Type 2 diabetes, by decreasing glucose and triglycerides alongside lowering circulating insulin, was made public during the 1980s. As the first of the chemicals (pioglitazone, troglitazone and rosliglitazone) proceeded to clinical trials, these observations were soon extended to demonstrate a rich and complex pharmacology. The promise of this mode of action included prevention of diabetes as well as making a significant impact on the incidence and severity of the life-shortening consequences of the established disease. There are now two of these drugs on the market: pioglitazone and rosiglitazone, and they are being used to treat significant numbers of diabetic patients. However, the use of these drugs and development of future generations of successful candidates has not met the expectations that were held out in the early 1980s. This can be attributed to two major prevailing conditions. Troglitazone became the first thiazolidinedione to be approved as a result of delays in the development of pioglitazone. Unfortunately, troglitazone produced a unique idiosyncratic and sometimes fatal, hepatoxicity that necessitated its removal from the marketplace; second, there has been an incomplete understanding of the biochemical mechanism of action of these drugs that has slowed (and perhaps derailed) attempts to produce second-generation compounds. The latter issue is the subject of this editorial, which suggests that it is time to take a fresh look at the pharmacology of insulin sensitisers.     

What has prevented the expansion of insulin sensitisers?

The ability to improve insulin sensitivity with synthetic compounds was uncovered by empirical discoveries by Takeda in the late 1970s. The potential of a class of thiazolidinediones for the treatment of Type 2 diabetes, by decreasing glucose and triglycerides alongside lowering circulating insulin, was made public during the 1980s. As the first of the chemicals (pioglitazone, troglitazone and rosliglitazone) proceeded to clinical trials, these observations were soon extended to demonstrate a rich and complex pharmacology. The promise of this mode of action included prevention of diabetes as well as making a significant impact on the incidence and severity of the life-shortening consequences of the established disease. There are now two of these drugs on the market: pioglitazone and rosiglitazone, and they are being used to treat significant numbers of diabetic patients. However, the use of these drugs and development of future generations of successful candidates has not met the expectations that were held out in the early 1980s. This can be attributed to two major prevailing conditions. Troglitazone became the first thiazolidinedione to be approved as a result of delays in the development of pioglitazone. Unfortunately, troglitazone produced a unique idiosyncratic and sometimes fatal, hepatoxicity that necessitated its removal from the marketplace; second, there has been an incomplete understanding of the biochemical mechanism of action of these drugs that has slowed (and perhaps derailed) attempts to produce second-generation compounds. The latter issue is the subject of this editorial, which suggests that it is time to take a fresh look at the pharmacology of insulin sensitisers.