Effect of Renal Impairment on the Pharmacokinetics and Tolerability of Tiagabine

Summary: Purpose: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB).
Methods: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4–6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB · HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively.
Results: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t1/2) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 I/h, and from 6.4 to 8.4 h, respectively.
Conclusions: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.     

Recent developments in molecular action of antihormones

 Antihormones are by definition antagonists of steroid hormone action. They interact with the ligand binding domains of steroid hormone receptors and competitively inhibit the action of the receptors by mechanisms that are not quite understood. In certain cases antihormones also exhibit agonistic activity especially in connection with certain naturally occurring receptor mutants. These observations together with findings of indiscriminate interaction of antihormones with several classes of steroid receptors have necessitated a search of more effective and reliable antihormones. Recent advances in the resolution of the crystal structure of the ligand binding domains of certain members of the steroid receptor family and identification of non-liganded activation of steroid receptors have produced considerable information that can be harnessed into a fruitful search for a new generation of antihormones. Received: 19 June 1997 / Accepted: 10 October 1997     

Training the "clinical scientist" through a combined industrial/academic fellowship

A novel two-year fellowship program is described which provides specialized training both in clinical drug research and drug development methodology for pharmacists with previous clinical experience. Pharmaceutical industry, university and hospital research facilities are used as the training laboratories, and collectively offer theoretical as well as practical research skills development. Traditional didactic and laboratory training are provided within university and hospital environments with emphasis in the conduct of clinical trials. Extramural experience with pharmaceutical industry provides a corollary experience which includes exposure to ethical, legal and regulatory issues involving both investigational and marketed drugs. Following successful completion of the fellowship, the pharmacist is expected to have developed the fundamental skills necessary for a career in academia, pharmaceutical industry, or clinical practice.     

Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children With Type 1 Diabetes: Association With Hyperglycemia

Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA_1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.     

Chloride: The queen of electrolytes?

BackgroundChannelopathies, defined as diseases that are caused by mutations in genes encoding ion channels, are associated with a wide variety of symptoms and have been documented extensively over the past decade. In contrast, despite the important role of chloride in serum, textbooks in general do not allocate chapters exclusively on hypochloremia or hyperchloremia and information on chloride other than channelopathies is scattered in the literature.Study designTo systematically review the function of chloride in man, data for this review include searches of MEDLINE, PubMed, and references from relevant articles including the search terms “chloride,” “HCl,” “chloride channel” “acid-base,” “acidosis,” “alkalosis,” “anion gap” “strong anion gap” “Stewart,” “base excess” and “lactate.” In addition, internal medicine, critical care, nephrology and gastroenterology textbooks were evaluated on topics pertaining the assessment and management of acid-base disorders, including reference lists from journals or textbooks.ConclusionChloride is, after sodium, the most abundant electrolyte in serum, with a key role in the regulation of body fluids, electrolyte balance, the preservation of electrical neutrality, acid-base status and it is an essential component for the assessment of many pathological conditions. When assessing serum electrolytes, abnormal chloride levels alone usually signify a more serious underlying metabolic disorder, such as metabolic acidosis or alkalosis. Chloride is an important component of diagnostic tests in a wide array of clinical situations. In these cases, chloride can be tested in sweat, serum, urine and feces. Abnormalities in chloride channel expression and function in many organs can cause a range of disorders.     

Endogenous Angiotensin II‐induced p44/42 Mitogen‐Activated Protein Kinase Activation Mediates Sodium Appetite but not Thirst or Neurohypophysial Secretion in Male Rats

The renin–angiotensin–aldosterone system makes a critical contribution to body fluid homeostasis, and abnormalities in this endocrine system have been implicated in certain forms of hypertension. The peptide hormone angiotensin II (AngII) regulates hydromineral homeostasis and blood pressure by acting on both peripheral and brain targets. In the brain, AngII binds to the angiotensin type 1 receptor (AT1R) to stimulate thirst, sodium appetite and both arginine vasopressin (AVP) and oxytocin (OT) secretion. The present study used an experimental model of endogenous AngII to examine the role of p44/42 mitogen‐activated protein kinase (MAPK) as a signalling mechanism to mediate these responses. Animals were given a combined treatment of furosemide and a low dose of captopril (furo/cap), comprising a diuretic and an angiotensin‐converting enzyme inhibitor, respectively, to elevate endogenous AngII levels in the brain. Furo/cap induced p44/42 MAPK activation in key brain areas that express AT1R, and this effect was reduced with either a centrally administered AT1R antagonist (irbesartan) or a p44/42 MAPK inhibitor (U0126). Additionally, furo/cap treatment elicited water and sodium intake, and irbesartan markedly reduced both of these behaviours. Central injection of U0126 markedly attenuated furo/cap‐induced sodium intake but not water intake. Furthermore, p44/42 MAPK signalling was not necessary for either furo/cap‐ or exogenous AngII‐induced AVP or OT release. Taken together, these results indicate that p44/42 MAPK is required for AngII‐induced sodium appetite but not thirst or neurohypophysial secretion. This result may allow for the discovery of more specific downstream targets of p44/42 MAPK to curb sodium appetite, known to exacerbate hypertension, at the same time as leaving thirst and neurohypophysial hormone secretion undisturbed.     

The synthetic artificial stem cell (SASC): Shifting the paradigm of cell therapy in regenerative engineering

Stem cells are of great interest in tissue regeneration due to their ability to modulate the local microenvironment by secreting bioactive factors (collectively, secretome). However, secretome delivery through conditioned media still requires time-consuming cell isolation and maintenance and also may contain factors antagonistic to targeted tissue regeneration. We have therefore engineered a synthetic artificial stem cell (SASC) system which mimics the paracrine effect of the stem cell secretome and provides tailorability of the composition for targeted tissue regeneration. We report the first of many applications of the SASC system we have formulated to treat osteoarthritis (OA). Choosing growth factors important to chondrogenesis and encapsulating respective recombinant proteins in poly (lactic-coglycolic acid) 85:15 (PLGA) we fabricated the SASC system. We compared the antiinflammatory and chondroprotective effects of SASC to that of adipose-derived stem cells (ADSCs) using in vitro interleukin 1B-induced and in vivo collagenase-induced osteoarthritis rodent models. We have designed SASC as an injectable therapy with controlled release of the formulated secretome. In vitro, SASC showed significant antiinflammatory and chondroprotective effects as seen by the up-regulation of SOX9 and reduction of nitric oxide, ADAMTS5, and PRG4 genes compared to ADSCs. In vivo, treatment with SASC and ADSCs significantly attenuated cartilage degeneration and improved the biomechanical properties of the articular cartilage in comparison to OA control. This SASC system demonstrates the feasibility of developing a completely synthetic, tailorable stem cell secretome which reinforces the possibility of developing a new therapeutic strategy that provides better control over targeted tissue engineering applications.

Stem cell science has become an essential component of regenerative engineering and has the potential to revolutionize healing outcomes once clinical translation is achieved (1). Regenerative engineering utilizes a transdisciplinary approach and is defined by the convergence of advanced material science, stem cell sciences, physics, developmental biology, and clinical translation to regenerative complex tissues and organs (2, 3). Mesenchymal stem cells, which are a multipotent cell type, possess the ability to self-renew and differentiate into various lineages such as adipocytes, bone, cartilage, muscle, skin, and tendon and have been used in preclinical studies to regenerate these respective and other connective tissues (4, 5). In addition to their differentiation ability, stem cells also have the ability to secrete bioactive factors during differentiation which will further drive repair and regeneration (6, 7) As a result, the role of stem cells as progenitor cells with associated bioactive factors is becoming increasingly important as a strategy to harness the regenerative potential of the tissues within the body (8).Stem cell therapy focuses on the delivery of cells to facilitate tissue repair and regeneration by a combination of antiinflammatory, immunomodulatory properties and multipotent differentiation capacity. However, in order to be used in a clinical setting, they must be isolated from human tissue and require constant growth and passage in in vitro culture environments. In addition, studies have reported that cells are at risk for undergoing spontaneous alterations in behavior and properties while being cultured (9). Contamination is also a risk due to improper technique or nonsterile conditions. Other limitations and challenges that should be considered when developing stem cell therapies include immune compatibility and rejection reactions, formation of malignant tumors due to uncontrolled proliferation, and transmission of infectious processes (10, 11).Following these concerns and further reportedly negligible levels of stem cell engraftment into the diseased tissue (12), more recent studies are highlighting the fact that the collection of paracrine factors secreted by stem cells (known as the secretome) is the main enforcer of therapeutics effects. Cell-free alternatives that utilize paracrine factors in a similar fashion have recently been considered (13–16). Secretome has been proposed as a cell-free alternative to cell therapy to overcome the limitations and associated risks with stem cell therapeutics. The secretome is defined as a set of biological factors and molecules that are secreted into the extracellular matrix (ECM) which play an essential role in a wide range of biological processes, including homeostasis, immunomodulation, inflammation, angiogenesis, and ECM organization (17). The functions of the secretome can be broken into four main functions: angiogenesis, antiapoptosis, antifibrosis, and antiinflammation (17). Various secreted proteins make up the cell secretome and can include growth factors, angiogenic factors, cytokines, chemokines, and extracellular vesicles for transport of lipids and proteins. The composition of the secretome is highly dynamic and is based on the cell type and microenvironment which it will be used in, allowing for greater design flexibility and versatility for use in a wide array of tissues (17, 18). The paracrine effect exhibited by the secretome has been shown to be very effective in regenerating different tissues (12) with several logistical advantages for use in a clinical setting such as longer shelf lives, availability, and scalability (19, 20).While the secretome provides many advantages over cell-based therapy, it shares many similar translational challenges, including time-consuming cell maintenance to obtain conditioned media and compositional sensitivity to the cell microenvironment. Stem cells secrete a mixture of biological factors in a controlled, sequential, and combinatorial fashion to exhibit the paracrine effect which has recently been shown to be a key driver for the regenerative process. To date, there has been no study conducted which attempts to mimic the paracrine functions of the stem cell. While single growth factor treatment may not be effective for complete regeneration, controlled delivery of a mixture of factors is needed to truly mimic cellular paracrine functions. Therefore, we have engineered the synthetic artificial stem cell (SASC). With the added ability to tailor the formulation for targeted tissues, SASC has the potential to be used in different systems by providing potent immunomodulatory and regenerative effects.In the present study, we aimed at developing the first SASC system to attenuate osteoarthritis (OA) progression by tailoring factors abundant in the stromal stem cell secretome that have specifically an anabolic, chondroprotective, and/or antiinflammatory effect in the joint (21–23). Katagiri et al. (23) found insulin-like growth factor (IGF) and transforming growth factor (TGF)-β1 to be important chondrogenic factors in bone marrow–derived stem cell conditioned media. Others have also reported the importance of fibroblast growth factor (FGF)-18 in chondrogenesis (specifically signaling through anabolic receptor FGFR3) (24–26) and of human growth hormone (HGH) (a proliferative factor which also signals for IGF1) (27, 28). As a pilot SASC composition, IGF1, TGF-β1, FGF-18, and HGH were combined at concentrations similar to conditioned media and delivered using a poly (lactic-coglycolic acid) (PLGA) 85:15 matrix. The antiinflammatory and chondroprotective effects of SASC have been evaluated in comparison with the current treatment standard, adipose-derived stem cells (ADSCs) (5), in both in vitro and in vivo OA models (Fig. 1). Furthermore, biomechanical outcomes of SASC treatment were also evaluated in vivo.Open in a separate windowFig. 1.A graphical summary of coculture in vitro (A) and rodent collagenase-induced in vivo (B) models. Figure made in Biorender.