Role of polymer–drug conjugates in organ-specific delivery systems

Polymers have been utilized to deliver the drug to targeted site in controlled manner, achieving the high-therapeutic efficacy. Polymeric drug conjugates having variable ligands as attachments have been proved to be biodegradable, stimuli sensitive and targeted systems. Numerous polymeric drug conjugates having linkers degraded by acidity or intracellular enzymes or sensitive to over expressed groups of diseased organ/tissue have been synthesized during last decade to develop targeted delivery systems. Most of these organs have number of receptors attached with different cells such as Kupffer cells of liver have mannose-binding receptors while hepatocytes have asialoglycoprotein receptors on their surface which mainly bind with the galactose derivatives. Such ligands can be used for achieving high targeting and intracellular delivery of the drug. This review presents detailed aspects of receptors found in different cells of specific organ and ligands with binding efficiency to these specific receptors. This review highlights the need of further studies on organ-specific polymer–drug conjugates by providing detailed account of polymeric conjugates synthesized till date having organ-specific targeting.     

Topical delivery of α-interferon from liposomal systems: an in vivo study with hairless mouse

Abstract

The deposition of a-interferon into living skin strata of hairless mouse following topical in vivo application of a glyceryl dilaurate: POE-10: cholesterol liposomal formulation was much higher than from a glyceryl distearate: POE-10: cholesterol liposomal formulation or from an aqueous solution. The kinetics and extent of drug deposition from the liposomal formulations appear to correspond to the extent of release of bilayer lipid components following topical application and subsequent action of the lipid components as skin permeation enhancers.     

Multicompartment vectors as novel drug delivery systems: selective activation of Tγδ lymphocytes after zoledronic acid delivery

Multicompartment nanoscopic carriers can be easily assembled by inducing the aggregation of anionic "hybrid" niosomes by means of cationic biocompatible polyelectrolytes. The resulting vesicle clusters, whose size and overall net charge can be easily controlled by varying the polyelectrolyte-to-particle charge ratio, show an interesting potential for multidrug delivery. In this article we provide strong evidence for their effective use in vitro as multicompartment vectors selectively directed toward monocyte/macrophage cells, showing that the monocyte/macrophage-mediated activation of Tγδ lymphocytes induced by zoledronic acid is enhanced by a factor 10(3) when the zoledronic acid is intracellularly delivered through these carriers. Furthermore, the multicompartment ?-polylysine niosome clusters, with their intrinsic selectivity toward macrophages, appear particularly suitable for implementing therapeutic strategies against chronically infected macrophages. FROM THE CLINICAL EDITOR: ?-polylysine niosome clusters, with their intrinsic selectivity toward macrophages, offer the potential for multidrug delivery. The effectiveness of aminobisphosphonate zoledronate is demonstrated to enhance the recruitment of Tγδ lymphocytes by macrophages by 2 orders of magnitude, suggesting a new therapeutic strategy for addressing pathologies featuring chronically infected macrophages.     

Does lactobionic acid affect the colloidal structure and skin moisturizing potential of the alkyl polyglucoside-based emulsion systems?

Moisturizing creams are the most prescribed products in dermatology, essential in maintaining healthy skin as well as in the topical treatment of some diseases. The irritation potential of commonly used emulsifiers and moisturizing ingredients, but also their mutual interactions, could affect the functionality and safety of those dermopharmaceutics. The aim of this study was to promote moisturizing alkyl polyglucoside (APG)-based emulsion as vehicle for lactobionic acid (LA), advantageous representative of the alphahydroxyacids (AHAs)-multifunctional moisturizers, assessing the safety for use (in vitro acute skin irritation test using cytotoxicity assay compared with in vivo data obtained using skin bioengineering methods) and in vivo moisturizing capacity (bioengineering of the skin). In order to investigate possible interactions between APG mild natural emulsifier-based emulsion and LA, a deeper insight into the colloidal structure of the placebo and the emulsion with LA was given using polarization and transmission electron microscopy, rheology, thermal and texture analysis. This study showed that APG-based emulsions could be promoted as safe cosmetic/dermopharmaceutical vehicles and carriers for extremely acidic and hygroscopic AHA class of actives (specifically LA); prospective safety for human use of both APG and LA with the correlation between in vivo and in vitro findings was shown. However, it was revealed that LA strongly influenced the colloidal structure of the emulsion based on APGs and promoted the formation of lamellar structures which reflects onto the mode of water distribution within the cream. The advantageous skin hydrating potential of LA-containing emulsion vs. placebo was unlikely to be achieved, pointing that emulsions stabilized by lamellar liquid crystalline structures probably are not satisfying carriers for highly hygroscopic actives in order to reach the full moisturizing potential. Safe and effective use on dry skin is presumed.     

Therapeutic potential of exosome‐based personalized delivery platform in chronic inflammatory diseases

In the inflammatory microenvironment, there are numerous exosomes secreted by immune cells (Macrophages, neutrophils, dendritic cells), mesenchymal stem cells (MSCs) and platelets as intercellular communicators, which participate in the regulation of inflammation by modulating gene expression and releasing anti-inflammatory factors. Due to their good biocompatibility, accurate targeting, low toxicity and immunogenicity, these exosomes are able to selectively deliver therapeutic drugs to the site of inflammation through interactions between their surface-antibody or modified ligand with cell surface receptors. Therefore, the role of exosome-based biomimetic delivery strategies in inflammatory diseases has attracted increasing attention. Here we review current knowledge and techniques for exosome identification, isolation, modification and drug loading. More importantly, we highlight progress in using exosomes to treat chronic inflammatory diseases such as rheumatoid arthritis (RA), osteoarthritis (OA), atherosclerosis (AS), and inflammatory bowel disease (IBD). Finally, we also discuss their potential and challenges as anti-inflammatory drug carriers.     

Pharmacokinetics of paracetamol and its metabolites in women at delivery and post‐partum

Aim

A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non‐pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post‐partum in which the different pathways were considered.

Methods

Population PK parameters using non‐linear mixed effect modelling were estimated in a two‐period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10–15 weeks post‐partum.

Results

Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post‐partum. Total clearance was higher in women at delivery compared with 12th post‐partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate.

Conclusion

The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.     

Trihalomethanes in drinking water and the risk of death from kidney cancer: does hardness in drinking water matter?

The objectives of this study were to (1) examine the relationship between total trihalomethanes (TTHM) levels in public water supplies and risk of development of kidney cancer and (2) determine whether hardness levels in drinking water modify the effects of TTHM on risk of kidney cancer induction. A matched case-control study was used to investigate the relationship between the risk of death attributed to kidney cancer and exposure to TTHM in drinking water in 53 municipalities in Taiwan. All kidney cancer deaths in the 53 municipalities from 1998 through 2007 were obtained. Controls were deaths from other causes and were pair-matched to the cancer cases by gender, year of birth, and year of death. Each matched control was selected randomly from the set of possible controls for each cancer case. Data on TTHM levels and levels of hardness in drinking water were also collected. The municipality of residence for cancer cases and controls was presumed to be the source of the subject's TTHM and hardness exposure via drinking water. Relative to individuals whose TTHM exposure level was <4.9 ppb, the adjusted OR (95% CI) for kidney cancer was 0.98 (0.77-1.25) for individuals who resided in municipalities served by drinking water with a TTHM exposure ≥4.9 ppb. However, evidence of an interaction was noted between the use of soft water and drinking water TTHM concentrations. Increased knowledge of the interaction between hardness and TTHM levels in reducing risk of kidney cancer development will aid in public policy decision and establishing standards to prevent disease occurrence.     

Nitrates in drinking water and the risk of death from brain cancer: does hardness in drinking water matter?

The objectives of this study were to (1) examine the relationship between nitrate levels in public water supplies and risk of death from brain cancer and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the influence of nitrates on development of brain cancer. A matched cancer case-control study was used to investigate the relationship between the risk of death from brain cancer and exposure to nitrates in drinking water in Taiwan. All brain cancer deaths of Taiwan residents from 2003 through 2008 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to cancer cases by gender, year of birth, and year of death. Information on the levels of nitrate-nitrogen (NO?-N), Ca, and Mg in drinking water was obtained from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO?-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO?-N exposure level was <0.38 ppm, the adjusted OR (95% CI) for brain cancer occurrence was 1.04 (0.85-1.27) for individuals who resided in municipalities served by drinking water with a NO?-N exposure ≥ 0.38 ppm. No marked effect modification was observed due to Ca and Mg intake via drinking water on brain cancer occurrence.     

In-silico simulations of advanced drug delivery systems: What will the future offer?

This commentary enlarges on some of the topics addressed in the Position Paper “Towards more effective advanced drug delivery systems” by Crommelin and Florence (2013). Inter alia, the role of mathematical modeling and computer-assisted device design is briefly addressed in the Position Paper. This emerging and particularly promising field is considered in more depth in this commentary. In fact, in-silico simulations have become of fundamental importance in numerous scientific and related domains, allowing for a better understanding of various phenomena and for facilitated device design. The development of novel prototypes of space shuttles, nuclear power plants and automobiles are just a few examples. In-silico simulations are nowadays also well established in the field of pharmacokinetics/pharmacodynamics (PK/PD) and have become an integral part of the discovery and development process of novel drug products. Since Takeru Higuchi published his seminal equation in 1961 the use of mathematical models for the analysis and optimization of drug delivery systems in vitro has also become more and more popular. However, applying in-silico simulations for facilitated optimization of advanced drug delivery systems is not yet common practice. One of the reasons is the gap between in vitro and in vivo (PK/PD) simulations. In the future it can be expected that this gap will be closed and that computer assisted device design will play a central role in the research on, and development of advanced drug delivery systems.     

Activity of tricyclic nucleoside 5′-phosphate in model systems of human ovarian cancer

Tricyclic nucleoside 5-phosphate (TCN-P) was evaluated in two models of human ovarian cancer. TCN-P reduced both colony number and volume in clonogenic assays employing human ovarian cancer cell lines. TCN-P cytotoxicity depended on the concentration, exposure duration and cell line studied, but not on cell line plating efficiency or growth rate in soft agarose. Comparison of experimental IC₅₀ concentrations for 1 hour or continuous TCN-P exposure with reported clinically relevant concentrations suggests that therapeutic TCN-P levels are more likely to be achieved by continuous infusions. Cell lines and sublines with resistance to several standard chemotherapeutic agents acquired both in vivo and in vitro were at most 2.6-fold cross-resistant to TCN-P with 1 hour drug exposure. Cross-resistance was not evident with continuous TCN-P exposure. Intermittent bolus TCN-P (100 mg/kg/d × 5) was ineffective in an in vivo xenograft model of human ovarian cancer. These data suggest that TCN-P is most likely to be clinically effective against ovarian cancer, and may be non-cross-resistant with several standard agents, if administered by continuous infusion. Preclinical evaluation of new agents, such as TCN-P, in these experimental models may provide information useful in subsequent clinical trials.Abbreviations CRI cross-resistance index - EGF epidermal growth factor - IC₅₀ drug concentration causing 50% inhibition of colony formation - LD₁₀ lethal dose in 10% of animals - NS normal saline - r correlation coefficient - RCV relative colony volume - RPMI Roswell Park Memorial Institute - SF surviving fraction - TCN tricyclic nucleoside - TCN-P tricyclic nucleoside 5-phosphate     

An accelerated stability study of 5‐flucytosine in intravenous solution

The stability of the antimycotic drug flucytosine (5FC) and the extent of 5fluorouracil (5FU) formation in 5FC intravenous solution was studied in an accelerated stability experiment. 5FC intravenous solution (10 mg/ml) was heated at 40, 60, 70, 80 and 90 C for a maximum of 131 days. At appropriate time intervals samples were taken and the concentrations of 5FC and 5FU were determined using a newly developed, stability indicating HPLCUV method. Heating the 5FC intravenous solution at 40, 60, 70, 80 and 90 C lead to 5FC decomposition of respectively 0, 8.9, 14.4, 52.5 and 61.6%. The Arrhenius plot of the 5FC decomposition is described by: Lnk5-FC decomposition = 80.1892 * 1/T 0.2396 and the 5FU formation is described by Lnk5FU formation = 13087 * 1/T + 34.4028. It is concluded that 5FC is very stable in intravenous solution at regular storing temperatures and can therefore be stored at ambient temperatures for several years before the critical limit of 95% 5FC is reached. However, the toxic and teratogen degradation product 5FU may be present in considerable amounts in the product, due to both impurities in the raw material and the formation from 5FC upon sterilisation and storage.     

Development of patient‐centred performance indicators to guide the delivery of pharmaceutical care in a district general hospital

The aim of this study was to audit clinical pharmacy practice in an acute hospital setting against the individual patient care guidelines set out in the CRAG "Framework for Practice" document, and then to develop practical, patientcentred performance indicators that could be used locally to monitor the delivery of pharmaceutical care. A series of four audits were undertaken to establish key elements in the process of providing pharmaceutical care to patients. Four standard statements describing the performance of the pharmacy service in providing patient care were developed through peer discussion and formulation of ideas based around these data. The four standard statements were then used as performance indicators to evaluate service performance at PRI and tested by means of a further audit cycle. The use of this methodology facilitated operation of a structured service appraisal system and provided a forum that allowed problems with practice to be discussed and resolved.     

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

Genetic variations of orosomucoid genes associated with serum alpha‐1‐acid glycoprotein level and the pharmacokinetics of paclitaxel in Japanese cancer

Alpha‐1‐acid glycoprotein (AGP) encoded by orosomucoid genes (ORM1 and ORM2) is an acute‐phase response protein and functions as a drug‐binding protein that affects pharmacokinetics (PK)/pharmacodynamics of binding drugs. To explore the effects of genetic variations of ORMs and a role of AGP on paclitaxel (PTX) therapy, we analyzed the duplication and genetic variations/haplotypes of ORMs in 165 Japanese cancer patients and then investigated their associations with serum AGP levels and the PK parameters of PTX. No effects of ORM duplications on serum AGP levels at baseline or PK of PTX were observed, but close associations of ORM1 ?559T > A with the increases of AGP levels and area under the curve (AUC) of PTX metabolites were detected. In addition, a significant correlation between the serum AGP level and the AUCs of PTX metabolites was observed, suggesting that AGP may function as a carrier of PTX from the blood into the liver via putative receptors. This study provided useful information on the possible clinical importance of ORM genetic polymorphisms and a novel role of AGP in PTX therapy. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4546–4559, 2011     

Regulator of G‐protein signalling 5 protects against atherosclerosis in apolipoprotein E‐deficient mice

Background and Purpose

Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.

Experimental Approach

RGS5^−/− apolipoprotein E (ApoE)^−/− and ApoE ^−/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.

Key Results

Atherosclerotic phenotypes were significantly accelerated in RGS5^−/− ApoE ^−/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.

Conclusions and Implications

RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

ApoE

apolipoprotein E

CHD

coronary heart disease

H&E

haematoxylin‐eosin

ICAM‐1

intercellular adhesion molecue‐1

LDL

low‐density lipoprotein

MEK

MAPK/ERK kinase

RGS

regulator of G‐protein signalling

SMC

smooth muscle cell

VCAM‐1

vascular cell adhesion molecule‐1

Tables of Links

Formation of 1-methyl-β-carbolines in rats from their possible carboxylic acid precursor

Summary In vivo metabolism of 1-methyl-1,2,3,4-tetrahydro--carboline-l-carboxylic acid (1-CTHH), a possible precursor of the endogenous -carbolines tetrahydroharman (THH) and harman was investigated in rats. Following intraperitoneal injection of [4-¹⁴C]1-CTHH, a rapid distribution of the radioactivity in the tissues was observed. The highest radioactivity was measured in the kidney and the lowest in the brain as well as in the fat tissue. Approximately 55% of the administered dose was excreted in the urine within 90 min. The radioactivity in the urine consisted of unchanged 1-CTHH (> 90%) besides harmalan and trace amounts of harman. Harmalan represents the major degradation product of 1-CTHH; it could be identified in all tissues examined and in the urine. The concentration in the blood, however, was low at all time points investigated. The peak concentration of harmalan in most tissues was measured between 15–30 min after injection. A time-dependent formation of THH was found in the lung and spleen indicating an important role of these organs in the biosynthesis of THE Furthermore, the metabolism of [4-¹⁴C]1-CTHH in the brain was studied following intracerebroventricular injection. The formation of harmalan in the brain was not affected by pretreatment with the aromatic amino acid decarboxylase inhibitor NSD 1015. Determination of the harmalan concentration in several brain regions revealed a high level in the hippocampus and hypothalamus and a small concentration in pons, corpus striatum, cerebellum and cerebal cortex 20 min after injection. The analyses of the radiolabelled compounds were performed by thin-layer chromatography and the identification was further confirmed by high-performance liquid chromatography. The results suggest that 1-CTHH can serve as a precursor of the endogenous -carbolines. The in vivo conversion of the compound proceeds mainly via an oxidative decarboxylation.Abbreviations BC -carboline - 1-CTHH 1-methyl-1,2,3,4-tetrahydro--carboline-l-carboxylic acid - HPLC high performance liquid chromatography - i.c.v. intracerebroventricular - i.p. intraperitoneal - PLP pyridoxal-5-phosphate - THH tetrahydroharman - TLC thin layer chromatography Send offprint requests to R. Susilo at the above address     

Moisture‐activated rheological structuring of nonaqueous poloxamine–poly(acrylic acid) systems designed as novel biomedical implants

This study reports the formulation/characterisation of novel polymeric platforms designed to behave as low‐viscosity systems in the nonaqueous state, however, following uptake of aqueous fluids, exhibit rheological structuring and mucoadhesion. The rheological/mechanical and mucoadhesive properties of platforms containing poly(acrylic acid) (PAA, 1%, 3%, 5%, w/w) and poloxamines (Tetronic 904, 901, 704, 701, 304), both in the absence and presence of phosphate buffered saline (PBS, pH 7.4) are described. With the exception of Tetronic 904, all formulations exhibited Newtonian flow in the nonaqueous state, whereas, all aqueous formulations displayed pseudoplastic flow. The consistency and viscoelastic properties were dependent on the concentrations of PAA and PBS and Tetronic grade. PBS significantly increased the consistency, viscoelasticity and mucoadhesion, reaching a maximum at a defined concentration of PBS that was dependent on PAA concentration and Tetronic grade. Formulations containing Tetronic 904 exhibited greatest consistency and elasticity both prior to and after dilution with PBS. Increasing PAA concentration enhanced the mucoadhesive properties. Prolonged drug release of metronidazole was observed from formulations containing 10% (w/w) PBS, 3% and, particularly, 5% (w/w) PAA. It is suggested that the physicochemical properties of formulations containing 3% or 5% (w/w) PAA and Tetronic 904, would render them suitable platforms for administration to body cavities. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1838–1854, 2010     

Effect of baclofen and haloperidol on γ-aminobutyric acid and dopamine systems in an animal model of tardive dyskinesia

1. The effects of 5 days treatment with baclofen (20 mg/kg, i.p.) or high doses of haloperidol (10 mg/kg, i.p.) were studied on dopamine and γ-aminobutyric acid levels of corpus striatum, frontal cortex and mid-brain of normal rats as well as those withdrawn for 4 days after 30 days of daily treatment with haloperidol (1 mg/kg).2. Baclofen treatment slightly but significantly increased (by 13%) GABA levels in the corpus striatum of normal rats. This, by inhibitory effects, probably depleted dopamine level in corpus striatum.3. In the mid-brain, no change in GABA level was observed after baclofen treatment. The frontal cortex, which receives dopaminergic nerve endings from cell bodies lying in the ventral tegmental area, showed high levels of dopamine.4. Administration of baclofen to haloperidol-withdrawn rats tended to further increase GABA levels in striatum; however, the change was not statistically significant. In contrast, mid-brain GABA levels were decreased by 21% when compared with haloperidol-withdrawn values taken as 100%.5. Baclofen treatment increased DA level by 66% in the frontal cortex and decreased it by 35% in striatum of rats.6. In normal rats, administration of high doses of haloperidol (10 mg/kg) increased GABA levels of the corpus striatum and the frontal cortex by 48 and 16%, respectively.7. In mid-brain, a slight increase (11%) was reported in GABA level.8. Haloperidol treatment decreased DA in striatum, but increased it in the mid-brain and the frontal cortex. High doses of haloperidol for 5 days to rats previously treated with haloperidol (1 mg/kg) daily for 30 days and subsequently withdrawn for 4 days produced no further change in GABA levels of various brain areas examined. In mid-brain, a slight decrease was seen in GABA level.9. Haloperidol treatment in high doses of haloperidol-withdrawn rats decreased DA level in corpus striatum by 43%, but increased it in the frontal cortex and mid-brain as was seen in normal animals.10. Our data demonstrated that high doses of haloperidol, like baclofen, enhanced the functioning of GABAergic neurons in striatum, which in turn, influenced the DAergic system in this brain area.     

Preparation and in vitro–in vivo evaluation of Witepsol® H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q10

Coenzyme Q₁₀ (CoQ₁₀) was formulated into self-nanoemulsifying drug delivery systems (SNEDDS) to overcome low bioavailability attributed to hydrophobic nature of the drug. Screening of oil phase, surfactants and co-surfactants were performed to select Witepsol^® H35, Solutol^® HS15 and Lauroglycol^® FCC, respectively. Ternary phase diagrams were drawn to identify nanoemulsifying region followed by optimization of SNEDDS formulation. The optimized formulation, CoQ₁₀, Witepsol^® H35, Solutol^® HS15 and Lauroglycol^® FCC in the weight ratio of 1:0.7:4:2, respectively, emulsified readily at 37 °C with mean emulsion droplet size of 32.4 nm. The stability test of the optimized formulation in pH 1.2 and 6.8 buffers confirmed no pH effect on emulsion droplet size. In vitro dissolution (emulsification) test and in vivo animal study of the formulation elucidated the complete emulsification of drug and improved oral bioavailability of poorly soluble CoQ₁₀.     

Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems

Rationale and objectives  

Our knowledge about genes involved in the control of basal motor activity that may contribute to the pathology of the hyperactivity disorders, e.g., attention deficit hyperactivity disorder (ADHD), is limited. Disruption of monoamine neurotransmitter signaling through G protein-coupled receptors (GPCR) is considered to be a major contributing factor to the etiology of the ADHD. Genetic association evidence and functional data suggest that regulators of G protein signaling proteins of the R7 family (R7 RGS) that form obligatory complexes with type 5 G protein beta subunit (Gβ5) and negatively regulate signaling downstream from monoamine GPCRs may play a role in controlling hyperactivity.