Targeting the dopamine receptor in schizophrenia: investigational drugs in Phase III trials

Introduction: Antipsychotic drugs date back to the 1950s and chlorpromazine. Soon after, it was established that blockade of dopamine and, in particular, the D-2 receptor was central to this effect. Dopamine continues to represent a critical line of investigation, although much of the work now focuses on its potential in other symptom domains. Areas covered: A search was carried out for investigational drugs using the key words `dopamine', `schizophrenia' and `Phase III' in an American clinical trial registry (clinicaltrials.gov), published articles using the National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. Drugs were excluded that were already FDA approved. Expert opinion: There remains interest, albeit diminished, in developing better antipsychotic compounds. The greatest enthusiasm currently centres on dopamine's role in negative and cognitive symptom domains. With theories conceptualising hypodopaminergic activity as underlying these deficits, considerable effort is focused on drug strategies that will enhance dopamine activity. Finally, a small body of research is investigating dopaminergic compounds vis-a-vis side-effect treatments. In domains beyond psychosis, however, dopamine arguably is not seen as so central, reflected in considerable research following other lines of investigation.

Iodo( trisyl) sulfane: Reactivity of a Stable Alkanesulfenyl Iodide towards Antithyroid Drugs

Iodination of tris(trimethylsilyl)methanethiol (trisylthiol, TsiSH) in tetrahydrofuran provides the new thermally stable alkanesulfenyl iodide iodo(trisyl)sulfane, TsiSI] as a violet solid. Iodo(trisyl)sulfane exhibits iodine-iodine contacts between pairs of TsiSI molecules in the solid state. Properties of TsiSI were studied by vibrational spectroscopy and with the help of density functional calculations. TsiSI reacts in the presence of triethylamine with the antithyroid drugs 6-n-propyl- and 6-methylthiouracil (PTU, MTU) and with N-methylmethimazole (MMI) to form unsymmetric disulfides that were investigated by means of X-ray crystallography. In the solid state, the PTU and MTU derivatives exist as hydrogen-bonded centrosymmetric dimers, whereas the MMI-derived disulfide is an unsymmetric monomer.

Small molecule inhibitors of HCV replication from Pomegranate

Hepatitis C virus (HCV) is the causative agent of end-stage liver disease. Recent advances in the last decade in anti HCV treatment strategies have dramatically increased the viral clearance rate. However, several limitations are still associated, which warrant a great need of novel, safe and selective drugs against HCV infection. Towards this objective, we explored highly potent and selective small molecule inhibitors, the ellagitannins, from the crude extract of Pomegranate (Punica granatum) fruit peel. The pure compounds, punicalagin, punicalin, and ellagic acid isolated from the extract specifically blocked the HCV NS3/4A protease activity in vitro. Structural analysis using computational approach also showed that ligand molecules interact with the catalytic and substrate binding residues of NS3/4A protease, leading to inhibition of the enzyme activity. Further, punicalagin and punicalin significantly reduced the HCV replication in cell culture system. More importantly, these compounds are well tolerated ex vivo and `no observed adverse effect level' (NOAEL) was established upto an acute dose of 5000 mg/kg in BALB/c mice. Additionally, pharmacokinetics study showed that the compounds are bioavailable. Taken together, our study provides a proof-of-concept approach for the potential use of antiviral and non-toxic principle ellagitannins from pomegranate in prevention and control of HCV induced complications.

Overview of nano-drugs characteristics for clinical application: the journey from the entry to the exit point

The ever-increasing number of diseases worldwide requires comprehensive, efficient, and cost-effective modes of treatments. Among various strategies, nanomaterials fulfill most of these criteria. The unique physicochemical properties of nanoparticles have made them a premier choice as a drug or a drug delivery system for the purpose of treatment, and as bio-detectors for disease prognosis. However, the main challenge is the proper consideration of the physical properties of these nanomaterials, while developing them as potential tools for therapeutics and/or diagnostics. In this review, we focus mainly on the characteristics of nanoparticles to develop an effective and sensitive system for clinical purposes. This review will present an overview of the important properties of nanoparticles, through their journey from its route of administration until disposal from the human body after accomplishing targeted functionality. We have chosen cancer as our model disease to explain the potentiality of nano-systems for therapeutics and diagnostics in relation to several organs (intestine, lung, brain, etc.). Furthermore, we have discussed their biodegradability and accumulation probability which can cause unfavorable side effects in healthy human subjects.

Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity

Predicting clinical response to anticancer drugs remains a major challenge in cancer treatment. Emerging reports indicate that the tumour microenvironment and heterogeneity can limit the predictive power of current biomarker-guided strategies for chemotherapy. Here we report the engineering of personalized tumour ecosystems that contextually conserve the tumour heterogeneity, and phenocopy the tumour microenvironment using tumour explants maintained in defined tumour grade-matched matrix support and autologous patient serum. The functional response of tumour ecosystems, engineered from 109 patients, to anticancer drugs, together with the corresponding clinical outcomes, is used to train a machine learning algorithm; the learned model is then applied to predict the clinical response in an independent validation group of 55 patients, where we achieve 100% sensitivity in predictions while keeping specificity in a desired high range. The tumour ecosystem and algorithm, together termed the CANScript technology, can emerge as a powerful platform for enabling personalized medicine.

Protamine-carboxymethyl cellulose magnetic nanocapsules for enhanced delivery of anticancer drugs against drug resistant cancers

Multidrug resistance is a major therapeutic challenge faced in the conventional chemotherapy. Nanocarriers are beneficial in the transport of chemotherapeutics by their ability to bypass the P-gp efflux in cancers. Most of the P-gp inhibitors under phase II clinical trial are facing failures and hence there is a need to develop a suitable carrier to address P-gp efflux in cancer therapy. Herein, we prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin against highly drug resistant HeLa cells. The experimental results revealed that improved cellular uptake, enhanced drug intensity profile with greater percentage of apoptotic cells was attained when doxorubicin loaded magnetic nanocapsules were used in the presence of external magnetic field. Hence, we conclude that this magnetic field assisted nanocapsule system can be used for delivery of chemotherapeutics for potential therapeutic efficacy at minimal dose in multidrug resistant cancers. From the Clinical Editor: Many cancer drugs fail when cancer cells become drug resistant. Indeed, multidrug resistance (MDR) is a major therapeutic challenge. One way that tumor cells attain MDR is by over expression of molecular pumps comprising of P-glycoprotein (P-gp) and multidrug resistant proteins (MRP), which can expel chemotherapeutic drugs out of the cells. In this study, the authors prepared novel protamine and carboxymethyl cellulose polyelectrolyte multi-layered nanocapsules modified with Fe3O4 nanoparticles for the delivery of doxorubicin. The results show that there was better drug delivery and efficacy even against MDR tumor cells. (C) 2015 Elsevier Inc. All rights reserved.

S center dot center dot center dot O chalcogen bonding in sulfa drugs: insights from multipole charge density and X-ray wavefunction of acetazolamide

Experimental charge density analysis combined with the quantum crystallographic technique of X-ray wavefunction refinement (XWR) provides quantitative insights into the intra-and intermolecular interactions formed by acetazolamide, a diuretic drug. Firstly, the analysis of charge density topology at the intermolecular level shows the presence of exceptionally strong interaction motifs such as a DDAA-AADD (D-donor, A-acceptor) type quadruple hydrogen bond motif and a sulfonamide dimer synthon. The nature and strength of intra-molecular S center dot center dot center dot O chalcogen bonding have been characterized using descriptors from the multipole model (MM) and XWR. Although pure geometrical criteria suggest the possibility of two intra-molecular S center dot center dot center dot O chalcogen bonded ring motifs, only one of them satisfies the ``orbital geometry'' so as to exhibit an interaction in terms of an electron density bond path and a bond critical point. The presence of `s-holes' on the sulfur atom leading to the S center dot center dot center dot O chalcogen bond has been visualized on the electrostatic potential surface and Laplacian isosurfaces close to the `reactive surface'. The electron localizability indicator (ELI) and Roby bond orders derived from the `experimental wave function' provide insights into the nature of S center dot center dot center dot O chalcogen bonding.

Recognizing drug targets using evolutionary information: implications for repurposing FDA-approved drugs against Mycobacterium tuberculosis H37Rv

Drug repurposing to explore target space has been gaining pace over the past decade with the upsurge in the use of systematic approaches for computational drug discovery. Such a cost and time-saving approach gains immense importance for pathogens of special interest, such as Mycobacterium tuberculosis H37Rv. We report a comprehensive approach to repurpose drugs, based on the exploration of evolutionary relationships inferred from the comparative sequence and structural analyses between targets of FDA-approved drugs and the proteins of M. tuberculosis. This approach has facilitated the identification of several polypharmacological drugs that could potentially target unexploited M. tuberculosis proteins. A total of 130 FDA-approved drugs, originally intended against other diseases, could be repurposed against 78 potential targets in M. tuberculosis. Additionally, we have also made an attempt to augment the chemical space by recognizing compounds structurally similar to FDA-approved drugs. For three of the attractive cases we have investigated the probable binding modes of the drugs in their corresponding M. tuberculosis targets by means of structural modelling. Such prospective targets and small molecules could be prioritized for experimental endeavours, and could significantly influence drug-discovery and drug-development programmes for tuberculosis.

Determination of drugs used in combined cardiovascular therapy

Cardiovascular diseases are nowadays the first cause of mortality worldwide, causing around the 30% of global deaths each year. The risk of suffering from cardiovascular illnesses is strongly related to some factors such as hypertension, high cholesterol levels, diabetes, obesity The combination of these different risk factors is known as metabolic syndrome and it is considered a pandemic due to the high prevalence worldwide. The pathology of the disorders implies a combined cardiovascular therapy with drugs which have different targets and mechanisms of action, to regulate each factor separately. The simultaneous analysis of these drugs turns interesting but it is a complex task since the determination of multiple substances with different physicochemical properties and physiological behavior is always a challenge for the analytical chemist. The complexity of the biological matrices and the difference in the expected concentrations of some analytes require the development of extremely sensitive and selective determination methods. The aim of this work is to fill the gap existing in this field of the drug analysis, developing analytical methods capable of quantifying the different drugs prescribed in combined cardiovascular therapy simultaneously. Liquid chromatography andem mass spectrometry (LCMS/MS) has been the technique of choice throughout the main part of this work, due to the high sensitivity and selectivity requirements.

Effect of crude oil and some petroleum products on Clarias Gariepinus fingerlings (Catfish: Claridae)

Ninety (90) hatchery bred fingerlings of Clarias gariepinus (mean weight: 0.96 ± 0.1g) were randomly placed in 15 plastic baths (25 litres each) at the Research laboratory and were exposed to different concentrations of oil products to determine their effects on the fish, to facilitate inferential deductions that will enhance effective aquatic environmental management. Three (3) replicate basins of 5 experimental treatments (crude oil, petrol oil, kerosene oil, engine oil and control) were used at a concentration of 1.25ml. L-1. The control experiment was devoid of oil treatment. Six (6) fingerlings were placed in each replicate basin, flooded with 20 litres of clean tap water and fed with nutrafin cichilid food, 2 times daily at 3% body weight. The results showed that the feeding behaviour and swimming performances of fish were reduced after 24 hours of the addition of the various oil pollutants. Mortality of fingerlings in the oiled basins increased as the hours of exposure increased (i.e. 24, 48, 72 and 96 hours). Recovery was not immediate in the treated basin while surviving fingerlings in the control basins grew up to post-fingerlings after 90 days (3 months). There were significant differences (P<0.01 and P<0.05) in the effect of crude oil and the petroleum products on the mortality rate of C. gariepinus when exposed to oil pollutants at 1.25ml. L-1 concentration

Aspects of mineral composition of male and female Heterobranchus bidorsalis adults exposed to different concentrations of Bonny-light crude oil

Studies were carried out to assess some macro and trace elements of mineral composition of the male and female Heterobranchus bidorsalis adults exposed to graded concentrations (1.00-8.00m/L-1) of Bonny-light crude oil (BLCO). The experiment was monitored for 4 days (toxicity) and 42days (recovery) periods. Significant decreases (P < 0.05)in the sodium (Na), potassium (K), magnesium (Mg), calcium (Ca), phosphorus (P), zinc (Zn), iron (Fe), vanadium (Va), lead (Pb) and manganese (Mn) contents of the male H. bidorsalis corresponded with the increasing concentrations of BLCO. In contrast, the female fishes recorded significant increases (P < 0.05) in the values of the above elements in their tissues as the concentrations of BLCO increased. Furthermore, the values of Na, K, Mg, Ca, P, Zn, Fe, Va, Pb and Mn recorded in the male fishes where generally lower than those of their female counterparts and the control fish. Increased values of these elements were also recorded during the recovery periods (days 14, 28 and 42) of this study in the magnitudes of 15% at day 14, 20% at day 28 and 20% at day 42. This implied that the removal of crude oil stress during this period improved the quantity of these minerals deposited in the fish tissues. The highest percent proportion of Zn and the lowest proportion of Pb recorded in both male and female H. bidorsalis adults agreed with the report of other workers for other fish species. KEYWORDS: Heterobranchus bidorsalis, Mineral composition, Bonny-light crude oil, Toxicity, Recovery.

Mass breeding of silver carp in a cement cistern with crude H.C.G.

The paper presents a resume on experiments carried on mass breeding of the silver carp Hypophthalmichthys molitrix in a cement cistern through administration of crude human chorionic gonadotropin. The experiments proves that human chorionic gonadotropin (H.C.G.) can be used for mass breeding of the fish in simple enclosures, with facilities of some input and output of water and a dose of 5 mg/kg and 18 mg/kg of body weight, for males and females respectively are required for the purpose. Observations were made by using pituitary glands in similar way. For successful breeding of about 80 kg female together, the expenditure towards cost of pituitary gland and H.C.G. are respectively 275 and 117 Rs.

Effects of natural gas pipeline condensate and crude oil spills, and comments on remediation, with emphasis on south Louisiana salt marshes: a review

This report reviews some of the natural ecological processes at work within a salt marsh as they relate to a spill of natural gas condensate - a mixture of aliphatic hydrocarbons, n-hexane, benzene, toluene, and xylene. It also reviews the environmental impacts of some of the components of natural gas condensate as well as related compounds (crude oil, higher molecular weight hydrocarbons, polycyclic aromatic hydrocarons - PAHs, linear alkyl-benzenes - LABs, etc.) on salt marsh ecosystems in southern Louisiana and elsewhere in the world. The behavior and persistence of these compounds once they have entered the environment is also considered.

Small scale manufacture of crude agar from Gracilaria seaweeds

A simplified process was worked out to prepare crude agar from red seaweeds (Gracilaria sp.). The process required careful preliminary cleaning and bleaching (sun-drying) of the weed. The agar was extracted by boiling with water in a mixture (2%) strong enough to set as a jelly. Freezing the jelly over a 3—day period in an ice-making machine, adjusted to work slowly, separated out ice and agar. The blocks were thawed out and the agar dried in the sun. The efficiency of extraction was over 800/A.