- Harvard Business School, Executive Education, AlumnusKings College London, Neuroscience, Alumnus, and 2 moreadd
- Neuroscientist/DMPK entrepreneuredit
- Pharmidex, UK, Directoredit
Activated charcoal (AC) can be taken orally as enterosorbent for treatment of pathological states related to exogenous and endogenous intoxications. Synthesized granulated AC with a highly developed active surface (SBET ~2700 m2/g) was... more
Activated charcoal (AC) can be taken orally as enterosorbent for treatment of pathological states related to exogenous and endogenous intoxications. Synthesized granulated AC with a highly developed active surface (SBET ~2700 m2/g) was used as a medical countermeasure (MCM) to acute radiation sickness (ARS) in rats after total body X-ray irradiation. AC demonstrates positive results in ARS treatment, as expressed in, (i) a decrease in body weight loss, (ii) a protection of bone marrow (BM) cells colony formation capacity, (iii) a reduction of BM chromosomal aberrations and small intestine and spleen tissue damage, (iv) an amelioration of white blood cell count, and (v) a mitigation of superoxide ion generation rate in the liver. AC oral prescription seems to be perspective modality of ARS treatment.
Research Interests:
Research Interests:
Research Interests:
Fungisome (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment of cutaneous leishmaniasis (CL), a... more
Fungisome (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment of cutaneous leishmaniasis (CL), a disfiguring form of the disease affecting the skin, is currently unknown. Here, we report the evaluation of the efficacy of F in the Leishmania major BALB/c murine model of CL, including a head-to-head comparison with the standard liposomal AmB formulation AmBisome (A). Upon intravenous administration at dose levels of 5, 10 and 15 mg/kg of body weight (on days 0, 2, 4, 6 and 8), F showed clear signs of toxicity (at 15 mg/kg), while A did not. After complete treatment (day 10), the tolerated doses of 5 and 10 mg/kg F had significant antileishmanial activity (ED = 4.0 and 12.8 mg/kg for qPCR-based parasite load and lesion size, respectively), although less than that of A at identical doses (ED = 3.0 and 8.8 mg/kg). The efficacy of F was inferior compared t...
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal... more
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal drug fexinidazole has completed Phase III trials with the anticipation that it will be the first oral treatment for HAT. This study used the recently validated bioluminescence imaging model to assess the dose and rate of kill effect of fexinidazole in infected mice, and the dose-dependent effect of fexinidazole on trypanosome infection. Pharmacokinetics of fexinidazole in plasma and central nervous system (CNS) compartments were similar in both infected and uninfected mice. Drug distribution within the CNS was further examined by microdialysis, showing similar levels in the cortex and hippocampus. However, high variability in drug distribution and exposure was found between mice.
Research Interests:
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis.... more
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-phosphonic acid (RPR 119990). The compound displaced [3H]AMPA from rat cortex membranes with a K(i) of 107 nM. In oocytes expressing human recombinant AMPA receptors, RPR 119990 depressed ion flux with a K(B) of 71 nM. The antagonist properties of this compound were confirmed on rat native AMPA receptors in cerebella granule neurons in culture and in hippocampal slices where it antagonized electrophysiological responses with IC50 values of 50 and 93 nM, respectively. RPR 119990 antagonized hippocampal evoked responses in vivo, demonstrating brain penetration at active concentrations. RPR 119990 is a potent anticonvulsant...
Research Interests: Electrophysiology, Skeletal muscle biology, Patch-clamp and imaging techniques, Transgenic Mice, Amyotrophic Lateral Sclerosis, and 12 moreLongevity, Mice, Animals, Neurons, Superoxide Dismutase, Rats, Disease Progression, Imidazoles, Glutamic Acid, Electroshock, Pharmacology and pharmaceutical sciences, and In Vitro Techniques
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal... more
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal drug fexinidazole has completed Phase III trials with the anticipation that it will be the first oral treatment for HAT. This study used the recently validated bioluminescence imaging model to assess the dose and rate of kill effect of fexinidazole in infected mice, and the dose-dependent effect of fexinidazole on trypanosome infection. Pharmacokinetics of fexinidazole in plasma and central nervous system (CNS) compartments were similar in both infected and uninfected mice. Drug distribution within the CNS was further examined by microdialysis, showing similar levels in the cortex and hippocampus. However, high variability in drug distribution and exposure was found between mice.
Research Interests:
Research Interests:
Piracetam kinetics in blood and cerebrospinal fluid
Research Interests:
CNS Drug Discovery- The Rewards and Challenge
Research Interests:
The Rewards and Challenges T he worldwide market for therapies for central nervous system (CNS) disorders is worth more than US-$50 billion and is set to grow sharply in the years ahead, largely because of a marked increase in the numbers... more
The Rewards and Challenges T he worldwide market for therapies for central nervous system (CNS) disorders is worth more than US-$50 billion and is set to grow sharply in the years ahead, largely because of a marked increase in the numbers of people aged over 65 years. By 2050, the worldwide population aged over 65 years is projected to constitute an extra billion individuals [1], mainly because of the 'greying' of the 'baby-boom' generation and the steady increase in lifespan. This increase in lifespan is further illustrated by the fact that when the Queen came to the throne in the UK in 1952, she sent 270 telegrams to individuals in the UK reaching the age of 100. In 2002, this number rose to 6,000 – by 2074, the UK can expect to have 1.2 million centenarians [2]. Because CNS disorders affect the older population disproportionately, the World Health Organisation has indicated that CNS disorders will be the major medical challenge of the 21st Century -it already affe...
The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the systemic circulation. The barrier consists of tight junctions between endothelial cells that contain egress transporters and catabolic... more
The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the systemic circulation. The barrier consists of tight junctions between endothelial cells that contain egress transporters and catabolic enzymes. To cross the BBB, a drug must possess the appropriate physicochemical properties to achieve a sufficient time-concentration profile in brain interstitial fluid (ISF). In this overview, we review techniques to measure BBB permeation, which is evidenced by the free concentration of compound in brain ISF over time. We consider a number of measurement techniques, including in vivo microdialysis and brain receptor occupancy following perfusion. Consideration is also given to the endothelial and nonendothelial cell systems used to assess both the BBB permeation of a test compound and its interactions with egress transporters, and computer models employed for predicting passive permeation and the probability of interactions with BBB transporters.
Research Interests:
An appropriate drug metabolism and pharmacokinetic (DMPK) profile remains a major hurdle to reducing risk and improving productivity in pharmaceutical R&D, accounting for approximately 40% of all drug failures. For orally administered... more
An appropriate drug metabolism and pharmacokinetic (DMPK) profile remains a major hurdle to reducing risk and improving productivity in pharmaceutical R&D, accounting for approximately 40% of all drug failures. For orally administered drugs, failure is often attributable to low intestinal absorption and/or high clearance, causing poor and variable bioavailability. Additional reasons for failure include drug-drug interactions and the presence of active metabolites. With a poor pharmacokinetic profile, it can be difficult to achieve the dose profile required for therapeutic efficacy. The main role that DMPK plays in drug discovery is therefore the prediction of drug metabolism and pharmacokinetics in humans. Successful prediction can be expected to reduce the rate of attrition during drug discovery and development. This has led to the recognition that DMPK is an essential component of the drug discovery process. Both this and the need to screen ever greater numbers of compounds have l...
Research Interests:
Research Interests:
Research Interests:
Acute (-)-nicotine administration (0.4 and 0.8 mg/kg s.c.) produced a regionally specific increase in the rate of catecholamine synthesis in the rat nucleus accumbens, hypothalamus and hippocampus but not elsewhere, including the... more
Acute (-)-nicotine administration (0.4 and 0.8 mg/kg s.c.) produced a regionally specific increase in the rate of catecholamine synthesis in the rat nucleus accumbens, hypothalamus and hippocampus but not elsewhere, including the caudate-putamen. In all regions rates of 5-hydroxytryptamine synthesis were unaffected. (-)-Cotinine (0.4 and 0.8 mg/kg), the major metabolite of (-)-nicotine was without effect. (-)-Nicotine-induced increase in catecholamine synthesis occurred by a direct stimulation of central nicotinic receptors, as mecamylamine (5 mg/kg) but not hexamethonium (5 mg/kg) was an effective antagonist. Following repeated daily injections of (-)-nicotine (0.8 mg/kg) for up to 28 days, the induced catecholamine response following a subsequent challenge was unaffected in the nucleus accumbens and hypothalamus, but was increased in the hippocampus. This effect persisted for up to 14 days following withdrawal. Rates of 5-hydroxytryptamine synthesis remained unaltered after chronic pretreatment.
Research Interests:
The major imperative of the pharmaceutical industry is to effectively translate insights gained from basic research into new medicines. This task is toughest for CNS disorders. Compared with non-CNS drugs, CNS drugs take longer to get to... more
The major imperative of the pharmaceutical industry is to effectively translate insights gained from basic research into new medicines. This task is toughest for CNS disorders. Compared with non-CNS drugs, CNS drugs take longer to get to market and their attrition rate is greater. This is principally because of the complexity of the human brain (the cause of many brain disorders remains unknown), the liability of CNS drugs to cause CNS side effects (which limits their use) and the requirement of CNS medicines to cross the blood-CNS barrier (BCNSB) (which restricts their ability to interact with their CNS target). In this review we consider the factors that are important in translating neuroscience research into CNS medicines.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
A chronic comparative study of the antiepileptic drugs carbamazepine (CBZ), and its epoxide metabolite CBZ-epoxide (CBZ-E) and valproic acid (VPA)
Epileptogenicity of rifampicin/clindamycin-Iimpregnated shunt catheter
Research Interests:
A comparative brain neuropharmacokinetic study of different antiepileptic drugs in rat frontal cortex using microdialysis.
Research Interests:
A microdialysis study of lamotrigine kinetics in rat brain.
Research Interests:
Chronic neuropharmacokinetic study of carbamazepine in rat frontal cortex using microdialysis
Research Interests:
A comparison of classical and microdialysis sampling techniques: A study of carbamazepine (CBZ) Pharmacokinetics
Research Interests:
Patsalos PN, Alavijeh MS, Semba J, Lolin YI (1992). A freely moving and behaving rat model for the chronic and simultaneous study of pharmacokinetics (blood) and neuropharmacokinetics (CSF):hematological and biochemical characterisation and kinetic evaluation using carbamazepine. Journal of Pharm...more
A freely moving and behaving rat model for the chronic and simultaneous study of pharmacokinetics (blood) and neuropharmacokinetics (CSF):hematological and biochemical characterisation and kinetic evaluation using carbamazepine.
Of all the protein classes under investigation in the pharmaceutical industry, kinases represent one of the most well-worked (at least 20% of drug discovery research has been focused on kinase inhibitors for oncology) and successful... more
Of all the protein classes under investigation in the pharmaceutical industry, kinases represent one of the most well-worked (at least 20% of drug discovery research has been focused on kinase inhibitors for oncology) and successful (currently 13 small-molecule inhibitors have been approved by the FDA). Despite this, significant challenges and opportunities exist for both the exploitation of kinase inhibitors in new therapeutic areas and the development of novel technologies and methodologies to support their discovery and development. This meeting brought together experts in the field to review both areas. The first part of the meeting focuses on new technologies and strategies for the discovery of kinase inhibitors, including novel technologies and the exploitation of covalent and allosteric ligands. The second part of the meeting is dedicated to the discovery and development of kinase inhibitors for new and emerging therapeutic areas, in particular in CNS and tropical diseases.
The pressing challenge pharmaceutical scientists can often be faced with is dealing with drug development candidate molecules with suboptimal drug delivery or pharmaceutical properties. Using the Biopharmaceutical Classification System,... more
The pressing challenge pharmaceutical scientists can often be faced with is dealing with drug development candidate molecules with suboptimal drug delivery or pharmaceutical properties. Using the Biopharmaceutical Classification System, analysis of marketed products suggests ≈30% fall into class II, demonstrating exemplary permeability but poor solubility. However, this figure rises to ≈70% when the analysis is applied to candidates coming through the development pipeline. Challenges with biopharmaceuticals often reside around achieving stability, minimizing immunogenicity, optimizing pharmacokinetics and providing, from the patient viewpoint, more convenient and better management of drug delivery. This symposium brought together international experts from both industry and academia to discuss pharmaceutical and biopharmaceutical properties, and strategies to optimize development and minimize developmental impact. Small-molecule new chemical entity topics included a formulation road...
Research Interests:
Research Interests:
ABSTRACT Most of the new indole-containing pseudopeptides (V), (VIII), and (X) possess the optimal range of lipophilicity for oral absorption, cell membrane penetration and blood-brain barrier permeation.
Research Interests:
Research Interests:
Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing... more
Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing neurodegeneration and decreased monoamine neurotransmitters. We investigated the effect of administration of a pro-oxidant diet on the levels of monoamines and metabolites in the brains of wildtype and transgenic mice expressing mutant APP and PS-1 (TASTPM mice). Three-month-old TASTPM and wildtype (C57BL6/J) mice were fed either normal or pro-oxidant diet for 3 months. The neocortex, cerebellum, hippocampus and striatum were assayed for their monoamine and monoamine metabolite content using HPLC with electrochemical detection. Striatal tyrosine hydroxylase (TOH) levels were analysed by Western blotting. In the striatum, female TASTPM mice had higher levels of DOPAC and male TASTPM mice had higher levels of 5-HIAA compared to wildtype mice. Administration of pro-oxidant diet increased striatal MHPG, turnover of NA and 5-HT levels in female TASTPM mice compared to TASTPM mice fed control diet. The pro-oxidant diet also decreased DOPAC levels in female TASTPM mice compared to those fed control diet. Striatal TOH did not depend on diet, gender or genotype. In the neocortex, the TASTPM genotype increased levels of 5-HIAA in male mice fed control diet compared to wildtype mice. In the cerebellum, the TASTPM genotype led to decreased levels of HVA (male mice only) and also decreased turnover of DA (female mice only) compared to wildtype mice. These data suggest a sparing of monoaminergic neurones in the cortex, striatum and hippocampus of TASTPM mice fed pro-oxidant diet and could be indicative of increased activity in corticostriatal circuits. The decreased cerebellar levels of HVA and turnover of DA in TASTPM mice hint at possible axonal degeneration within this subregion.
Research Interests: Neurochemistry, Diet, Oxidative Stress, Western blotting, Transgenic Mice, and 16 moreHumans, Mice, Female, Animals, Male, Tyrosine Hydroxylase, High Pressure Liquid Chromatography, Axonal Degeneration, Presenilins, Western blot, Brain Chemistry, Transgenic Mouse Technology, Alzheimer Disease, Neurosciences, Oxidants, and Amyloid Beta Precursor Protein
The effect of denzimol (DNZ) on the disposition of carbamazepine (CBZ) and its primary metabolite carbamazepine-10,11-epoxide (CBZ-E) in serum, liver, spleen and seven brain regions of the rat was assessed. Coadministration with DNZ for 5... more
The effect of denzimol (DNZ) on the disposition of carbamazepine (CBZ) and its primary metabolite carbamazepine-10,11-epoxide (CBZ-E) in serum, liver, spleen and seven brain regions of the rat was assessed. Coadministration with DNZ for 5 or 10 days resulted in an increase in CBZ and a decrease in CBZ-E concentrations in serum, liver and spleen, consistent with a metabolic (hepatic cytochrome P450 mono-oxygenases) inhibitory interaction. After 15 days of co-administration the concentration of CBZ-E was also increased in these tissues, suggestive of epoxide hydratase inhibition in addition. The magnitude of these concentration changes was much greater in the brain indicating that the total serum concentration of CBZ or CBZ-E may not be a reliable index of the neuropharmacological severity of CBZ-DNZ interaction.
Research Interests: Drug interactions, Spleen, Brain, Liver, Animals, and 4 moreMale, Rats, Carbamazepine, and Imidazoles
Research Interests:
Research Interests:
Percutaneous coronary intervention (PCI) is used to treat blocked coronary arteries. Bare-metal stents (BMS) were first used in PCI but often necessitated repair procedures due to in-stent restenosis. Drug-eluting stents (DES) were... more
Percutaneous coronary intervention (PCI) is used to treat blocked coronary arteries. Bare-metal stents (BMS) were first used in PCI but often necessitated repair procedures due to in-stent restenosis. Drug-eluting stents (DES) were developed to address this problem as the stent-incorporated anti-proliferative drugs prevented restenosis. However late-stent thrombosis arose with the use of DES due to polymer hypersensitivity and impaired re-endothelialization. Evidence suggests that using a combination of biofunctionalized polymers and antibody/peptide motifs can prevent thrombosis while ensuring in situ endothelialization. The advent of nanotechnology has engendered techniques like layer-by-layer self-assembly, and localized drug and gene delivery using nanoparticles. Therefore, this review seeks to explore the convergence of biotechnology and nanotechnology for the next generation coronary stent coatings, with an emphasis on its development from bench to beside.
Research Interests:
Research Interests:
Research Interests:
Research Interests: British, Pharmacokinetics, Cerebrospinal Fluid, Brain, Animals, and 4 moreMale, Microdialysis, Rats, and Triazines
Research Interests:
Research Interests:
Liposomes radiolabelling with diagnostic radionuclides is an excellent tool for studying pharmacokinetics with the view of developing liposome-based drug delivery agents. The aim of the present study is to evaluate the in vitro and in... more
Liposomes radiolabelling with diagnostic radionuclides is an excellent tool for studying pharmacokinetics with the view of developing liposome-based drug delivery agents. The aim of the present study is to evaluate the in vitro and in vivo behavior of a (99m)Tc-labeled liposome by applying either a direct labeling strategy via a carboxyl group, LP-COOH, or a surface chelating method via pyridyl ethyl cysteine compound (with the intermediate [⁹⁹mTc(I)(CO)₃(H₂O)(3)](+)), LP-PEC. ⁹⁹mTc-LP-COOH was obtained in high radiolabelling yield and radiochemical purity, while ⁹⁹mTc(I)(CO)₃-LP-PEC was initially purified before being in vitro and in vivo evaluated. ⁹⁹mTc-LP-COOH was less stable in the presence of competitive for ⁹⁹mTc ligands than ⁹⁹mTc(I)(CO)₃-LP-PEC. According to DLS measurements, the presence of serum as well as the applied radiolabelling conditions did not affect the liposomes' size. The different radiolabelling methods seemed to exert an influence on the biodistribution pattern of the liposomes with the ⁹⁹mTc(I)(CO)₃-LP-PEC showing slow blood clearance, which was also confirmed by in vivo scintigraphic imaging. Nevertheless, passive tumor targeting was attained at a similar extent no matter which radiolabelling technique was followed.