Activated charcoal (AC) can be taken orally as enterosorbent for treatment of pathological states... 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.
International journal for parasitology. Drugs and drug resistance, Aug 12, 2018
Fungisome (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effec... 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...
International journal of antimicrobial agents, Jan 25, 2017
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 mill... 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.
The Journal of pharmacology and experimental therapeutics, 2001
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists ar... 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...
International journal of antimicrobial agents, Jan 25, 2017
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 mill... 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.
The human brain represents the pinnacle of biological evolution. With grooves and spirals that gi... more The human brain represents the pinnacle of biological evolution. With grooves and spirals that give it the appearance of a shelled walnut, it weighs on average 1.3kg and contains 100 billion nerve cells (or neurons), with 10 times as many glial support cells. These cells are organised in a highly complex three-dimensional (3-D) array of interconnecting fibres, with information flow mediated by flux of electrical charge along communicating neuronal fibres (axons) at a speed of up to 250 miles/hour. This flow of information is mediated by the movement of charged ions across the axonal membrane; communication between neurons is via release of neurotransmitter into the synaptic space between adjacent cells. These communication points are numerous and in total the human brain contains 10 14 such synapses. Any given neuron may have several thousand synaptic connections to many other neurons, forming a highly complex network -the number of possible connections is virtually without limit. The activity of the brain weaves meaningful patterns to control all of our senses, actions, emotions and thoughts. Although constituting only 2% of the weight of the body, the brain Neurobiol, 2000;20:217-30. 8. Siegal T, Ruinstein R, Bokstein F, et al., In vivo assessment of the window of barrier opening after osmotic blood brain barrier disruption in humans, J Neurosurg, 2000;92:599-605. 9 Siegal T, Zylber-Katz E, Strategies for increasing drug delivery to the brain, Clin Pharmacokinet, 2002;41:171-86. 10. Kroll RA, Neuwelt EA, Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means, Neurosurgery, 1998;42:1083-1100.
The Rewards and Challenges T he worldwide market for therapies for central nervous system (CNS) d... 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...
Current protocols in pharmacology / editorial board, S.J. Enna (editor-in-chief) ... [et al.], 2013
The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the... 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.
An appropriate drug metabolism and pharmacokinetic (DMPK) profile remains a major hurdle to reduc... 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...
In situ endothelialization of cardiovascular implants has emerged in recent years as an attractiv... more In situ endothelialization of cardiovascular implants has emerged in recent years as an attractive means of targeting the persistent problems of thrombosis and intimal hyperplasia. This study aimed to investigate the efficacy of immobilizing anti-CD34 antibodies onto a POSS-PCU nanocomposite polymer surface to sequester endothelial progenitor cells (EPCs) from human blood, and to characterize the surface properties and hemocompatibility of this surface. Amine-functionalized fumed silica was used to covalently conjugate anti-CD34 to the polymer surface. Water contact angle, fluorescence microscopy, and scanning electron microscopy were used for surface characterization. Peripheral blood mononuclear cells (PBMCs) were seeded on modified and pristine POSS-PCU polymer films. After 7 days, adhered cells were immunostained for the expression of EPC and endothelial cell markers, and assessed for the formation of EPC colonies. Hemocompatibility was assessed by thromboelastography, and platelet activation and adhesion assays. The number of EPC colonies formed on anti-CD34-coated POSS-PCU surfaces was not significantly higher than that of POSS-PCU (5.0±1.0 vs. 1.7±0.6, p>0.05). However, antibody conjugation significantly improved hemocompatibility, as seen from the prolonged reaction and clotting times, decreased angle and maximum amplitude (p<0.05), as well as decreased platelet adhesion (76.8±7.8 vs. 8.4±0.7, p<0.05) and activation. Here, we demonstrate that POSS-PCU surface immobilized anti-CD34 antibodies selectively captured CD34 + cells from peripheral blood, although only a minority of these were EPCs. Nevertheless, antibody conjugation significantly improves the hemocompatibility of POSS-PCU, and should therefore continue to be explored in combination with other strategies to improve the specificity of EPC capture to promote in situ endothelialization.
The need to discover and develop safe and effective new medicines is greatest for disorders of th... more The need to discover and develop safe and effective new medicines is greatest for disorders of the CNS. A core requirement for an effective neurotherapeutic agent is an ability to cross the blood-brain barrier and remain in the brain interstitial fluid (ISF) for a sufficient duration and concentration to evoke the desired therapeutic effect. Measuring the free concentration of a neuroactive compound in brain ISF is therefore an essential step in the critical path towards the development of a CNS medicine. In vivo microdialysis provides a powerful method for the measurement of endogenous and exogenous substances in the ISF surrounding the probe and so it represents an important tool in CNS drug discovery. It can also be used to measure the pharmacodynamic response of neuroactive compounds by measuring neurotransmitters and second messengers. Another approach to measure both pharmacokinetics and the pharmacodynamics of neuroactive compounds is the measurement of receptor occupancy, which has the advantage of being applicable to the study of humans as well as experimental animals. Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds clearly improve understanding of the efficacy and safety of drug candidates, which improves both the efficiency and the effectiveness of CNS medicines research.
Acute (-)-nicotine administration (0.4 and 0.8 mg/kg s.c.) produced a regionally specific increas... 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.
The major imperative of the pharmaceutical industry is to effectively translate insights gained f... 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.
An unmet need exists for the development of next-generation multifunctional nanocomposite materia... more An unmet need exists for the development of next-generation multifunctional nanocomposite materials for biomedical applications, particularly in the field of cardiovascular regenerative biology. Herein, we describe the preparation and characterization of a novel polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer with covalently attached anti-CD34 antibodies to enhance capture of circulating endothelial progenitor cells (EPC). This material may be used as a new coating for bare metal stents used after balloon angioplasty to improve re-endothelialization. Biophysical characterization techniques were used to assess POSS-PCU and its subsequent functionalization with anti-CD34 antibodies. Results
Activated charcoal (AC) can be taken orally as enterosorbent for treatment of pathological states... 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.
International journal for parasitology. Drugs and drug resistance, Aug 12, 2018
Fungisome (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effec... 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...
International journal of antimicrobial agents, Jan 25, 2017
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 mill... 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.
The Journal of pharmacology and experimental therapeutics, 2001
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists ar... 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...
International journal of antimicrobial agents, Jan 25, 2017
Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 mill... 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.
The human brain represents the pinnacle of biological evolution. With grooves and spirals that gi... more The human brain represents the pinnacle of biological evolution. With grooves and spirals that give it the appearance of a shelled walnut, it weighs on average 1.3kg and contains 100 billion nerve cells (or neurons), with 10 times as many glial support cells. These cells are organised in a highly complex three-dimensional (3-D) array of interconnecting fibres, with information flow mediated by flux of electrical charge along communicating neuronal fibres (axons) at a speed of up to 250 miles/hour. This flow of information is mediated by the movement of charged ions across the axonal membrane; communication between neurons is via release of neurotransmitter into the synaptic space between adjacent cells. These communication points are numerous and in total the human brain contains 10 14 such synapses. Any given neuron may have several thousand synaptic connections to many other neurons, forming a highly complex network -the number of possible connections is virtually without limit. The activity of the brain weaves meaningful patterns to control all of our senses, actions, emotions and thoughts. Although constituting only 2% of the weight of the body, the brain Neurobiol, 2000;20:217-30. 8. Siegal T, Ruinstein R, Bokstein F, et al., In vivo assessment of the window of barrier opening after osmotic blood brain barrier disruption in humans, J Neurosurg, 2000;92:599-605. 9 Siegal T, Zylber-Katz E, Strategies for increasing drug delivery to the brain, Clin Pharmacokinet, 2002;41:171-86. 10. Kroll RA, Neuwelt EA, Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means, Neurosurgery, 1998;42:1083-1100.
The Rewards and Challenges T he worldwide market for therapies for central nervous system (CNS) d... 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...
Current protocols in pharmacology / editorial board, S.J. Enna (editor-in-chief) ... [et al.], 2013
The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the... 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.
An appropriate drug metabolism and pharmacokinetic (DMPK) profile remains a major hurdle to reduc... 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...
In situ endothelialization of cardiovascular implants has emerged in recent years as an attractiv... more In situ endothelialization of cardiovascular implants has emerged in recent years as an attractive means of targeting the persistent problems of thrombosis and intimal hyperplasia. This study aimed to investigate the efficacy of immobilizing anti-CD34 antibodies onto a POSS-PCU nanocomposite polymer surface to sequester endothelial progenitor cells (EPCs) from human blood, and to characterize the surface properties and hemocompatibility of this surface. Amine-functionalized fumed silica was used to covalently conjugate anti-CD34 to the polymer surface. Water contact angle, fluorescence microscopy, and scanning electron microscopy were used for surface characterization. Peripheral blood mononuclear cells (PBMCs) were seeded on modified and pristine POSS-PCU polymer films. After 7 days, adhered cells were immunostained for the expression of EPC and endothelial cell markers, and assessed for the formation of EPC colonies. Hemocompatibility was assessed by thromboelastography, and platelet activation and adhesion assays. The number of EPC colonies formed on anti-CD34-coated POSS-PCU surfaces was not significantly higher than that of POSS-PCU (5.0±1.0 vs. 1.7±0.6, p>0.05). However, antibody conjugation significantly improved hemocompatibility, as seen from the prolonged reaction and clotting times, decreased angle and maximum amplitude (p<0.05), as well as decreased platelet adhesion (76.8±7.8 vs. 8.4±0.7, p<0.05) and activation. Here, we demonstrate that POSS-PCU surface immobilized anti-CD34 antibodies selectively captured CD34 + cells from peripheral blood, although only a minority of these were EPCs. Nevertheless, antibody conjugation significantly improves the hemocompatibility of POSS-PCU, and should therefore continue to be explored in combination with other strategies to improve the specificity of EPC capture to promote in situ endothelialization.
The need to discover and develop safe and effective new medicines is greatest for disorders of th... more The need to discover and develop safe and effective new medicines is greatest for disorders of the CNS. A core requirement for an effective neurotherapeutic agent is an ability to cross the blood-brain barrier and remain in the brain interstitial fluid (ISF) for a sufficient duration and concentration to evoke the desired therapeutic effect. Measuring the free concentration of a neuroactive compound in brain ISF is therefore an essential step in the critical path towards the development of a CNS medicine. In vivo microdialysis provides a powerful method for the measurement of endogenous and exogenous substances in the ISF surrounding the probe and so it represents an important tool in CNS drug discovery. It can also be used to measure the pharmacodynamic response of neuroactive compounds by measuring neurotransmitters and second messengers. Another approach to measure both pharmacokinetics and the pharmacodynamics of neuroactive compounds is the measurement of receptor occupancy, which has the advantage of being applicable to the study of humans as well as experimental animals. Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds clearly improve understanding of the efficacy and safety of drug candidates, which improves both the efficiency and the effectiveness of CNS medicines research.
Acute (-)-nicotine administration (0.4 and 0.8 mg/kg s.c.) produced a regionally specific increas... 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.
The major imperative of the pharmaceutical industry is to effectively translate insights gained f... 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.
An unmet need exists for the development of next-generation multifunctional nanocomposite materia... more An unmet need exists for the development of next-generation multifunctional nanocomposite materials for biomedical applications, particularly in the field of cardiovascular regenerative biology. Herein, we describe the preparation and characterization of a novel polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer with covalently attached anti-CD34 antibodies to enhance capture of circulating endothelial progenitor cells (EPC). This material may be used as a new coating for bare metal stents used after balloon angioplasty to improve re-endothelialization. Biophysical characterization techniques were used to assess POSS-PCU and its subsequent functionalization with anti-CD34 antibodies. Results
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Papers by Mo S. Alavijeh