New Safe Medicines Faster: a Proposition for a Pan-European Research Effort

Nature Reviews. Drug Discovery. May, 2002  |  Pubmed ID: 12120415

Providing support for downstream drug development has not traditionally been a primary focus of public research funding programmes. However, the European Commission has decided to include the drug development process in the European Union's Sixth Framework Programme for Research and Technological Development (2002-2006). If the present proposal is adopted, research consortia and networks must be ready to exploit the proposed funds. 'Integrated Projects' and 'Networks of Excellence' will allow complex topics to be tackled simultaneously by many research groups and associated stakeholders, but these will be very demanding to implement.

Centrally-mediated Antinociceptive Actions of GABA(A) Receptor Agonists in the Rat Spared Nerve Injury Model of Neuropathic Pain

European Journal of Pharmacology. Jun, 2005  |  Pubmed ID: 15936014

Gamma aminobutyric acid (GABA) plays a major role in the central hyperexcitabilty associated with nerve damage. The precise antinociceptive actions mediated by GABA(A) receptor agonists remain unclear as previous studies have shown mixed results in neuropathic pain models. Thus, various drugs which modulate GABA(A) receptor function were tested in the rat spared nerve injury (SNI) model of neuropathic pain. The selective GABA(A) receptor agonist gaboxadol dose-dependently (6 and 15 mg/kg, s.c.) reversed hindpaw mechanical allodynia and hyperalgesia for at least 150 min after administration. The GABA(A) receptor agonist muscimol (0.02-2 mg/kg, s.c.) also dose-dependently reversed mechanical allodynia, although the maximal effect achieved was less than that observed for gaboxadol. Mechanical hyperalgesia was attenuated only by the highest dose of muscimol. In contrast, the selective GABA(A) receptor agonist isoguvacine (20 mg/kg, s.c.) which has poor central nervous system penetration, and the benzodiazepine-site ligand zolpidem (20 mg/kg, s.c.) were ineffective against either nociceptive behaviour. In the rotarod test, both gaboxadol (15 mg/kg) and zolpidem impaired motor function for at least 60 min after injection; muscimol (2 mg/kg) and gaboxadol (6 mg/kg) were ineffective. Importantly, the ataxic effects induced by gaboxadol resolved 1-2 h after administration, a time point where clear antiallodynic and antihyperalgesic actions still occurred. Thus, systemic administration of blood-brain penetratable selective GABA(A) receptor agonists attenuate nociceptive behaviours in the SNI rat model of neuropathic pain that can be considered to occur independently of other effects on motor function.

How First-time-in-human Studies Are Being Performed: a Survey of Phase I Dose-escalation Trials in Healthy Volunteers Published Between 1995 and 2004

Journal of Clinical Pharmacology. Oct, 2005  |  Pubmed ID: 16172177

First-time-in-human studies are small, time-lagged dose-escalation studies including volunteer subjects evaluating safety and tolerability. There is little consensus in the design of a first-time-in-human study, and it is difficult to get an overview of studies performed. One hundred five studies comprising 3323 healthy volunteers published in the 5 major clinical pharmacology journals since 1995 were analyzed. The average trial was placebo controlled, double blind including 32 subjects at 5 dose levels but with great variation in cohort size and dose-escalation method. The parallel single-dose design was the most common design, with the crossover designs being more frequent in the early publications. Despite discussions on the optimization of phase I trials, little seems to be happening. The development of study designs and evaluation methods for cancer trials is extensive, but formal statistically based methods and more scientific study designs are unusual in phase I dose-escalation trials in healthy volunteers.

Venlafaxine Compromises the Antinociceptive Actions of Gabapentin in Rat Models of Neuropathic and Persistent Pain

Psychopharmacology. Aug, 2006  |  Pubmed ID: 16783541

Neuropathic pain is associated with a number of disease states of diverse aetiology that can share common pathophysiological mechanisms. Antiepileptic drugs modulate ion channel function and antidepressants increase extracellular monoamine levels, and both drug classes variously attenuate signs and symptoms of neuropathic pain. Thus, coadministration of the antiepileptic gabapentin and the antidepressant venlafaxine may provide superior pain relief to administration of either drug alone.

The Importance of Genetic Background on Pain Behaviours and Pharmacological Sensitivity in the Rat Spared Serve Injury Model of Peripheral Neuropathic Pain

European Journal of Pharmacology. Jun, 2007  |  Pubmed ID: 17383631

Neuropathic pain conditions can encompass a diverse constellation of signs and symptoms consisting of sensory deficits, allodynia and hyperalgesia. Animal models of neuropathic pain have enabled the identification of key pathophysiological changes occurring within nociceptive pathways as a result of injury, and serve an invaluable role for preclinical screening of novel analgesic candidates. We have produced the first systematic description of the development and maintenance, and the pharmacological sensitivity of nociceptive behaviours in four rat strains with different genetic background (outbred Sprague-Dawley and inbred Brown Norway, Lewis and Fischer 344 rats), using the spared nerve injury model of peripheral neuropathic pain. Hindpaw mechanical hypersensitivity was evident from 7 to 30 days post-injury in all four strains, developing most quickly and severely in Fischer 344 rats; Lewis rats were least affected. Morphine (6 but not 3 mg/kg, s.c.) and gabapentin (100 but not 50 mg/kg, s.c.) had significant antiallodynic and antihyperalgesic actions in all four strains after spared nerve injury, although marked differences in potency across strains were observed. Two strains (Fischer 344 rats and Lewis) were insensitive to the antihyperalgesic properties of gaboxadol (15 mg/kg) whereas gaboxadol (6 mg/kg) was equipotent to morphine (6 mg/kg) in two other strains (Sprague-Dawley and Brown Norway). The observed pharmacogenetic variations have important implications for the preclinical testing of drugs, and provide a basis for development of pharmacogenomics in neuropathic pain.

Effective Integration of Systems Biology, Biomarkers, Biosimulation and Modelling in Streamlining Drug Development

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. May, 2007  |  Pubmed ID: 17408933

The European Federation of Pharmaceutical Sciences (EUFEPS) has long established itself as leaders in the field of interdisciplinary meetings to discuss issues that face drug development. It's ever popular and well attended "Optimizing Drug Development" series has tackled numerous issues, most recent of which have been drug interactions, getting the dose right, candidate selection, and biomarkers (Lesko et al., 2000; Rolan et al., 2003; Stanski et al., 2005; Tucker et al., 2001). Over a course of 3 productive days, the meeting on "Effective Integration of Systems Biology, Biomarkers, Biosimulation and Modelling in Streamlining Drug Development", held in Basel, Switzerland was jointly sponsored by EUFEPS, European Biosimulation Network of Excellence (BioSim), American College of Clinical Pharmacology (ACCP), European Centre of Pharmaceutical Medicine (ECPM), and Swiss Society of Pharmaceutical Sciences (SGRW). The meeting was focused on emerging aspects related to the quantitative understanding of underlying pathways in drug discovery and clinical development, i.e. moving from an empirical to a model-based, quantitative drug development process. The objectives of the meeting were: (1) to highlight the current state of the art on biomarkers (as they relate to quantitative fingerprinting of disease), systems biology, modelling and simulation; (2) to illustrate the applications of these emerging tools in increasing the efficiency and productivity of new drug development by case examples; (3) to understand the gaps in the technology and organizational implementations in governance, and (4) allow an opportunity for cross-disciplinary interaction, i.e., scientists with more theoretical and technical modelling and simulation expertise of the BioSim network and researchers experienced in applying modelling and simulation techniques in day-to-day drug development were drawn together. This report summarizes the outcome from this meeting.

Effective Integration of Systems Biology, Biomarkers, Biosimulation, and Modeling in Streamlining Drug Development

Journal of Clinical Pharmacology. Jun, 2007  |  Pubmed ID: 17463216

Differential Effects of Repeated Low Dose Treatment with the Cannabinoid Agonist WIN 55,212-2 in Experimental Models of Bone Cancer Pain and Neuropathic Pain

Pharmacology, Biochemistry, and Behavior. Nov, 2008  |  Pubmed ID: 18611408

Pain due to bone malignancies is one of the most difficult types of cancer pain to fully control and may further decrease the patients' quality of life. Animal models of chronic pain conditions resulting from peripheral inflammatory reactions or nerve injuries are responsive to treatment with cannabinoid agonists. However, the use of cannabinoid agonists in humans may be hampered by CNS related side effects and development of tolerance. In the present study, we investigated the effect of repeated low dose administration of the synthetic cannabinoid agonist WIN 55,212-2 on bone cancer pain and neuropathic pain in mice. In addition, we investigated the development of CNS related side effects and tolerance. We found that 0.5 mg/kg/day for 18 days reduced pain related behavior and expression of spinal glial fibrillary acidic protein in the bone cancer pain model but not in the neuropathic pain model. Furthermore, this treatment strategy was not found to induce measurable CNS related side effects or tolerance. Cancer cell viability assays and bone volume fraction assessed by micro computed tomography (microCT) demonstrated that these effects were not due to changes in cancer progression. The difference in WIN 55,212-2 efficacy between the bone cancer and neuropathic pain models may reflect the different pain generating mechanisms, which may be utilized in designing new therapeutic drugs.

The EUFEPS Workshop on Institutional Peer Review "The Ultimate Tool to Advance the Pharmaceutical Sciences?" A Continuing Story

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. Nov, 2008  |  Pubmed ID: 18790717

Pharmacokinetics of Fexofenadine: Evaluation of a Microdose and Assessment of Absolute Oral Bioavailability

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. May, 2010  |  Pubmed ID: 20307657

A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP). Fexofenadine was administered to 6 healthy male volunteers in a three way cross-over design. A microdose (100microg) of (14)C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100microg) of (14)C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine was collected and analysed for total (14)C. Good concordance between the microdose and therapeutic dose pharmacokinetics was observed. Microdose: CL 13L/h, CL(R) 4.1L/h, V(ss) 54L, t(1/2) 16h; therapeutic dose: CL 16L/h, CL(R) 6.2L/h, V(ss) 64L, t(1/2) 12h. The absolute oral bioavailability of fexofenadine was 0.35 (microdose 0.41, therapeutic dose 0.30). Despite a 1200-fold difference in dose of fexofenadine, the microdose predicted well the pharmacokinetic parameters following a therapeutic dose for this transporter dependent compound.

Low Dose of Donepezil Improves Gabapentin Analgesia in the Rat Spared Nerve Injury Model of Neuropathic Pain: Single and Multiple Dosing Studies

Journal of Neural Transmission (Vienna, Austria : 1996). Dec, 2010  |  Pubmed ID: 20890617

The use of cholinergic drugs, either alone or in combination with other drugs, has been suggested as an approach to improve treatment outcome for patients suffering from neuropathic pain. The present study was undertaken in the rat spared nerve injury model of neuropathic pain to evaluate the effect of the cholinesterase inhibitor donepezil when administered (1) alone and (2) as low-dose in combination with the first-line recommendation gabapentin. The co-administration studies were performed following single and multiple dosing. Single, parenteral dosing of donepezil (1, 1.5 and 3 mg/kg s.c.) produced a dose-dependent reversal of the neuropathic pain behaviour. Co-administration of a sub-effective dose of donepezil (0.5 mg/kg s.c.) and low doses of gabapentin (10 and 30 mg/kg s.c.) resulted in a three- to fourfold increase of the analgesic effect, in comparison with gabapentin administered alone. Following multiple, oral dosing, gabapentin (25 mg/kg p.o.) was administered once daily over 20 days. Addition of donepezil (1.5 mg/kg p.o.) from day 11 to day 20 resulted in improved analgesia during the period of combination therapy, in comparison with the gabapentin monotherapy period. Furthermore, the treatment effects were stable in both the mono- and the combination therapy period, indicating that tolerance development does not occur within the studied time frame. In conclusion, the results from this preclinical study support the use of donepezil as adjunctive to gabapentin to improve the therapeutic outcome in the management of neuropathic pain.

Comparative Pharmacokinetics Between a Microdose and Therapeutic Dose for Clarithromycin, Sumatriptan, Propafenone, Paracetamol (acetaminophen), and Phenobarbital in Human Volunteers

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. Jun, 2011  |  Pubmed ID: 21540108

A clinical study was conducted to assess the ability of a microdose (100 μg) to predict the human pharmacokinetics (PK) following a therapeutic dose of clarithromycin, sumatriptan, propafenone, paracetamol (acetaminophen) and phenobarbital, both within the study and by reference to the existing literature on these compounds and to explore the source of any nonlinearity if seen. For each drug, 6 healthy male volunteers were dosed with 100 μg (14)C-labelled compound. For clarithromycin, sumatriptan, and propafenone this labelled dose was administered alone, i.e. as a microdose, orally and intravenously (iv) and as an iv tracer dose concomitantly with an oral non-labelled therapeutic dose, in a 3-way cross over design. The oral therapeutic doses were 250, 50, and 150 mg, respectively. Paracetamol was given as the labelled microdose orally and iv using a 2-way cross over design, whereas phenobarbital was given only as the microdose orally. Plasma concentrations of total (14)C and parent drug were measured using accelerator mass spectrometry (AMS) or HPLC followed by AMS. Plasma concentrations following non-(14)C-labelled oral therapeutic doses were measured using either HPLC-electrochemical detection (clarithromycin) or HPLC-UV (sumatriptan, propafenone). For all five drugs an oral microdose predicted reasonably well the PK, including the shape of the plasma profile, following an oral therapeutic dose. For clarithromycin, sumatriptan, and propafenone, one parameter, oral bioavailability, was marginally outside of the normally acceptable 2-fold prediction interval around the mean therapeutic dose value. For clarithromycin, sumatriptan and propafenone, data obtained from an oral and iv microdose were compared within the same cohort of subjects used in the study, as well as those reported in the literature. For paracetamol (oral and iv) and phenobarbital (oral), microdose data were compared with those reported in the literature only. Where 100 μg iv (14)C-doses were given alone and with an oral non-labelled therapeutic dose, excellent accord between the PK parameters was observed indicating that the disposition kinetics of the drugs tested were unaffected by the presence of therapeutic concentrations. This observation implies that any deviation from linearity following the oral therapeutic doses occurs during the absorption process.

Excellence in Education and Training Advances Competitiveness of the Pharmaceutical Industry in Europe

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. Sep, 2011  |  Pubmed ID: 21782938

This commentatory should be read in connection with the subsequent article about current trends in the evolvement of the pharmaceutical industries. It points to importance for the industries to have access to pharmaceutical sciences researchers educated and trained at the highest level through the newly established public-private system of courses in Europe supported by EU.