Paul E Rolan

• The University of Adelaide

Purpose Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to tol...

This article investigates 14 additional symptoms present in women with dysmenorrhea. It discusses central sensitization, migraine, stabbing pains.

The encouraging pace of discovery and development in the field of regenerative medicine holds tremendous potential for bringing therapies to the clinic that may offer meaningful benefit to patients, particularly in diseases with no or suboptimal therapeutic options. Academic researchers will continue to play a critical role in developing concepts a...

Background Chronic migraine (CM) is problematic, and there are few effective treatments. Recently, it has been hypothesized that glial activation may be a contributor to migraine; therefore, this study investigated whether the potential glial inhibitor, ibudilast, could attenuate CM. Methods The study was of double-blind, randomized, placebo-contr...

Background: Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, ibudilast attenuates glial activation and is able to...

This phase I, open-label study investigated the effects of steady-state brivaracetam administration on steady-state pharmacokinetics of carbamazepine, and steady-state carbamazepine administration on single-dose and steady-state pharmacokinetics of brivaracetam, in 14 healthy participants who received brivaracetam 200mg single doses on days 1 and 2...

Objective: To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. Methods: This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biog...

We report a 49-year-old female migraineur who experienced paradoxical hyperphagia and concurrent intrusive food thoughts leading to rapid weight gain and a substantial increase in waist circumference. A significant reduction in migraine frequency was also observed during topiramate treatment, a widely used migraine prophylactic agent which is gener...

Long-term opioid therapy has been associated with low cortisol levels due to central suppression of the hypothalamic-pituitary-adrenal axis. The implications of hypocortisolism on wellbeing have not been established. Our aim was to determine whether intervention with physiologic glucocorticoid replacement therapy improves wellbeing and analgesic re...

Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine...

AimThe principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability.Methods The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg int...

Translating promising preclinical drug discoveries to successful clinical trials remains a significant hurdle in pain research. Although animal models have significantly contributed to understanding chronic pain pathophysiology, the majority of research has focused on male rodents using testing procedures that produce sex difference data that do no...

Sensory illusions may reveal fundamental features of the nervous system. The thermal grill illusion is such a pain illusion, where interlaced warm and cool temperature bars (thermal grill) produce a paradoxical burning sensation. Previous studies have only systematically investigated the thermal grill illusion in pain-free volunteers. The objective...

Migraine continues to be the most common of the debilitating headaches. Existing acute headache treatments are not always satisfactory, and current research is focussed on targeting neuroinflammatory pathways with drugs that are devoid of vascular action. Current prophylactic drugs are largely centred around antihypertensive, anticonvulsant and ant...

Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in Phase III clinical development for epilepsy. This study assessed the effect of brivaracetam 400 mg/day on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive (OC) containing 30 µg ethinylestradiol and 150 µg levonorgestrel, in healthy pre-menopausal wom...

Chronic pain patients have increased peripheral blood mononuclear cell Interkeukin-1β production following TLR2 and TLR4 simulation. Here we have used a human-to-rat and rat-to-human approach to further investigate whether peripheral blood immune responses to TLR agonists might be suitable for development as possible systems biomarkers of chronic p...

Pharmacokinetic information is essential for the design of dosage regimens and for demonstrating that the optimum dose and frequency of dosing have been selected. The information also provides an understanding of the physiological processes affecting plasma concentrations and their relationship to effects.

Background: Supraspinal activity-dependent neuroplasticity may be important in the transition from acute to chronic pain. We examined neuroplasticity in a cortical region not considered to be a primary component of the central pain matrix in chronic tension-type headache (CTTH) patients. We hypothesised that neuroplasticity would be exaggerated in...

Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produ...

IntroductionPatients with chronic headache who consume large amounts of analgesics are often encountered in clinical practice. Excessive intake of analgesics is now considered to be a cause, rather than simply a consequence, of frequent headaches, and as such the diagnosis "medication-overuse headache" (MOH) has been formulated. Despite the prevale...

The triptans are a group of compounds with high efficacy for the acute treatment of migraine and cluster headache. They have a relatively wide therapeutic index, and although a number of minor pharmacokinetic interactions have been observed, few are likely to be clinically significant. Given the differences in principal elimination pathways, potent...

Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR e...

Individual information on chronic pain sufferers in this study. (DOCX)

J. Neurochem. (2012) 122, 976–994. A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats,...

Patients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes. This study compared the effects of pregabalin (300 mg) and the tetracycline...

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The contribution of (S)-warfarin to the clinical effect of rac-warfarin is well understood. The extent to which (R)-warfarin contributes to the clinical effect of rac-warfarin is unclear. WHAT THIS STUDY ADDS • Using unequivocally pure (R)- and (S)-warfarin we have demonstrated that (R)-warfarin contribute...

Paul Rolan speaks to Roshaine Gunawardana, Commissioning Editor: Paul Rolan graduated in Medicine (MBBS) from the University of Adelaide, Australia, in 1979 and trained in internal medicine and clinical pharmacology. In 1987, he went to the UK to work at the Wellcome Research Laboratories where he was responsible for the exploratory development of...

Objective Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it. Methods This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16) and healthy control subjects (n = 16) u...

This study compared the responses between patients with unilateral sciatica and pain-free volunteers following administration of intradermal capsaicin. METHODS Fourteen patients with unilateral sciatica and 12 pain-free volunteers received one injection per hour over 4 h of 1 µg and 10 µg capsaicin, into each calf. For each dose, spontaneous pain (...

Peptide deformylase (PDF) inhibitors represent a potential new class of antibiotics targeting a large number of bacterial species. We studied the pharmacokinetics and safety of LBM415, a novel PDF inhibitor, administered as a single oral dose at 100-3,000 mg in the fasted state and at 1,000 mg in the fed state in healthy volunteers. LBM415 was then...

Recent evidence implicates an adaptive immune response in the central nervous system (CNS) mechanisms of neuropathic pain. This review identifies how neuropathic pain alters CNS immune privilege to facilitate T cell infiltration. Once in the CNS, T cells may interact with the local antigen presenting cells, microglia, via the major histocompatibili...

Recent evidence demonstrates that peripheral immune cells contribute to the nociceptive hypersensitivity associated with neuropathic pain by infiltrating the central nervous system (CNS). We have recently developed a rat model of graded chronic constriction injury (CCI) by varying the exposure of the sciatic nerve and control non-nerve tissue to su...

The mechanisms underlying neuropathic pain are not well understood, resulting in unsatisfactory treatment outcomes for many patients. Animal models underpin much of the current understanding of pain mechanisms due to their perceived ability to mimic pain hypersensitivities; however, are limited by their binomial approach (pain vs. control), which d...

Stress is widely demonstrated as a contributing factor in tension-type headache (TTH). The mechanisms underlying this remain unclear at present. Recent research indicates the importance of central pain processes in tension-type headache (TTH) pathophysiology. Concurrently, research with animals and healthy humans has begun to elucidate the relation...

Analysis of saccadic eye movements (SEMs) has previously been used to detect drug- and sleep-deprivation-induced sedation, but never in combination. We compared the effects of sleep deprivation and opioids on 10 opioid-naive with nine opioid-tolerant participants. The naive-participant study evaluated the effects of sleep deprivation alone, morphin...

Ibudilast is a relatively nonselective phosphodiesterase inhibitor which has been marketed for almost 20 years in Japan for treating asthma. More recently it has been found to have anti-inflammatory activity in both the peripheral immune system and in the CNS via glial cell attenuation. This CNS-directed anti-inflammatory activity is of potential u...

The test-retest reliability of temporal summation (TS) and diffuse noxious inhibitory control (DNIC) has not been reported to date. Establishing such reliability would support the possibility of future experimental studies examining factors affecting TS and DNIC. Similarly, the use of manual algometry to induce TS, or an occlusion cuff to induce DN...

To examine effects of stress on noxious inhibition and temporal summation (TS) in tension-type headache. Stress is the most commonly reported trigger of a chronic tension-type headache (CTH) episode; however, the mechanisms underlying this are unclear. Stress affects pain processing throughout the central nervous system, including, potentially, mec...

To compare the dose-response relationships of two formulations [Tween- or hydroxypropyl-b-cyclodextrin (HP-b-CD)-based] of intradermal capsaicin in healthy volunteers and to assess the effect of potential covariates of response. One, 10, 30 and 100 microg in 10 ml were compared for the outcomes of flare, spontaneous pain, mechanical allodynia and h...

Stress is the most commonly reported trigger of an episode of chronic tension-type headache (CTTH); however, the causal significance has not been experimentally demonstrated to date. Stress may trigger CTTH through hyperalgesic effects on already sensitized pain pathways in CTTH sufferers. This hypothesis could be partially tested by examining pain...

Mental stress is a noted contributing factor in chronic tension-type headache (CTH), however the mechanisms underlying this are not clearly understood. One proposition is that stress aggravates already increased pain sensitivity in CTH sufferers. This hypothesis could be partially tested by examining effects of mental stress on threshold and supra-...

To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen. Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14...

Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects. Three successive panels of 12 healthy male subjects recei...

This chapter focuses on physiological and laboratory markers of drug effect. The selection and measurement of relevant drug effects are important parts of clinical pharmacology. The biomarkers have served as surrogate endpoints and have provided the basis for regulatory approval of new drugs. Most of the biomarkers are identified in the studies of...

IntroductionBasic conceptsBioavailability and bioequivalenceDrug interactionsThe elderlyRenal impairmentLiver diseaseDisposition, rates and routes of elimination of radiolabelled drugPharmacokinetic–pharmacodynamic modellingPopulation analysisThe rest of the typical clinical pharmacokinetics packageThe ideal drug from the point of view of pharmacok...

The objective of the study was to evaluate the pharmacokinetics (and how they are affected by food), CNS pharmacodynamics and the adverse event profile of brivaracetam after single increasing doses. Healthy males (n = 27, divided into three alternating panels of nine subjects) received two different single oral doses of brivaracetam (10-1400 mg) an...

An expert group met in Leiden to review the state-of-the-art in detecting drug-related safety problems and to review the role of biomarkers and modelling techniques. It was clear that new drugs are not necessarily safer than old drugs, despite much larger clinical trial programs. Larger or longer clinical trials may be unfeasible and postmarketing...

Migraine is a benign self-limiting condition for which the objective of treatment is to maximize the patient's quality of life by reducing the frequency of attacks and attenuating the pain and suffering of an individual attack as quickly and safely as possible. Evaluating the efficacy of antimigraine treatments, particularly those for the managemen...

Sublingual buprenorphine formulations have been developed as treatments for opioid dependence. In three studies, opioid naïve healthy male subjects received Subutex tablets (buprenorphine 2 and 8 mg [N=27] or 12 and 16 mg [N=27]) or Suboxone (two formulations) tablets (buprenorphine 8 mg/naloxone 2 mg [N=36]) sublingually, under a naltrexone block...

To evaluate potential pharmacokinetic interactions between phenobarbitone and retigabine, a new antiepileptic drug. Fifteen healthy men received 200 mg of retigabine on day 1. On days 4-32, phenobarbitone 90 mg was administered at 22.00 h. On days 26-32, increasing doses of retigabine were given to achieve a final dose of 200 mg every 8 h on day 32...

The Ninth European Federation for Pharmaceutical Sciences (EUFEPS) Conference on Optimizing Drug Development was held in Basel, Switzerland, December 10-12, 2001. The overall objective of the conference was to find new ways of advancing the integration of biomarkers into drug development and clinical practice to make drug development more efficient...

To evaluate pharmacokinetic and pharmacodynamic interactions between tamsulosin and acenocoumarol. Twelve healthy volunteers received tamsulosin 0.4 mg or placebo once daily for 9 days in a double-blind, cross-over study. On day 5 of each study period, a single 10-mg oral dose of racemic acenocoumarol was administered. The ratios (point estimates (...

The primary objective of the present study was to investigate the safety, tolerability, and pharmacokinetics of a single dose of NN2211, a long-acting glucagon-like peptide 1 (GLP-1) derivative, in healthy male subjects. The secondary objective was to investigate the pharmacodynamics of NN2211. In a double-blind, randomized dose, escalation, placeb...

Glucagon-like peptide-1 (GLP-1), a polypeptide hormone secreted by the l-cells in the gastrointestinal tract, has shown promising effects as a new treatment modality for patients with Type II (non-insulin-dependent) diabetes mellitus. However, the pharmacokinetic profile of native GLP-1 with a rapid elimination has limited its therapeutic potential...

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of val...

Carbamazepine, a drug used in the treatment of seizure disorders, and citalopram, a highly selective serotonin reuptake inhibitor used for the treatment of depression and other psychiatric disorders, are both metabolized predominantly by the cytochrome P4503A4 isozyme. In this study, the effect of subchronic administration of citalopram on the stea...

Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. Thirty-six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a s...

In this paper, we systematically review the available experimental and clinical evidence concerning the causation of headache by refractive error. Despite the apparent belief of both medical and optometric professionals that provision of an appropriate correction may alleviate various types of headache, there is little if any robust evidence in sup...

Objective: To evaluate the potential oral pharmacokinetic interaction between phenobarbital (PHENO) and retigabine (RGB), a new antiepileptic drug. Methods: Fifteen men received a single 200-mg dose of RGB on Day 1. From Days 4 to 32, 90 mg of PHENO were administered at 10 PM. From Days 26 to 32, increasing doses of RGB (starting dose of 100 mg q8h...

Citalopram and theophylline may be prescribed together to treat patients with depression and asthmatic disease. Because theophylline has a low therapeutic index, small changes in plasma levels may result in therapeutic failure or adverse effects. Both citalopram and theophylline are metabolized by cytochrome P450 (CYP) isozymes. Theophylline is met...

Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess t...

Recent studies of the visual cortex in patients with migraine have generally concluded that migraine (particularly migraine with aura) is associated with a state of functional cortical hyperexcitability. The mechanisms giving rise to this hyperexcitability have hitherto been unclear. This paper reports two studies that used a novel investigative te...

The bioequivalence of recombinant human growth hormone (rhGH) for reconstitution, at either 24 IU or 8 mg, and three strengths of liquid formulation of rhGH (5, 10 or 15 mg per 1.5 ml, hGH) was tested in two randomized, single-blind, four-period, crossover studies in healthy subjects. The study drugs were administered by subcutaneous injection at a...

Objective: Metrifonate, through its active metabolite dichlorvos, is an acetylcholinesterase inhibitor effective in the treatment of Alzheimer’s disease (AD). Patients with AD often require treatment with warfarin, which has a narrow therapeutic index. In view of the many reported interactions of warfarin, it was essential to ascertain whether the...

The novel selective 5-hydroxytryptamine (5-HT)1B/1D agonist, zolmitriptan (Zomig, formerly known as 311C90), has shown good efficacy in the acute oral treatment of migraine. Zolmitriptan acts both centrally and peripherally, therefore it is important to assess central nervous system effects. At single doses of 25-50 mg (up to 8 times the likely the...

Objectives. EEG is a direct and objective measure of CNS activity. Druginduced changes in the EEG usually occur at lower doses than behavioural and subjective changes. This study was designed to compare EEG changes, as a marker of CNS activity, following sub-symptomatic doses of racemic bupivacaine and levobupivacaine and to assess their safety and...

Zolmitriptan is a new oral acute treatment for migraine. It is a selective and potent agonist at the serotonin (5-HT)(1B/1D) receptor and was developed to improve on the oral bioavailability, tissue selectivity and CNS penetration of earlier compounds. Animal studies confirmed that these objectives had been attained. In man, zolmitriptan is rapidly...

Objective Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults.Methods Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan dur...

Seven randomized studies in healthy volunteers have investigated interactions between zolmitriptan (Zomig, formerly 311C90), a 5HT1B/1D agonist for acute migraine therapy, and selected drugs with which there was a possibility of interaction or a likelihood of concurrent use. Co-administration of oral dihydroergotamine, ergotamine, pizotifen, fluoxe...

Members of the new class of antimigraine compounds, 5HT1B/1D agonists, as well as ergotamine, may cause vasoconstriction through stimulation of 5HT receptors on peripheral vessels. The cardiovascular effects of 20 mg oral zolmitriptan (Zomig, formerly 311C90), 2 mg oral ergotamine and the combination were assessed in a randomized double-blind, plac...

Valsartan (CGP 48933), an orally active angiotensin II antagonist, is eliminated mainly by hepatic clearance. To characterize the compound(s) excreted in the bile, biliary excretion of valsartan was investigated by collection of bile after an intravenous dose of valsartan. In addition, to determine the exposure to valsartan when liver function is i...

An open, controlled, randomized, crossover study was conducted in healthy males to assess the possible occurrence of a pharmacokinetic/pharmacodynamic interaction between warfarin and the selective serotonin re-uptake inhibitor citalopram. Twelve subjects received a single 25 mg dose of racemic warfarin either alone or on Day 15 of a 21-day oral do...

To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function. Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal fail...

Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT1D agonist for the acute treatment of migraine. After an initial test i.v. infusion, bioavailability was assessed by comparison of AUC after an i.v. infusion (3.5 mg) and an oral tablet (10 m...

Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radio...

The aim of this study was to compare the pharmacokinetics of the anti-epileptic agent, lamotrigine, in patients with chronic renal failure and healthy volunteers. Non-compartmental pharmacokinetics of a single oral dose (200 mg) of the anti-epileptic agent, lamotrigine, and its main metabolite, lamotrigine N2-glucuronide, were determined for 10 pat...

Non-invasive methods for assessment of the vascular effects of antimigraine drugs were evaluated with respect to their utility, variability and sensitivity in a double-blind, placebo-controlled, three-period crossover study in six healthy volunteers using an intravenous vasoconstrictor, methoxamine, as a probe drug. Changes in the internal diameter...

The potential pharmacokinetic interaction between atovaquone and phenytoin was investigated in 12 healthy male volunteers. Each volunteer received a single 600 mg oral dose of phenytoin in the two treatment periods. On one occasion phenytoin was taken alone and on the other pre-treatment with 2000 mg atovaquone taken as two doses of 1000 mg as a mi...

The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a substituted benzaldehyde, was designed to interact with haemoglobin to increase oxygen affinity and has been shown to inhibit sickling in vitro. We administered tuc...

The single- and multiple-dose pharmacokinetics of and tolerability to a new microfluidized suspension of atovaquone were studied in human immunodeficiency virus-seropositive patients with CD4 counts of < or = 200 cells per mm3 in order to define a dosing regimen for the treatment of Pneumocystis carinii pneumonia. This was an open study with groups...

1 311C90 is a novel and selective agonist at 5-HT1D receptors, with central and peripheral actions, currently in development for the acute oral treatment of migraine. 2 The pharmacokinetic and tolerability profiles of single oral doses from 1–50 mg 311C90 were investigated in 12 healthy male volunteers in a double-blind, placebo-controlled, dose-es...

Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover...