A systematic review of qualitative research exploring patient and health professional perspectives of breakthrough cancer pain.

PURPOSE: Breakthrough cancer pain (BtCP) is a prevalent health issue which is difficult to manage. A plethora of quantitative research in this area exists. There is a paucity of research on the perspectives of health professionals and patients surrounding domains impacting effective treatment, including definitions of BtCP, treatment, and education opportunities. This review aims to identify and synthesize the extent of qualitative research exploring health professional and patient perspectives of BtCP. METHODS: A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach was undertaken. The approach was registered with Prospero. MEDLINE, EMBASE, and Web of Science were searched for peer-reviewed literature published any date prior to May 19, 2022. Eligible sources must have considered health professional and/or patient perspectives of BtCP. A narrative synthesis approach was utilized. RESULTS: Three sources met the review criteria. One source explored nurse perspectives, while two sources explored patient perspectives. Study quality was moderate to high. Overlapping themes across the three studies included communication, defining BtCP, impact of BtCP, management of BtCP, perceptions of BtCP, analgesia and pain relief, and training and professional development. CONCLUSION: Given limited research investigating clinician and patient perspectives of BtCP, a rich understanding informed by exploratory qualitative methods around identification, best management strategies, professional development, and factors promoting and inhibiting best practice remains unclear. Further qualitative inquiry is warranted, and it is expected such research will inform BtCP clinical guidelines.

Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation.

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 also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(-1)), morphine (20 mg kg(-1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (-9.5 s, P<0.01 and -7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.

Pharmacokinetics and unexpected safety issues of LBM415, a novel oral peptide deformylase inhibitor.

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 administered at dosages ranging from 100 mg q.d. to 1,000 mg t.i.d. for 11 days. Dose-proportional pharmacokinetics was observed, with a peak plasma concentration (C(max)) of 17.85 ± 5.96 µg/ml at 1,000 mg b.i.d. (the projected therapeutic dose) and an area under the concentration-time curve (AUC)(0-24h) of 36.83 ± 10.36 µg/ml·h. The half-life, as determined after a 1,000-mg single dose, was 2.18 ± 0.61 h. The compound was well tolerated at low doses, but at the highest dose, 1,000 mg t.i.d., reversible cyanosis and low oxygen saturation, attributable to methemoglobinemia, were detected on day 11. Oxygen saturation was as low as 88% in one subject on day 11.

Central mechanisms of stress-induced headache.

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 sensitivity in an experimental model of stress-induced headache in CTTH sufferers. Such examinations have not been reported to date. We measured pericranial muscle tenderness and pain thresholds at the finger, head and shoulder in 23 CTTH sufferers (CTH-S) and 25 healthy control subjects (CNT) exposed to an hour-long stressful mental task, and in 23 CTTH sufferers exposed to an hour-long neutral condition (CTH-N). Headache developed in 91% of CTH-S, 4% of CNT, and 17% of CTH-N subjects. Headache sufferers had increased muscle tenderness and reduced pain thresholds compared with healthy controls. During the task, muscle tenderness increased and pain thresholds decreased in the CTH-S group compared with CTH-N and CNT groups. Pre-task muscle tenderness and reduction in pain threshold during task were predictive of the development and intensity of headache following task. The main findings are that stress induced a headache in CTTH sufferers, and this was associated with pre-task muscle tenderness and stress-induced reduction in pain thresholds. The results support the hypothesis that stress triggers CTTH through hyperalgesic effects on already increased pain sensitivity in CTTH sufferers, reducing the threshold to noxious input from pericranial structures.

Reliability of temporal summation and diffuse noxious inhibitory control.

BACKGROUND: 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 DNIC of TS to mechanical stimuli, has not been reported to date. Such devices may offer a simpler method than current techniques for inducing TS and DNIC, affording assessment at more anatomical locations and in more varied research settings. METHOD: The present study assessed the test-retest reliability of TS and DNIC using the above techniques. Sex differences on these measures were also investigated. RESULTS: Repeated measures ANOVA indicated successful induction of TS and DNIC, with no significant differences across test-retest occasions. Sex effects were not significant for any measure or interaction. Intraclass correlations indicated high test-retest reliability for all measures; however, there was large interindividual variation between test and retest measurements. CONCLUSION: The present results indicate acceptable within-session test-retest reliability of TS and DNIC. The results support the possibility of future experimental studies examining factors affecting TS and DNIC.

Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease.

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 use in the treatment of multiple sclerosis, neuropathic pain, and in the improved efficacy and safety of opioids by decreasing opioid tolerance, withdrawal and reinforcement. Its suitable pharmacokinetics and generally good tolerability make it a promising potential treatment for these conditions.

A placebo-controlled pharmacodynamic and pharmacokinetic interaction study between tamsulosin and acenocoumarol.

AIM: To evaluate pharmacokinetic and pharmacodynamic interactions between tamsulosin and acenocoumarol. METHODS: 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. RESULTS: The ratios (point estimates (90% confidence intervals)) of values in the presence and absence of tamsulosin were: AUCPT 1.01 (0.98, 1.03); maximum prothrombin time (Ptmax) 0.99 (0.94, 1.05); AUC (R)-acenocoumarol 1.02 (0.90, 1.16), and AUC (S)-acenocoumarol 1.03 (0.89, 1.20). Both combinations, tamsulosin and placebo with acenocoumarol, were well-tolerated. CONCLUSIONS: Multiple doses of tamsulosin had no effect on the pharmacokinetics or pharmacodynamics of a single high dose of acenocoumarol.

The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men.

AIMS/HYPOTHESIS: 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. NN2211 is a fatty acid derivative of GLP-1, which pre-clinically has shown a protracted pharmacokinetic profile, while maintaining its biological activity. This study aimed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of NN2211 in healthy male subjects following seven days treatment. METHODS: In a double-blind, randomized, dose escalation, placebo controlled study, healthy male subjects were enrolled at five consecutive dose levels of NN2211 (1.25, 5.0, 7.5, 10.0, 12.5 microg/kg). Six subjects were allocated at random at each dose level to active or placebo treatment with a ratio of 2:1. Dosing with NN2211 was performed on day 1, and days 5-11. The 84-h pharmacokinetics and 24-h glucose and insulin profiles were assessed on day 1 and day 11. RESULTS: Following s. c. administration the half-life of NN2211 was found to be 12.6 +/- 1.1 h, with a subsequent accumulation index after a daily dose for seven days of 1.4-1.5. There were dose-proportional increases in exposure (AUC and C(max)) with increasing doses. Overall, there were no statistically significant differences from placebo in the 24-h glucose and insulin profiles. In subjects treated with NN2211 rather than placebo, there was a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system. There were no serious adverse events but three subjects were nonetheless withdrawn because of dizziness, fever and nausea. There were no clinically relevant changes in vital signs, ECG parameters, physical examination or safety laboratory parameters. A significantly lower diuresis was observed in the actively treated subjects, without a clinically relevant change in packed cell volume. CONCLUSIONS/INTERPRETATION: This study shows NN2211 has a pharmacokinetic profile supporting a daily dose in human beings, but also that subjects treated with NN2211 rather than placebo, had a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system.

Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir.

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 valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C(max)) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C(max) by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.

Lack of effect of citalopram on the steady-state pharmacokinetics of carbamazepine in healthy male subjects.

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 steady-state pharmacokinetics of carbamazepine was evaluated in 12 healthy male subjects. Carbamazepine was administered orally twice daily as a 100-mg dose from days 1 to 3, as a 200-mg dose twice a day from days 4 to 6, and as a 400-mg dose once a day from days 7 to 35. Citalopram, 40 mg, administered once daily, was added to the carbamazepine-dosing regimen on days 22 to 35. The steady-state plasma concentration profiles of carbamazepine and its active metabolite, carbamazepine 10,11-epoxide, on day 35 (in the presence of steady-state levels of citalopram) were compared to the corresponding carbamazepine and epoxide metabolite profiles on day 21 (in the absence of citalopram). No significant differences were found between mean steady-state values for maximal drug concentration, area under the curve, or time of maximal concentration values for carbamazepine and its epoxide metabolite before and after the addition of citalopram to the daily carbamazepine dosing regimen (p > 0.05). These results suggest that the use of citalopram in patients stabilized on carbamazepine should not produce clinically significant changes in carbamazepine plasma concentrations.

Influence of cirrhosis on lamotrigine pharmacokinetics.

AIMS: 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. METHODS: Thirty-six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. RESULTS: The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child-Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child-Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half-life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). CONCLUSIONS: Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child-Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.

Why do we still not know whether refractive error causes headaches? Towards a framework for evidence based practice.

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 support of this position. We identify four serious methodological and theoretical difficulties with studies to date, which currently render it impossible to assess the relationship between refractive error and headache. The provision by the International Headache Society of the diagnostic category "headache associated with refractive error" is called into question. Five research questions are posited in the form of a framework for the development of evidence-based practice in optometry and the treatment of headache.

Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsorption.

AIMS: 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 the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. METHODS: This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c. RESULTS: All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. CONCLUSIONS: Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.

Cortical hyperexcitability is cortical under-inhibition: evidence from a novel functional test of migraine patients.

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 technique, derived from basic research in vision science, to examine specific deficits of inhibitory processing in primary visual cortex. The technique is termed the metacontrast test, and it examines visual masking under highly specified conditions. In Study 1, 12 migraine with aura patients (MA), 12 age-matched migraine without aura patients (MO) and 12 age- and sex-matched headache-free control subjects (C) were compared using the metacontrast test. MA patients were significantly less susceptible to visual masking in the metacontrast test than both MO and C groups: this result is highly consistent with a deficit in cortical inhibitory processing in MA patients. Study 2 examined MA patients taking a variety of migraine prophylactics, again using the metacontrast test. Test results normalized in those MA patients taking sodium valproate, but not in those taking other prophylactics. Sodium valproate is a GABA-A agonist that is known to cross the blood-brain barrier: GABA-ergic networks act as the primary inhibitory mechanism in visual cortex. Taken together, the results of these studies argue that cortical hyperexcitability, at least in MA patients, is likely to be a result of deficient intracortical inhibitory processes.

Bioequivalence between ready-to-use recombinant human growth hormone (rhGH) in liquid formulation and rhGH for reconstitution.

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 dose of 2.5 mg rhGH/m(2)body surface area or as a fixed dose of 5 mg rhGH. Endogenous hGH release was suppressed by a continuous somatostatin infusion. The 90% confidence intervals for the estimated mean ratios of AUC(0-24 h)and C(max)(analysis of variance) between all products were within 80-125% in both studies. Also, no significant differences (P> 0.05; Wilcoxon signed rank test) were found between t(max)for the liquid formulations of rhGH. These data demonstrate that there is bioequivalence between rhGH for reconstitution and the liquid formulations of rhGH.

Effect of citalopram on plasma levels of oral theophylline.

BACKGROUND: 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 metabolized by CYP1A2; however, the extent to which citalopram interacts with this isozyme in vivo is not known. OBJECTIVE: This study was conducted to investigate whether citalopram alters plasma levels of oral theophylline. METHODS: In an open-label, multiple-dose study, healthy nonsmoking volunteers 18 to 45 years of age were administered a single oral dose of theophylline (300 mg) on day 1. Beginning on day 3, citalopram 40 mg was administered daily through day 24 to achieve steady-state plasma levels. On day 23 a single oral dose of theophylline 300 mg was coadministered with citalopram 40 mg. Fasting plasma levels of theophylline were measured on day 1 (in the absence of citalopram) and on day 23 (in the presence of steady-state plasma concentrations of citalopram) periodically for 36 hours. RESULTS: Thirteen subjects (8 men and 5 women) participated; all completed the study. One subject was not included in the pharmacokinetic calculations. Citalopram treatment had no effect on the pharmacokinetic characteristics of theophylline. CONCLUSIONS: Citalopram dosing to steady state did not inhibit or induce the metabolism of theophylline in this population of healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with citalopram.

Simultaneous investigation of indinavir nonlinear pharmacokinetics and bioavailability in healthy volunteers using stable isotope labeling technique: study design and model-independent data analysis.

Indinavir follows nonlinear pharmacokinetics upon oral administration at clinical doses. A study employing the stable isotope administration technique in a three-treatment design was conducted to identify the source of the nonlinearity and to determine the dose-dependency of systemic bioavailability. In treatment A, 400 mg of unlabeled indinavir (D0) was coadministered orally with 16 mg of a hexadeutero analogue of indinavir (D6) intravenously. In treatment B, 800 mg of D0 po was coadministered with 16 mg of D6 intravenously. In treatment C, 16 mg of iv D6 was infused concurrently with 16 mg iv of D0. Plasma concentrations of D0 and D6 were determined by an LC/MS/MS assay method. Concentrations of indinavir in plasma increased greater than dose-proportionally over the 400- to 800-mg dose range. No meaningful kinetic isotope effects were found in treatment C. Plasma concentrations of D6 were dependent on the coadministered D0-indinavir dose and were lowest in treatment C, higher in treatment A, and highest in treatment B. The bioavailability of indinavir was high (60-65%) and comparable between the 400- and 800-mg doses. There was a significant contribution of nonlinear kinetics in the systemic circulation to the observed disproportional increase in plasma concentrations following oral dosing. The high bioavailability at clinically relevant doses suggests a high degree of saturation of first-pass metabolism. These results further demonstrate that the concomitant administration technique in combination with the LC/MS/MS method can provide a realistic and reliable means of elucidating important pharmacokinetic properties of drug candidates during product development.

The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women.

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 during a randomized, double-blind, placebo-controlled study. Blood pressure, heart rate, ECG, and central nervous system effects were monitored, and pharmacokinetic parameters of zolmitriptan and its metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had little effect on systolic blood pressure in the young adults. In the elderly, mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg higher in both age groups. These changes were transient. Postural changes in blood pressure were unaffected. There was a dose-related increase in sedation, but the magnitude of the effects was small. Mean observed peak plasma concentration (Cmax) and area under the plasma concentration-time profile [AUC(0-infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in both age groups but higher in young women than in young men. Metabolite/parent ratios probably the result of greater first-pass metabolism in young men. Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to 2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N-oxide, and the indole acetic acid metabolites were higher in the elderly, associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well tolerated, with an effect of age on its effects on blood pressure and the pharmacokinetics of its metabolites. The data suggest no need for dose adjustment for age. In young subjects, concentrations were higher in women than in men, but the differences were insufficient to justify dosage adjustment.

Lack of an effect of zolmitriptan (Zomig, 311C90) on psychometric task performance: results of a placebo-controlled study in healthy volunteers.

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 therapeutic dose), zolmitriptan can cause sedation; therefore, a study was designed to examine the dose-response. A double-blind, randomized, placebo-controlled, six-limb crossover study in 13 healthy volunteers compared the effects of single oral doses of zolmitriptan (5, 10, 15 or 20 mg) and lorazepam (2 mg) on various psychometric tests. Zolmitriptan doses less than 20 mg had no statistically significant effects on choice reaction time, the Stroop test, visual analog scale (VAS) assessments of physical sedation, tranquilization and other types of feelings, the logical reasoning test or the adaptive tracking test. There was a mild transient increase in the subjective assessment on VAS of mental sedation which was dose related and occurred mainly with the highest zolmitriptan dose and were not reflected in objective measures of drug effects. In contrast, lorazepam (used as a positive control) was associated with statistically significant impairment in all tests (except tranquilization) for up to 10 h after dosing. The results demonstrate that therapeutic doses of zolmitriptan are unlikely to cause clinically significant impairment in psychometric performance.