Effect of intrauterine growth pattern on serum visfatin concentrations in full-term infants at birth and at 6 months of life.

OBJECTIVE: Visfatin is a hormone discovered in fat cells and is directly related to diabetes. We aimed to investigate the relationship between intrauterine growth pattern and serum visfatin concentrations in full-term infants at birth and at 6 months of life. METHODS: Cord blood visfatin concentrations were assessed in 90 full-term neonates enrolled into; Group I: 30 appropriate for gestational age (AGA) neonates to healthy mothers, Group II: 30 intra-uterine growth restricted (IUGR) neonates, 19 were born to mothers with pre-eclampsia, Group III: 30 large for gestational age (LGA) neonates, 16 were infants of diabetic mothers (IDMs). Neonates were followed up at six months of age for visfatin concentrations. RESULTS: Cord blood visfatin concentrations were increased in IUGR compared to AGA group (p = 0.002). Cord blood visfatin concentrations were increased in LGA compared to AGA and IUGR groups (P <  0.001, P <  0.001). Cord blood visfatin concentrations were positively correlated to birth weight in AGA, LGA groups (r = 0.39, p = 0.045, r = 0.449, p = 0.013 respectively). Visfatin concentrations in neonates born to mothers with pre-eclampsia and IDMs were higher than in those born to mothers without pre-eclampsia and to non-diabetic mothers (p = 0.040, p = 0.002 respectively). At six months, serum visfatin concentrations decreased compared to cord blood visfatin concentrations in IUGR and LGA groups (p <  0.001). Levels in LGA were still higher than IUGR (p = 0.004). Serum visfatin concentrations were positively correlated to cord visfatin in IUGR neonates (r = 0.497, p = 0.005). CONCLUSION: Cord blood visfatin concentrations were increased in LGA and IUGR neonates. At six months, serum visfatin concentrations decreased compared to cord blood visfatin concentrations in LGA and IUGR groups, still higher in the former than the latter.

Factors determining headache at onset of acute ischemic stroke.

Headache is a frequent accompaniment of acute ischaemic stroke. The predisposing factors and underlying mechanisms are currently incompletely defined. We analysed prospectively collected data relevant to headache occurring at ischaemic stroke onset in consecutive patients included in the Henry Ford Hospital Stroke Data Bank. Patients with headache (HA+) and without headache (HA-) were compared for demographic factors, medical history, medications, examination findings, laboratory findings, and stroke localization and subtype. Group comparisons for categorical data were performed with chi(2) test, and for continuous variables with two-sample t-tests. Stepwise logistic regression analysis, including all variables with P<0.25, was used to define the independent predictors of onset headache. Three hundred and seventy-five patients had complete headache and clinical datasets and were included in the analysis (HA+, N=118; HA-, N=257). Multivariate analysis revealed that the independent predictors of HA+ were: infarct in the distribution of the posterior circulation [P=0.0076, odds ratio (OR) 2.15, 95% confidence interval (CI) 1.23, 3.77], absence of history of hypertension (P=0.0106, OR 0.48, 95% CI 0.27, 0.84), and treatment with warfarin at the time of the index stroke (P=0.0135, OR 4.89, 95% CI 1.39, 17.21). The occurrence of headache at onset of ischaemic stroke is determined by posterior circulation distribution of the ischaemic event, absence of history of hypertension and treatment with warfarin at the time of the index stroke. These results suggest that preserved elasticity and maintenance of the intracranial vasculature in a relaxed state, in combination with coagulation system derangements, and activation of dense perivascular afferent nerves, play a role in the pathogenesis of onset headache.

LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine.

Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, i.e. headache score improvement from moderate/severe at baseline to mild/none at 2 h. Of 45 enrolled patients, 44 patients (20M:24F; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P = 0.017 vs. placebo), 86% for sumatriptan (P < 0.01 vs. placebo) and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < 0.01 for all comparisons) on all other measures of improvement in pain and migraine associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; one mild, one severe). Fifty-three percent of patients who took sumatriptan (n = 8; seven mild, one moderate) and 31% of those who received placebo reported AEs (n = 5; four mild, one severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis.

5-HT1F receptor agonists in acute migraine treatment: a hypothesis.

Serotonin-1F receptor (5-HT1F) agonists may relieve acute migraine without vasoconstriction. We conducted a review of preclinical and clinical data that assessed the potential link between migraine and 5-HT1F activation. (i) A high correlation exists between the potency of various 5-HT1 receptor agonists in the guinea pig dural plasma protein extravasation assay and their 5-HT1F receptor binding affinity. (ii) 5-HT1F receptors are on the trigeminal system, and may participate in blocking migraine pain transmission through the trigeminal ganglion and nucleus caudalis. (iii) 5-HT1F receptors are located on glutamate-containing neurones and their activation might inhibit glutamate release; glutamate excess may play a role in migraine. (iv) Selective 5-HT1F receptor agonists (LY334370; LY344864) are effective in preclinical migraine models and are non-vasoconstrictive. (v) LY334370 is effective in acute migraine, and does not cause any symptoms/signs of coronary vasoconstriction. Preclinical experiments and clinical observations argue for a role of selective 5-HT1F agonists in migraine.

Emerging trends in the pharmacotherapy of chronic pain.

The pharmacotherapy for pain is dominated by conventional analgesics such as the opioids and the non-steroidal anti-inflammatory drugs. Recent advances in the understanding of the mechanisms of pain in general and chronic pain in particular, opened the field of analgesic therapy to newer pharmacological targets, which are aimed at improved efficacy and enhanced tolerability over conventional antipain treatments. Many novel targets are still in preclinical development, but some have made it into human trials and have shown promise. Newer anticonvulsants, new generation cyclooxygenase inhibitors, better tolerated glutamate modulators and balanced serotonin/noradrenaline re-uptake inhibitors are some targets that have shown promise in the clinic. These and other compounds that are in advanced phases of development for chronic pain are reviewed in this paper. It is hoped that the decade of pain control and research will lead us to an arsenal of effective and safe analgesics that will conquer the problem of chronic pain.

The nociceptive flexion reflex in humans -- review article.

The nociceptive flexion reflex (NFR) is a physiological, polysynaptic reflex allowing for painful stimuli to activate an appropriate withdrawal response. NFR is easily measurable in clinical setting, and is a reliable and objective tool for measurement of an individual's pain experience. An exhaustive review of the literature, covering multiple search engines, indicates that the NFR method is valuable in studying the impact of diverse pharmacological and non-pharmacological interventions on the flexion reflex, in conditions of acute pain and in healthy volunteers. More recently, the NFR method has gained particular attention as a research tool in studies of central sensitization and persistent or chronic pain.

Selective seratonin 1F (5-HT(1F)) receptor agonist LY334370 for acute migraine: a randomised controlled trial.

BACKGROUND: Triptans (5-HT(1B/1D) receptor agonists) are effective drugs for acute migraine, but the side-effect of coronary vasoconstriction restricts their use in patients who are at risk of coronary artery disease. We have studied the efficacy of LY334370, a selective serotonin 1F (5-HT(1F)) receptor agonist with preclinical efficacy and no vasoconstriction, for migraine relief. METHODS: We gave LY334370 (20, 60, or 200 mg) or placebo to 99 outpatients with moderate or severe migraine headaches in a double blind, parallel group study. We measured efficacy by sustained response, response at 2 h, pain free at 2 h, and sustained pain free. FINDINGS: The proportions of patients with defined endpoints for placebo and LY334370 20, 60, and 200 mg, respectively, were: sustained response, two of 26 (8%), three of 22 (14%), 11 of 30 (37%), and 11 of 21 (52%) (dose response p<0.001); response, five of 26 (19%), four of 22 (18%), 15 of 30 (50%), and 15 of 21 (71%) (p<0.001); pain free, one of 26 (4%), none of 22, eight of 30 (27%), and eight of 21 (38%) (p=0.001); sustained pain free, one of 26 (4%), none of 22, seven of 30 (23%), and seven of 21 (33%) (p=0.002); recurrence rates, one of five (20%), none of four, four of 15 (27%), and three of 15 (20%). More patients given LY334370 than placebo reported asthenia, somnolence, and dizziness. INTERPRETATION: Our findings show that LY334370 is effective in treatment of acute migraine through selective trigeminovascular neuronal inhibition.

Diagnosis of migraine: empirical analysis of a large clinical sample of atypical migraine (IHS 1.7) patients and proposed revision of the IHS criteria.

The International Headache Society (IHS) diagnostic criteria for headache improved the accuracy of primary headache diagnoses, including migraine. However, many migraineurs receive an 'atypical migraine' diagnosis according to the IHS nosology (IHS 1.7), indicating that they approximate but do not fully meet all IHS criteria. This study characterized and sub-classified patients with atypical migraine. Within a clinical sample of 382 headache sufferers, 83 patients met IHS criteria for 'atypical migraine'. Patients receiving the IHS 1.7 designation did not converge to form a homogeneous group. Rather, distinct and clinically relevant subgroups were empirically derived (e.g. migraine with atypical pain parameters, brief migraine, chronic migraine). The results call for revisions of the IHS diagnostic criteria for migraine that would minimize the number of patients receiving an atypical diagnosis. Revisions would include decreasing the minimum headache duration criteria from 4 h to 2 h, and developing a classification for 'chronic migraine' for migraine greater than 15 days per month. The proposed revision provides a means of diagnosing the daily and near-daily headache commonly observed in clinical populations.

Acute treatments: some blind alleys.

The introduction of sumatriptan, a selective 5-HT(1B/1D) agonist, for the treatment of migraine sparked a new era of drug research in this field. Many novel targets have since been developed, and tested in the clinic. The promise of these approaches is to deliver an anti-migraine compound with the optimal efficacy and safety profile. In this chapter, blind alleys in anti-migraine development are discussed. The failing soldiers have included the NK-1 antagonists, some second-generation 5-HT(1B/1D) agonists, CP-122,288, 4991W93, the neurosteroid ganaxolone, selective 5-HT(1F) (LY334370) and 5-HT(1D) agonists (PNU-142,633), and the endothelin-1 antagonist bosentan. Some of these promising targets failed to demonstrate clinical efficacy, while others were stopped for preclinical toxicity.

Acute treatments: future developments.

In Chapter 14, blind alleys in acute anti-migraine drug development were discussed. In this chapter, future therapies are covered. There is growing interest and support for the use of CGRP antagonists, nitric oxide synthase inhibitors, and ionotropic glutamate receptor antagonists. The hope is to strike the balance of high efficacy with minimal to no safety concern and good tolerability. Some of the targets discussed in this chapter have been in early efficacy trials and others are in first human dose stages. Large-scale efficacy and safety trials are eagerly awaited.

Comments on the failure of intensive self-regulatory treatment with chronic daily headache.

Non-pharmacological therapy of primary headache conditions including chronic daily headache (CDH) is not well-studied. Barton and Blanchard report on their experience with intensive self-regulatory treatment in a cohort of patients with CDH. This negative trial provides preliminary observations that need further investigations in controlled, adequately powered clinical study.

Transcranial magnetic stimulation confirms hyperexcitability of occipital cortex in migraine.

OBJECTIVES: We hypothesized that the hyperexcitability of occipital cortex neurons may predispose migraine subjects to develop spreading depression, the putative basis of migraine with aura (MwA). To date there is no direct physiologic correlate confirming this in patients. Accordingly, we evaluated the differences in the threshold of occipital cortex excitation between MwA patients and normal controls (C) using transcranial magnetic stimulation (TMS). METHODS: TMS was performed using the Cadwell MES 10 stimulator. A circular coil 9.5 cm in diameter was applied to the occipital scalp (7 cm above the inion). Stimulator intensity was increased in 10% increments until subjects reported visual phenomena or 100% intensity was reached. Stimulation intensity was then fine-tuned to determine the threshold at which phosphenes were just visualized. RESULTS: Eleven MwA patients, mean age 37 +/- 7 years, were compared with 11 C, mean age 37.7 +/- 7 years. The difference in the proportion of subjects with phosphene generation between MwA patients and C was significant (MwA patients 100% versus C 27.3%, p = 0.001). The mean threshold level for MwA patients was 44.2 +/- 8.6 versus 68.7 +/- 3.1 for C (p = 0.0001). All threshold levels for MwA patients were lower than the lowest threshold for C; the MwA patient with the lowest threshold had an aura after stimulation. CONCLUSIONS: The threshold for excitability of occipital cortex is lower in MwA patients compared with C. This is a direct neurophysiologic correlate for clinical observations that have indicated hyperexcitability of the occipital cortex in migraineurs.

Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. The 042 Clinical Trial Study Group.

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.

Optimizing the dose of zolmitriptan (Zomig, 311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, dose range-finding study. The 017 Clinical Trial Study Group.

This study investigated the efficacy of zolmitriptan (Zomig, formerly 311C90) in acute migraine therapy. Patients with a history of migraine were randomized in a double-blind, multicenter, placebo-controlled, dose range-finding study of oral zolmitriptan 1, 2.5, 5, or 10 mg versus placebo for the treatment of a severe or moderate migraine headache. Patients with persistent or recurrent headache 4 to 24 hours after the initial dose, who did not take escape medication, were eligible to receive a second blinded dose of either zolmitriptan or placebo. Of 1,144 patients treated, 999 evaluable patients completed the study. The headache response rates with zolmitriptan doses > or = 2.5 mg were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78% at 4 hours (all significantly superior to placebo). Also, zolmitriptan effectively relieved migraine-associated symptoms such as nausea, photophobia and phonophobia, and reduced activity impairment. Rates of headache recurrence, headache persistence, and use of escape medication were lower with zolmitriptan doses > or = 2.5 mg than with placebo. In patients with persistent or recurrent headache, a second zolmitriptan dose effectively treated both headache and nonheadache symptoms. Zolmitriptan was well tolerated, with a lower incidence of adverse events being reported with doses < or = 2.5 mg than with those > or = 5 mg. Zolmitriptan is a well tolerated and effective acute migraine therapy providing rapid relief of migraine headache within 1 hour. A clear dose-response relationship between efficacy and tolerability suggests that 2.5 mg is the optimal initial dose for the acute treatment of a migraine attack.

Cerebral blood flow in chronic posttraumatic headache.

BACKGROUND AND PURPOSE: Headache is the most common neurologic symptom following minor closed head injury. There is often a lack of objective evidence supporting an organic basis of cerebral pathology in these cases. This pilot study considers the possibility of alterations in cerebral blood flow, indicating evidence of an organic disorder in posttraumatic headache. METHODS: Regional cerebral blood flow studies of 35 patients with chronic posttraumatic headache (PTH) (International Headache Society criteria), identified retrospectively from our cerebral blood flow data base, were compared with those of 49 nonheadache controls and 92 migraineurs (Ad Hoc Committee criteria). Regional cerebral blood flow (initial slope index method) was measured using the xenon Xe 133 inhalation technique. RESULTS: Compared to migraineurs and controls, and after adjusting for differences (analysis of covariance) in baseline variables such as blood pressure, hematocrit, and PCO2, patients with PTH had: (1) significantly lower mean initial slope indices (P < 0.001, P = 0.002, respectively); (2) regional interhemispheric flow differences (rIFD), with higher distribution of regional asymmetrical probe pairs (rIFD > or = 7%: P[PTH versus control] = 0.006, P[PTH versus migraine] = 0.016: rIFD > or = 10%; P[PTH versus control] = 0.011, P[PTH versus migraine] = 0.003); and (3) more hemispheric asymmetries (P[PTH versus control] = 0.023, P[PTH versus migraine] = 0.57). Lower mean initial slope indices and hemispheric asymmetry (mean interhemispheric flow difference > or = 3.2%) predicted PTH over control (P = 0.023 and 0.002, respectively). Lower mean initial slope indices predicted PTH over migraine (P = 0.002). CONCLUSIONS: Patients with PTH have reduced regional cerebral blood flow, and regional and hemispheric asymmetries. These cerebral hemodynamic alterations support an organic basis to chronic posttraumatic headache.

Migraine prophylactic drugs: proof of efficacy, utilization and cost.

OBJECTIVES: In order to understand the pattern of utilization of migraine prophylactic drugs by US physicians, we reviewed the scientific rigor of published trials of anti-migraine medications, assessed their cost, and tested the correlation, if any, between utilization, scientific rigor and cost. MATERIALS AND METHODS: Scientific rigor of published reports. We identified all placebo-controlled, randomized, double-blind trials of migraine prophylactic agents through Medline search, major Headache textbooks and proceedings of major scientific meetings where headache-related topics are discussed. We excluded trials that did not include placebo treatment during the active phase of the study. The trials were reviewed and rated for scientific rigor using a 5-point scale (scientific score [ss]; 1 = low, 5 = good), blinded to the physicians' utilization data and cost of the drugs. Studies that did not show benefit of the active drug over placebo were scored -1 to -5, thus allowing for the reverse logic of negative studies. US physicians utilization. Neurologists and primary care physicians (PCP) completed phone-mail-phone questionnaires which inquired about first and second choices of migraine prophylaxis. These choices were averaged to obtain a weighted average percent usage of each drug. Cost. The average wholesale price (AWP) of each drug was obtained from data published by Adelman and Von Seggern, and from the Amerisource (7/9/96) catalog. STATISTICAL ANALYSIS: Spearman's correlation coefficient was used to assess the relationship between the average ss, physician use, and cost of each drug. RESULTS: Propranolol (ss = 1.44), amitriptyline (ss = 2.33) and verapamil (ss = 1.00) were the three preferred migraine prophylactic drugs by both neurologists and PCPs. Approximately 10% of neurologists said that divalproex (ss = 3.75) would be their first or second choice. The selective serotonin reuptake blockers were favored by 13.21% of PCPs. All other prophylactic drugs were felt to be first or second line of treatment by less than 10% of either neurologists or PCPs. Except for one study (ss = 1) that showed that propranolol reduced the migraine frequency by 76% over placebo, trials of the three most preferred medications failed to demonstrate that the active drug is > 50% better than placebo, i.e. the difference in headache frequency when on placebo vs active drug is > 50%. Of the drugs available in the United States, flurbiprofen and metoprolol achieved the best ss (5.00 and 4.33, respectively) but their efficacy over placebo (23% and 14-33%, respectively) and cost ($67.2 and $65.6) were unfavorable. Neurologists and PCPs chose migraine prophylaxis on the basis of scientific merit (r = 0.644, p = 0.018; r = 0.576, p = 0.05, respectively) but not cost (r = -0.254, p = 0.45; r = -0.255, p = 0.455). CONCLUSION: The three most commonly chosen migraine prophylactic agents have not been shown irrefutably to prevent migraine. Furthermore, their benefit, if any, does not exceed 50% over placebo. The well-conducted recent trials that demonstrated the efficacy of divalproex in migraine prevention are steps in the right direction of finding the "ideal migraine preventative agent". Until that drug is discovered, it is difficult to argue that one migraine prophylactic medication is superior to another and accordingly should be used as a first line of treatment.