Biomedical subjects

Giorgio Sandrini

Publications and source records attributed to Giorgio Sandrini.

At least 19 recordsLinked to original sources

PubMed2007

Use of the sustained pain-free plus no adverse events endpoint in clinical trials of triptans in acute migraine.

OBJECTIVE: To assess the relationship between the sustained pain free (SPF) and adverse event (AE) rates associated with six oral serotonin 5-HT(1B/1D) receptor agonists (triptans) used for the treatment of acute migraine, employing data from a previous meta-analysis (that included almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan, but not frovatriptan) in order to provide a rationale for the use of the rate of patients who are SPF plus no AE (SNAE) as an endpoint in trials of medications for acute migraine. BACKGROUND: The attributes of drug treatment for acute migraine that are most important to people who experience them are complete pain relief, lack of recurrence, rapid onset and lack of AEs. The endpoints used to assess therapy for acute migraine do not always address these elements. METHODS: The relationship between SPF and AE rates was explored using nonparametric regression techniques, and the box-plot method was used to identify outliers. The estimated SNAE rate for each triptan was calculated with and without assuming independence between efficacy and tolerability. RESULTS: At the level of the individual agent, there was a significant relationship between the efficacy and tolerability of each triptan, with the exception of almotriptan 12.5 mg, which had an AE rate approximately 30% lower than would be expected, and eletriptan 20 mg, which had an AE rate approximately 20% higher than would be expected, on the basis of their efficacy. Almotriptan 12.5 mg and eletriptan 20 mg had the highest and lowest base-case values for SNAE, respectively, and both qualified statistically as outliers to the distribution of SNAE values obtained with the other triptans. The probability that each triptan was superior to the reference agent (sumatriptan 100 mg) in terms of SNAE was calculated across all possible values (at the level of the individual patient) for the relationship between efficacy and tolerability. Again, almotriptan 12.5 mg and eletriptan 20 mg had the highest and lowest values for their SNAE rates, respectively, and almotriptan 12.5 mg qualified statistically as an outlier from the distribution of the probabilities obtained for the other triptans. CONCLUSION: This analysis determined that higher SPF rates were strongly associated with higher AE rates, with the notable exception of almotriptan 12.5 mg, which had a lower than expected AE rate, resulting in the highest SNAE rate of the included triptans and doses. SNAE is a useful measure that can be used to discriminate between therapies and this endpoint incorporates the attributes that are most relevant to patient satisfaction with treatment. We recommend calculation of the SNAE rate at the level of the individual patient in future clinical trials of medication for the treatment of acute migraine to facilitate selection of a treatment for acute migraine that offers the best chance for effective management.

Acute Disease↗

PubMed2006

Kinematic and electromyographic study of the nociceptive withdrawal reflex in the upper limbs during rest and movement.

This study set out to evaluate nociceptive withdrawal reflex (NWR) excitability and the corresponding mechanical response in the upper limbs during rest and movement. We used a three-dimensional motion analysis system and a surface EMG system to record, in 10 healthy subjects, the NWR in eight upper limb muscles and the corresponding mechanical response in two experimental conditions: rest and movement (reaching for, picking up, and moving a cylinder). The NWR was elicited through stimulation of the index finger with trains of pulses delivered at multiples of the pain threshold (PT). We correlated movement types (reach-to-grasp, grasp-and-lift), movement phases (acceleration, deceleration), and muscle activity types (shortening, lengthening, isometric) with the presence/absence of the NWR (reflex-muscle pattern), with NWR size values, and with the mechanical responses. At rest, when the stimulus was delivered at 4x PT, the NWR was present, in all muscles, in >90% of trials, and the mechanical response consisted of wrist adduction, elbow flexion, and shoulder anteflexion. At this stimulus intensity, during movement, the reflex-muscle pattern, reflex size, and mechanical responses were closely modulated by movement type and phase and by muscle activity type. We did not find, during movement, significant correlations with the level of EMG background activity. Our findings suggest that a complex functional adaptation of the spinal cord plays a role in modulating the NWR in the transition from rest to movement and during voluntary arm movement freely performed in three-dimensional space. Study of the upper limb NWR may provide a window onto the spinal neural control mechanisms operating during movement.

Adaptation, Physiological↗

PubMed2006

Prostaglandins, glutamate and nitric oxide synthase mediate nitroglycerin-induced hyperalgesia in the formalin test.

Increasing evidence supports a possible role for nitric oxide (NO) in the transmission of pain signals and in the development of central mechanisms of hyperalgesia. Previously, we have shown that nitroglycerin, an NO donor, is able to induce a long-lasting hyperalgesic state in rats. Nitroglycerin-induced hyperalgesia can be detected as an increase in the nociceptive behavior evoked by the formalin test. In the present study we investigated the possible mediators in the nitroglycerin-induced hyperalgesic state. Male Sprague-Dawley rats were injected with nitroglycerin and pretreated with indomethacin, 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate (MK-801) or N(omega)-nitro-L-arginine methyl ester (L-NAME). The results obtained showed that inhibition of prostaglandins or NO synthesis prevents nitroglycerin-induced hyperalgesia in Phase II of the formalin test. A similar inhibitory effect was also observed following pretreatment with the glutamate antagonist MK801. The present findings point to the role of prostaglandins, NO synthesis and glutamate activity in the induction of nitroglycerin-induced hyperalgesia.

Animals↗

PubMed2006

Botulinum toxin and neuromotor rehabilitation: An integrated approach to idiopathic cervical dystonia.

Currently, the best treatment option for idiopathic cervical dystonia (ICD) is injection of botulinum toxin (BTX) into the affected muscles, whereas rehabilitative approaches have given disappointing results. We evaluated whether the association of an ad hoc rehabilitative program may improve the clinical efficacy of BTX treatment in a single-center, cross-over, controlled study. Forty patients with ICD were randomly assigned to two different treatment groups: (1) BTX type A (BTX-A) plus a specific program of physical therapy (BTX-PT) or (2) BTX-A alone (BTX-0). Patients in the BTX-PT group showed a longer duration of the clinical benefit (118.8 vs. 99.1 days) and needed a lower dose of BTX at reinjection (284.5 vs. 325.5 units). In addition, they showed more marked reductions in their disability in activities of daily living (-9.7 vs. -4.85 points) and subjective pain (-13.35 vs. 6.95 points) scores. Association of BTX-A therapy with a specific program of physical therapy may improve ICD treatment outcome.

Activities of Daily Living↗

PubMed2006

Uncommon primary headaches.

PURPOSE OF REVIEW: The new International Classification of Headache Disorders was recently published by the International Headache Society. Several uncommon primary headaches, including some new clinical entities (e.g. hypnic headache), were included in the section on 'Cluster headache and other trigeminal autonomic neuralgias' and 'Other primary headaches'. The recent classification offers an interesting opportunity to evaluate the clinical role and to discuss the mechanisms of some of the more relevant uncommon primary headaches. RECENT FINDINGS: Due to the low incidence of these uncommon headache forms, their diagnostic criteria, pathogenetic mechanisms and therapy are still debated. Differential diagnosis versus secondary headaches is also a crucial issue. In this review, some of the most important uncommon primary headaches are discussed in light of the most recent contributions to the literature. SUMMARY: The review focuses on the update of the main uncommon primary headaches, intending to clarify some controversial points and to indicate some headlines for further research.

Diagnosis, Differential↗

PubMed2006

Eletriptan: a review and new perspectives.

Eletriptan is a second-generation 5-hydroxytryptamine(1B/1D) receptor agonist, or triptan, indicated for the acute treatment of migraine. Eletriptan has a favorable pharmacokinetic and pharmacodynamic profile expressed by bioavailability, half-life and high selectivity for cranial arteries. It has been shown to be effective and well tolerated in a wide preapproval development program, which included over 11,000 patients and treated more than 74,000 migraine attacks. In clinical trials, eletriptan has been demonstrated to be one of the most effective oral therapies for the acute treatment of migraine and has shown a very high safety and tolerability profile across the studies performed. Eletriptan showed the most favorable cost-effectiveness profile when compared with other agents in its class.

Animals↗

PubMed2005

The lower limb flexion reflex in humans.

The flexion or flexor reflex (FR) recorded in the lower limbs in humans (LLFR) is a widely investigated neurophysiological tool. It is a polysynaptic and multisegmental spinal response that produces a withdrawal of the stimulated limb and resembles (having several features in common) the hind-paw FR in animals. The FR, in both animals and humans, is mediated by a complex circuitry modulated at spinal and supraspinal level. At rest, the LLFR (usually obtained by stimulating the sural/tibial nerve and by recording from the biceps femoris/tibial anterior muscle) appears as a double burst composed of an early, inconstantly present component, called the RII reflex, and a late, larger and stable component, called the RIII reflex. Numerous studies have shown that the afferents mediating the RII reflex are conveyed by large-diameter, low-threshold, non-nociceptive A-beta fibers, and those mediating the RIII reflex by small-diameter, high-threshold nociceptive A-delta fibers. However, several afferents, including nociceptive and non-nociceptive fibers from skin and muscles, have been found to contribute to LLFR activation. Since the threshold of the RIII reflex has been shown to correspond to the pain threshold and the size of the reflex to be related to the level of pain perception, it has been suggested that the RIII reflex might constitute a useful tool to investigate pain processing at spinal and supraspinal level, pharmacological modulation and pathological pain conditions. As stated in EFNS guidelines, the RIII reflex is the most widely used of all the nociceptive reflexes, and appears to be the most reliable in the assessment of treatment efficacy. However, the RIII reflex use in the clinical evaluation of neuropathic pain is still limited. In addition to its nocifensive function, the LLFR seems to be linked to posture and locomotion. This may be explained by the fact that its neuronal circuitry, made up of a complex pool of interneurons, is interposed in motor control and, during movements, receives both peripheral afferents (flexion reflex afferents, FRAs) and descending commands, forming a multisensorial feedback mechanism and projecting the output to motoneurons. LLFR excitability, mediated by this complex circuitry, is finely modulated in a state- and phase-dependent manner, rather as we observe in the FR in animal models. Several studies have demonstrated that LLFR excitability may be influenced by numerous physiological conditions (menstrual cycle, stress, attention, sleep and so on) and pathological states (spinal lesions, spasticity, Wallenberg's syndrome, fibromyalgia, headaches and so on). Finally, the LLFR is modulated by several drugs and neurotransmitters. In summary, study of the LLFR in humans has proved to be an interesting functional window onto the spinal and supraspinal mechanisms of pain processing and onto the spinal neural control mechanisms operating during posture and locomotion.

Electric Stimulation↗

PubMed2005

Comparative analysis of the neuronal activation and cardiovascular effects of nitroglycerin, sodium nitroprusside and L-arginine.

In this study, we compare the biological effects, Fos expression and cardiovascular responses induced in the rat, of different nitric oxide modulators (nitroglycerin, sodium nitroprusside and L-arginine). Nitroglycerin and sodium nitroprusside induced a similar pattern of neuronal activation in several areas, which include the paraventricular and supraoptic nuclei of the hypothalamus, central nucleus of the amygdala, parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius. However, only nitroglycerin activated the periaqueductal grey and nucleus trigeminalis caudalis. L-arginine-induced neuronal activation was restricted to the paraventricular and supraoptic nuclei of the hypothalamus. As regards cardiovascular effect, both nitroglycerin and sodium nitroprusside induced moderate hypotension (nitroglycerin: -23.3%, sodium nitroprusside: -24.3%) that lasted 40 min in the case of sodium nitroprusside and 80 min in the case of nitroglycerin. L-arginine did not significantly influence blood pressure. These data suggest that nitroglycerin, sodium nitroprusside and L-arginine are associated with different biological effects on both the central nervous system and the cardiovascular system. Of the NO-related drugs tested in this study, only nitroglycerin confirmed its ability to activate brainstem areas implicated in nociception.

Analysis of Variance↗

PubMed2005

Activation of the transcription factor NF-kappaB in the nucleus trigeminalis caudalis in an animal model of migraine.

The infusion of nitroglycerin (NTG) induces an inflammatory state in perivascular meningeal tissues of rat via the activation, inter alia, of nuclear factor kappa B (NF-kappaB). This phenomenon has been related to the mechanisms involved in the pathophysiology of migraine, a common neurovascular disorder. In the present study, we sought to elucidate whether NF-kappaB activation might have a role in the determinism of migraine attacks also at the neuronal level. Therefore, we investigated the transcriptional activity of NF-kappaB in the brainstem of rats systemically injected with NTG and killed 4h later. Activation of NF-kappaB in brain areas was detected by means of both the immunohistochemical technique and the Western blot analysis. A significant increase of nuclear immunostaining of p65, an indicator of NF-kappaB activation, was detected in lamina I and II of nucleus trigeminalis caudalis in rats injected with NTG when compared with the control group. Western blot analysis confirmed the activation of the NF-kappaB pathway showing an increase in the optical density of p65 in nuclear extracts of lower brainstem of rats injected with the nitric oxide (NO) donor. The present study contributes to expand on our understanding of the complex mechanisms by which NTG may trigger migraine-like headaches in migraineurs. Furthermore, these findings pave the way to new bio-molecular and pharmacological avenues for the development of innovative migraine therapies.

Animals↗

PubMed2005

Neurophysiological approach to central pain modulation in primary headaches.

The study of CNS pain-modulating pathways has led to important discoveries about the role of central nociceptive structures such as PAG and hypothalamus in the pathophysiology of episodic and chronic primary headaches. Functional neuroimaging studies have revealed that primary headaches are characterised by different patterns of activation of central pain modulatory structures. A future model of headache pathophysiology investigating the contribution of CNS pain-modulating pathways will probably increase our understanding of pain processing in primary headaches. Herein we review the neurophysiological approaches to assess central pain modulation in primary headaches with emphasis on the diffuse noxious inhibitory control, a form of endogenous pain inhibition. In addition, patients' data will be presented that highlights the utility of such methods for primary headache's pathophysiology and clinical monitoring.

Headache↗

PubMed2005

Patients with headache and functional dyspepsia present meal-induced hypersensitivity of the stomach.

Headache is a frequent feature of functional gastrointestinal disorders but there is no data on the responsible pathophysiological mechanism. The aim of this study was to verify whether alteration of post-prandial gastric tone or sensitivity might explain this association. Fourteen patients affected by functional dyspepsia (7 migraine without aura) and 7 healthy volunteers (HV) underwent gastric tone measurement in fasting condition and after the administration of a liquid meal by barostat. Gastric volume (GV) and accommodation were calculated as difference between mean post-prandial and mean fasting volume. Mean postprandial GV increase and fasting perception and discomfort threshold (DTh) were similar among the 3 groups. DTh after meal was lower in dyspeptic headache patients than in HV and dyspeptic without headache patients. Patients with migraine and functional dyspepsia may be characterised by meal-induced hypersensitivity of the stomach.

Adult↗

PubMed2004

Topiramate in migraine prophylaxis--results from a placebo-controlled trial with propranolol as an active control.

Topiramate (TPM) has shown efficacy in migraine prophylaxis in two large placebo-controlled, dose-ranging trials. We conducted a randomised, double-blind, multicentre trial to evaluate the efficacy and safety of two doses of topiramate vs placebo for migraine prophylaxis, with propranolol (PROP) as an active control. Subjects with episodic migraine with and without aura were randomised to TPM 100 mg/d, TPM 200 mg/d, PROP 160 mg/d (active control), or placebo. The primary efficacy measure was the change in mean monthly migraine frequency from the baseline phase relative to the double-blind treatment phase. Five hundred and seventy-five subjects were enrolled from 61 centres in 13 countries. TPM 100 mg/d was superior to placebo as measured by reduction in monthly migraine frequency, overall 50% responder rate, reduction in monthly migraine days, and reduction in the rate of daily rescue medication use. The TPM 100 mg/d and PROP groups were similar with respect to reductions in migraine frequency, responder rate, migraine days, and daily rescue medication usage. TPM 100 mg/d was better tolerated than TPM 200 mg/d, and was generally comparable to PROP. No unusual or unexpected safety risks emerged. These findings demonstrate that TPM 100 mg/d is effective in migraine prophylaxis. TPM 100 mg/d and PROP 160 mg/d exhibited similar efficacy profiles.

Adult↗

PubMed2004

Muscle MRI in adult-onset acid maltase deficiency.

We report the spectrum of muscle involvement on magnetic resonance imaging in 11 patients with a molecularly confirmed diagnosis of adult-onset acid maltase deficiency at different clinical stages. Muscle magnetic resonance imaging showed a selective progressive pattern of muscle involvement with a constant involvement of the adductor magnus and semimembranosus at the early stage of the disease and a later fatty infiltration of the long head of the biceps femoris, semitendinosus and of the anterior thigh muscles. In the advanced phases a selective sparing of sartorius, rectus, and gracilis muscles and peripheral portions of the vastus lateralis was also evident. Muscle strength and magnetic resonance imaging findings were positively correlated. The results suggest that muscle magnetic resonance imaging may provide valuable diagnostic guidance for the assessment of accurate selective muscular involvement in acid maltase deficiency and may help monitor the progression of the disorder. Further control studies in a larger cohort are needed to evaluate the specificity of these findings.

Adult↗

PubMed2004

Effects of diffuse noxious inhibitory controls on temporal summation of the RIII reflex in humans.

The aim of this study was to investigate the effects of diffuse noxious inhibitory controls (DNICs) on the temporal summation of the nociceptive flexion reflex (RIII reflex) in humans. Recordings were obtained from 36 healthy adults (16 M, 20 F), and the area and temporal summation threshold (TST) of the RIII reflex were measured. The subjective intensity of the painful sensation was rated on an 11-point visual analogue scale (VAS). Neurophysiological and VAS measurements were recorded after activation of DNICs by means of the cold pressor test (CPT), which involved immersing the hand in cold water (2-4 degrees C). A slight significant lower TST was found in the females versus the males. In all the subjects, the CPT induced a significant TST increase and RIII area reduction compared with the control session. The VAS results paralleled those of the RIII reflex area and TST. During the CPT, a significant difference in the percentage TST increase emerged between females and males, being lower in the former. Similarly, we found a significantly lower percentage reduction of the RIII area in women than in men during the CPT. To summarize, activation of DNICs through the CPT significantly increased the TST of the RIII reflex in healthy subjects. This inhibitory effect was gender-specific. Whereas other findings are based on psychophysical evaluations, the results of this experimental study provide an objective neurophysiological demonstration that DNICs attenuate temporal summation in humans and confirm the presence of significant differences in pain modulation mechanisms between men and women.

Adult↗

PubMed2003

Nitroglycerin induces hyperalgesia in rats--a time-course study.

Nitroglycerin is a nitric oxide (NO) donor which activates nuclei involved in nociceptive transmission following systemic administration. The effect of nitroglycerin on the nociceptive threshold was studied in rats by means of two experimental tests that explore different modalities of pain: the tail-flick test and the formalin test. Nitroglycerin induced a significant reduction in the latency of the tail flick 2 and 4 h after its administration. Similarly, formalin-induced pain-related behaviour increased significantly 2 and 4 h after nitroglycerin administration.

Animals↗

PubMed2003

Tolerability of the triptans: clinical implications.

The triptans represent a relatively new class of compounds effective in the treatment of migraine. The safety and tolerability of these drugs have been extensively investigated since the first triptan (sumatriptan) became commercially available. A report on a very large population of patients tested during clinical trials and in postmarketing studies, confirms that these drugs are safe and well tolerated when correctly used. Adverse events are frequently reported, but are usually mild and only a few patients discontinue therapy because of them. These adverse events include, in particular, the so-called 'triptan symptoms' (tingling, sensation of warmth, etc.). The exact mechanism of chest symptoms reported by 20% of patients with migraine treated with triptans remains unclear, but are exceptionally related to a cardiac mechanism. CNS adverse events (i.e. somnolence) are also reported, but it is a matter of debate whether they are related to the pharmacological properties (i.e. lipophilicity) of the drug or are symptoms of the disease itself. The potential risk for drug overuse must be taken into account when the triptans are given to patients with a high frequency of migraine attacks. Clinical interaction of triptans with other drugs metabolised in the liver may theoretically influence the incidence of adverse events, but there is little evidence to support this assumption. There is no evidence of a teratogenic risk of triptans in pregnant women taking these drugs.

Brain↗

PubMed2003

Central components of the analgesic/antihyperalgesic effect of nimesulide: studies in animal models of pain and hyperalgesia.

UNLABELLED: The analgesic action of NSAIDs has been attributed to the peripheral inhibition of prostaglandin synthesis via the blockade of the enzyme cyclo-oxygenase (COX) and prevention of bradykinin and cytokine-induced hyperalgesia via inhibition of the release of tumour necrosis factor-alpha. However, it is becoming increasingly evident that NSAIDs exert their analgesic effect through several mechanisms. Recent data suggest that significant expression of COX-2 is found in the central nervous system, where COX-2 seems to have, together with nitric oxide, an important role in spinal nociceptive transmission. Nitroglycerin is a nitric oxide donor and induces a hyperalgesic state, partially mediated by central mechanisms. Nimesulide is a preferential COX-2 inhibitor widely used to treat pain. In this study, we evaluated the analgesic effect of nimesulide in several animal models of pain, intending to provide additional information on the characteristics of the analgesic effect of nimesulide, with specific focus on a possible central component. STUDY DESIGN: Nimesulide was compared with vehicle in groups of 4-10 rats that were randomly tested with different models of pain. The experimental design also included study of the effect of nimesulide upon nitroglycerin-induced neuronal activation at central sites. Analysis of variance was used to evaluate the influence of time and treatments. Differences between groups at specific time-points were analysed by post-hoc t-test. A probability level of less than 5% was regarded as significant. METHODS: The analgesic effect of nimesulide (or vehicle) was evaluated in male Sprague-Dawley rats. The animals underwent tail-flick and formalin tests, both performed in baseline conditions and after nitroglycerin-induced hyperalgesia. Two separate groups of rats were treated with nitroglycerin alone or nimesulide followed by nitroglycerin, and their brains were processed for immunocytochemical detection of Fos protein, a marker of neuronal activation. RESULTS: Nimesulide showed a significant analgesic effect in both the tail-flick and the formalin tests in baseline conditions. In addition, the drug proved effective in counteracting nitroglycerin-induced hyperalgesia in both tests. Brain mapping of nuclei activated by the administration of nitroglycerin showed that nimesulide pretreatment significantly inhibited neuronal activation in several areas, namely the supraoptic nucleus, ventrolateral column of the periaqueductal grey, locus coeruleus, nucleus tractus solitarius and area postrema. We conclude that nimesulide possesses a strong analgesic and antihyperalgesic activity, the mechanisms of action of which are partly central.

Analgesia↗

PubMed2002

Effects of nimesulide on nitric oxide-induced hyperalgesia in humans--a neurophysiological study.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to induce analgesia mainly via the inhibition of cyclo-oxygenase. Several reports suggest that chronic pain is mediated by central sensitization, an N-methyl-D-aspartate (NMDA)-mediated phenomenon influenced by cyclo-oxygenase activity and nitric oxide (NO). In this double-blind study, we evaluated the effects of a preferential inhibitor of the inducible isoform of cyclo-oxygenase-2, nimesulide, on the spinal nociceptive flexion reflex (RIII reflex) before and after administration of an NO donor in healthy volunteers. Nimesulide caused a reduction of the RIII reflex area, which persisted after NO donor administration. Conversely, in the placebo group the RIII reflex area significantly increased following the administration of the NO donor. These data suggest a central effect for nimesulide, possibly related to a reduction of nociceptive activity at spinal level.

Adult↗