Baclofen-loaded solid lipid nanoparticles: preparation, electrophysiological assessment of efficacy, pharmacokinetic and tissue distribution in rats after intraperitoneal administration.

Intrathecal baclofen administration is the reference treatment for spasticity of spinal or cerebral origin, but the risk of infection or catheter dysfunctions are important limits. To explore the possibility of alternative administration routes, we studied a new preparation comprising solid lipid nanoparticles (SLN) incorporating baclofen (baclofen-SLN). We used SLN because they are able to give a sustained release and to target the CNS. Wistar rats were injected intraperitoneally with baclofen-SLN or baclofen solution (baclofen-sol group) at increasing dosages. At different times up to 4 h, efficacy was tested by the H-reflex and two scales evaluating sedation and motor symptoms due to spinal lesions. Rats were killed and baclofen concentration determined in blood and tissues. Physiological solution or unloaded SLN was used as controls. After baclofen-SLN injection, the effect, consisting in a greater and earlier reduction of the H/M ratio than baclofen-sol group and controls, was statistically significant from a dose of 5 mg/kg and was inversely correlated with dose. Clinical effect of baclofen-SLN on both the behavioral scales was greater than that of baclofen-sol and lasted until 4th hour. Compared with baclofen-sol, baclofen-SLN produced significantly higher drug concentrations in plasma from 2nd hour until 4th hour with a linear decrement and in the brain at all times. In conclusion, our study demonstrated the efficacy of a novel formulation of baclofen, which exploits the advantages of SLN preparations. However, for clinical purposes, high baclofen concentrations in brain tissue and sedation may be unwanted effects, requiring further studies and optimization of dosages.

Functional involvement of central nervous system at high altitude.

Acute mountain sickness is a common discomfort experienced by unacclimatized persons on ascent to high altitude. We tested the hypothesis that exposure to high altitude affects cortical excitability using transcranial magnetic stimulation. We specifically analyzed the motor cortex excitability in normal subjects at high altitude and in a control condition near sea level. Mean resting motor threshold (RMT) was significantly higher at high altitude than at sea level (69.3 +/- 10.4 versus 56.3 +/- 10.9%; P = 0.042). Mean short intracortical inhibition (SICI) was significantly lower at high altitude than at sea level (percentage of test motor-evoked potential = 79.3 +/- 19.8 versus 28.7 +/- 17.5%; P = 0.0004). Symptoms of acute mountain sickness correlated with resting motor threshold changes induced by high altitude (R 2 = 0.53, P = 0.037). SaO2 correlated with SICI changes induced by high altitude (R 2 = 0.45, P = 0.036). We suggest that high altitude deeply changes cortical excitability by affecting both inhibitory and excitatory circuits and that this is reflected in acute mountain sickness symptoms.

On the origin of sensory impairment and altered pain perception in Prader-Willi syndrome: a neurophysiological study.

INTRODUCTION: High pain threshold is a supportive diagnosis criterion for Prader-Willi syndrome (PWS), but its pathogenesis is poorly understood. In this study we investigate sensory pathways in PWS, in order to evaluate peripheral or central involvement in altered sensory perception. METHODS: 14 adult PWS patients, 10 obese non-diabetic people and 10 age-matched controls underwent: (a) motor/sensory nerve conduction velocities at the upper and lower limbs; (b) palmar/plantar sympathetic skin response; (c) somatosensory evoked potentials from upper/lower limbs; (d) quantitative sensory testing to measure sensory threshold for vibration, warm and cold sensation, heat and cold-induced pain and (e) blood sample analysis to evaluate glucose and insulin levels and to calculate the quantitative insulin-sensitivity check index (QUICKI). RESULTS: Electroneurographic examination, sympathetic skin response and somatosensory evoked potentials were all within normal ranges. In the PWS group, thermal and pain thresholds but not vibratory were significantly higher than in healthy and obese people (p<0.05). Sensory threshold did not correlate with BMI nor with QUICKI. CONCLUSIONS: Our data suggest that altered perception in PWS does not seem attributable to a peripheral nerve derangement due to metabolic factors or obesity. Impairment of the small nociceptive neurons of dorsal root ganglia or involvement of hypothalamic region may not be excluded.

The cortico-diaphragmatic pathway involvement in amyotrophic lateral sclerosis: neurophysiological, respiratory and clinical considerations.

Cortico-diaphragmatic pathway was investigated by means of transcranial magnetic stimulation (TMS), in 14 patients affected by definite amyotrophic lateral sclerosis (ALS) without clinical signs of respiratory impairment. Spirometry, gas analysis, and measurement of static inspiratory and expiratory pressures were performed in all patients. Forced vital capacity, forced expiratory volume at the first and second peak expiratory flow, sniff effort from FRC level (SNIP), maximal inspiratory and expiratory pressure at mouth (MIP/MEP), maximal transdiaphragmatic pressure (Pdimx) were considered. TMS was performed, recording by surface electrodes from hemidiaphragm, bilaterally. Latency of cortical and spinal motor-evoked potentials (Cx-MEP/Sp-MEP) and central motor conduction time (CMCT) were measured. None of the patients showed altered spirometry and gas levels. Seven patients showed decreased Pdimx and eight of MEP values. Four patients showed a delayed Sp-MEP. In one patient the Cx-MEP was abolished while the mean values of both Cx-MEP and CMCT were significantly increased (19.2+/-4.1 ms, P<0.0001; 10.8+/-4.8 ms, P<0.0001). Cx-MEP and CMCT did not show significant correlations with any of the respiratory measures. The patients with prolonged Sp-MEP, showed longer disease duration, lower Norris score, lower Pdimx and MEP values. In conclusion, cortico-diaphragmatic study is a sensitive measure to reveal subclinical diaphragmatic impairment although not correlated to respiratory measures.

Sleep cycling alternating pattern (CAP) expression is associated with hypersomnia and GH secretory pattern in Prader-Willi syndrome.

BACKGROUND AND PURPOSE: Hypersomnia, sleep-disordered breathing and narcoleptic traits such as rapid eye movement (REM) sleep onset periods (SOREMPs) have been reported in Prader-Willi syndrome (PWS). In a group of young adult patients with genetically confirmed PWS we evaluated sleep and breathing polysomnographically, including cycling alternating pattern (CAP), and we analyzed the potential interacting role of sleep variables, sleep-related breathing abnormalities, hypersomnia, severity of illness variables and growth hormone (GH) secretory pattern. PATIENTS AND METHODS: Eleven males and 7 females (mean age: 27.5+/-5.5 years) were submitted to a full night of complete polysomnography and the multiple sleep latency test (MSLT). GH secretory pattern was evaluated by a standard GH-releasing hormone plus arginine test. Sixteen non-obese healthy subjects without sleep disturbances were recruited as controls. RESULTS: Compared to controls PWS patients showed reduced mean MSLT score (P<0.001), reduced mean latency of sleep (P=0.03), increased REM sleep periods (P=0.01), and increased mean CAP rate/non-rapid eye movement (NREM) (P<0.001). Only four PWS patients had apnea/hypopnea index (AHI)>or=10. Conversely, significant nocturnal oxygen desaturation was frequent (83% of patients) and independent from apneas or hypopneas. In the PWS group, CAP rate/NREM showed a significant negative correlation with MSLT score (P=0.02) independently from arousals, respiratory disturbance variables, severity of illness measured by Holm's score or body mass index (BMI). PWS patients with CAP expression characterized by higher proportion of A1 subtypes presented less severe GH deficiency (P=0.01). CONCLUSIONS: Our study suggests a relationship between hypersomnia and CAP rate, and between CAP expression and GH secretory pattern in PWS, possibly reflecting underlying central dysfunctions.

Obesity and peripheral neuropathy risk: a dangerous liaison.

This study investigates motor (MNCS) and sensory (SNCS) nerve conduction in a sample of non-diabetic obese people without symptoms suggestive of neuropathy and looks for a possible metabolic alteration. Twenty-one patients and 20 age-matched controls underwent (a) MNCS (median, ulnar, peroneal, and tibial) and SNCS (median, ulnar, and sural); (b) quantitative sensory testing to measure sensory threshold for vibration, warm and cold sensation (WS-CS), heat and cold-induced pain; and (c) blood sample analysis to evaluate glucose and insulin levels and calculate the quantitative insulin-sensitivity check index (QUICKI). The obese group showed significantly decreased compound muscle action potential amplitude of tibial and peroneal nerves and decreased sensory action potential amplitude of all nerves. Most of the sensory thresholds were altered in obese patients. Insulin serum levels were significantly increased while QUICKI decreased in obese patients. WS and CS from the index and little fingers and WS from the big toe significantly correlated with QUICKI. Thermal and pain thresholds from the index and thermal thresholds from the little finger correlated with QUICKI values. The non-diabetic obese patients showed a subclinical involvement of different diameter sensory fibers. Such impairment was related to hyperinsulinemia and insulin sensitivity. The increase in sensory threshold of obese patients might be due to a metabolic alteration, potentially leading to a future clinical neuropathy.

Botulinum toxin in post-stroke patients: stiffness modifications and clinical implications.

OBJECTIVE: To objectively quantify stiffness and clinical changes in the upper limb of poststroke patients following botulinum toxin (BT) injection. METHODS: Eighteen consecutive chronic post-stroke spastic patients were injected Botulinum toxin A in the forearm flexor spastic muscles. Spasticity was clinically evaluated with the Ashworth scale. Stiffness was measured with indices (passive stiffness index (ISI) and total stiffness index (TSI) obtained by mechanical wrist displacements induced by a torque motor,which could also provide the stretch reflex threshold speed (SRTS) from flexor muscles. Functional status was measured with the Barthel index and a specific hand ability scale, pain with a visual analogue scale (VAS). The ranges of voluntary wrist extension (EROM) and flexion (FROM) and wrist isometric extension and flexion (IE-IF) strength were also calculated. RESULTS: IE and EROM significantly increased, being respectively p < 0.01 and p < 0.05; also SRTS was augmented (p < 0.001),while TSI showed lower values (p < 0.001); the Ashworth score decreased at least one point. Hand function for selected tasks improved in 50% of patients, the Barthel index only in 4 (22 %), forearm pain was completely relieved in 3 patients (17 %). CONCLUSIONS: BT can be considered a valid therapeutic tool in all spastic patients, because of immediate advantages: reduction of muscle hypertonia, pain relief, improvement in selected motor performances.