Intrathecal Bolus Research Articles

Kinetics of ASO Distribution and Pharmacodynamics in the CNS after an Intrathecal Bolus Dose in Rat (S38.008)

Kinetics of ASO Distribution and Pharmacodynamics in the CNS after an Intrathecal Bolus Dose in Rat (S38.008)

Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery.

The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment of pharmacokinetic principles for optimizing regional drug exposure along the neuraxis. Here, we have utilized high-resolution single-photon emission tomography with X-ray computed tomography to study the behavior of multiple molecular imaging tracers following an IT bolus injection, with supporting histology, autoradiography, block-face tomography, and MRI. Using simultaneous dual-isotope imaging, we demonstrate that the regional CNS tissue exposure of molecules with varying chemical properties is affected by IT space anatomy, cerebrospinal fluid (CSF) dynamics, CSF clearance routes, and the location and volume of the injected bolus. These imaging approaches can be used across species to optimize the safety and efficacy of IT drug therapy for neurological disorders.

Ziconotide Trialing by Intrathecal Bolus Injections: An Open-Label Non-Randomized Clinical Trial in Postoperative/Posttraumatic Neuropathic Pain Patients Refractory to Conventional Treatment.

The aim of this open-label, non-randomized, clinical trial was to evaluate the feasibility of trialing ziconotide by intrathecal bolus injections. Twenty-three patients, who had peripheral neuropathic pain refractory to pharmacological treatment and were under consideration for Spinal Cord Stimulation, received up to three ziconotide bolus injections according to a comprehensive algorithm. After a first injection of 2.5 μg, the patients progressed in the algorithm depending on the presence or absence of pain reduction and significant adverse events. A patient was considered a "responder" if experiencing pain reduction and no significant adverse event on two consecutive occasions at the same dosage. We found a low proportion of responders (13%). However 30% of patients experienced ≥30% pain reduction on a least one injection, yielding a number needed to treat of ∼3 for clinically significant pain relief. Pain intensity changed significantly over time (0-6 h) (p = 0.047) after a mean ziconotide dose of 2.75 μg. Adverse events were as expected, and no serious adverse event occurred. We did not find any statistical association between response to Spinal Cord Stimulation and response to ziconotide. Ziconotide bolus injection trialing seems feasible, but the proportion of responders in the present study was low. Adverse events were as expected, and no serious adverse event occurred. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (slow tissue penetration due to high hydrophilicity) calls the rationale for bolus trialing into question.

Human NgR-Fc decoy protein via lumbar intrathecal bolus administration enhances recovery from rat spinal cord contusion.

Axonal growth and neurological recovery after traumatic spinal cord injury (SCI) is limited by the presence of inhibitory proteins in myelin, several of which act via the NgR1 protein in neurons. A truncated soluble ligand-binding fragment of NgR1 serves as a decoy and promotes recovery in acute and chronic rodent SCI models. To develop the translational potential of these observations, we created a human sequence-derived NgR1(310)-Fc protein. This protein is active in vitro. When the human NgR1 decoy is administered by continuous intracerebroventricular infusion to rats with a spinal contusion injury at doses of 0.09-0.53 mg/kg/d, neurological recovery is improved. Effective doses double the percentage of rats able to bear weight on their hindlimbs. Next, we considered the half-life and distribution of NgR1(310)-Fc after bolus delivery to the lumbar intrathecal space. The protein is found throughout the neuraxis and has a tissue half-life of approximately 2 days in the rat, and 5 days in the nonhuman primate. At an intermittent, once every 4 day, lumbar bolus dosing schedule of 0.14 mg/kg/d, NgR1(310)-Fc promoted locomotor rat recovery from spinal cord contusion at least as effectively as continuous infusion in open field and grid walking tasks. Moreover, the intermittent lumbar NgR1(310)-Fc treatment increased the growth of raphespinal axons into the lumbar spinal cord after injury. Thus, human NgR1(310)-Fc provides effective treatment for recovery from traumatic SCI in this preclinical model with a simplified administration regimen that facilitates clinical testing.

Timing of intrathecal baclofen therapy in persons with acquired brain injury: Influence on outcome

Objective: Evaluation of the effects of intrathecal baclofen therapy (ITB) delivered by a pump implanted at a very early stage in acquired brain injury (ABI).Study design: This investigation was a longitudinal prospective observational study, including a series of 13 ABI implanted within 6 months of the acute events.Main outcome measure: The Modified Ashworth Scale (MAS) and Spasms Frequency Score (SFS) have been used as a primary outcome measure. The Disability Rating Scale (DRS) and Level of Cognitive Functioning (LCF) scores have been computed in order to verify possible interferences of baclofen therapy at an early stage on a global outcome. An intrathecal bolus test was not performed. Drug tolerability was tested by oral administration of baclofen 100 mg.Results: Reduction of spasticity and spasms frequency were measured 3 months after patients received the implant and at the 1-year follow-up. There was no difference found for global outcome measure between the group of patients who received the implant earlier (within 3 months) compared to the group who received it later (between 3–6 months).Conclusion: ITB therapy in ABI should be considered as early as possible. The implants are safe and effective in reducing spasticity. An intrathecal bolus test was not compulsory in ABI.

Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release.

Lipoxins and resolvins have anti-inflammatory and pro-resolving actions and accumulating evidence indicates that these lipid mediators also attenuate pain-like behavior in a number of experimental models of inflammation and tissue injury-induced pain. The present study was undertaken to assess if spinal administration of lipoxin A4 (LXA4) or 17 (R)-resolvin D1 (17(R)-RvD1) attenuates mechanical hypersensitivity in the carrageenan model of peripheral inflammation in the rat. Given the emerging role of spinal cytokines in the generation and maintenance of inflammatory pain we measured cytokine levels in the cerebrospinal fluid (CSF) after LXA4 or 17(R)-RvD1 administration, and the ability of these lipid metabolites to prevent stimuli-induced release of cytokines from cultured primary spinal astrocytes. We found that intrathecal bolus injection of LXA4 and17(R)-RvD1 attenuated inflammation-induced mechanical hypersensitivity without reducing the local inflammation. Furthermore, both LXA4 and 17(R)-RvD1 reduced carrageenan-induced tumor necrosis factor (TNF) release in the CSF, while only 17(R)-RvD1attenuated LPS and IFN-γ-induced TNF release in astrocyte cell culture. In conclusion, this study demonstrates that lipoxins and resolvins potently suppress inflammation-induced mechanical hypersensitivity, possibly by attenuating cytokine release from spinal astrocytes. The inhibitory effect of lipoxins and resolvins on spinal nociceptive processing puts them in an intriguing position in the search for novel pain therapeutics.

An assessment of intrathecal catheters in the perioperative period: an analysis of 84 cases

Intrathecal opioid administration yields high quality analgesia with an associated low incidence of side effects and complication. The benefits of spinal "opioid only technique" include absence of neuronal blockade, infusion pump malfunction and sympathetic blockade. This technique declined after serious side effects were reported in the 1990s. To report on the safety and efficacy of the intrathecal catheter repeat bolus morphine technique for postoperative analgesia in patients having thoracotomy. A 22 gauge intrathecal catheter was inserted through the lumbar 3-4 interspace prior to induction of anaesthesia for postoperative analgesia. Repeat bolus preservative-free morphine was administered for 48 h, target VAS was <4. The mean morphine administered via ITC in 48 h was 2.56 mg (± SD 0.88 mg). Only one patient required rescue morphine. There were no serious complications or sequelae at 6-month follow-up. Intrathecal morphine for post-op analgesia is efficacious and safe in a post-thoracotomy population.

Physiology of the Intrathecal Bolus: The Leptomeningeal Route for Macromolecule and Particle Delivery to CNS

Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF, and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebrospinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active "pumping" of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought.

Prospective Study of Intrathecal Morphine versus Patient Controlled Analgesia in Cardiac Patients

Prospective Study of Intrathecal Morphine versus Patient Controlled Analgesia in Cardiac Patients Median sternotomy, the most common access used for cardiac surgery, is usually associated with severe early postoperative pain. Aggressive sternotomy pain control facilitates recovery, early mobilisation and decreases post-operative morbidity with direct implications for clinical resource utilisation and cost. Strategies to achieve effective early postoperative pain control after cardiac surgery have been reported to include; the use of opioids delivered as intravenous infusion, intravenous patient-controlled analgesia, epidural infusion, epidural patient-controlled analgesia, single intrathecal bolus, and intermittent subcutaneous boluses. Local anaesthetic agents have been injected into the surgical site, or thoracic epidural space as boluses and/or infusion.

Novel epidural baclofen infusion trial for intractable spasticity with long-term follow-up observation and a focused review of the literature

Background Intrathecal baclofen (ITB) infusion has been increasingly used in patients with intractable spasticity. Prior to the implantation of the permanent pump, a trial is usually conducted to document efficacy. Intrathecal bolus injection of baclofen, followed by serial evaluations to confirm the improvement of spasticity, has been most commonly used during such trials. However, for patients who refused to undergo ITB trial injection due to previous untoward complications such as intractable headache, there has been no other alternatives. Objective To report the first case of a successful epidural baclofen infusion trial, conducted as outpatient in a lady with severe spasticity due to multiple sclerosis; to report the long term follow-up observation (3 years) following the permanent intrathecal pump placement; and to conduct a focused review of the literature pertaining to epidural baclofen. Design Case report. Setting: Tertiary-care pain clinic. Case Report: A 62-year-old female with progressive spasticity of bilateral lower extremities and left upper extremity due to multiple sclerosis, not responding to multiple oral antispasticity drugs, was referred to clinic for ITB therapy. The patient adamantly declined ITB bolus trial due to previous episode of severe headache following lumbar puncture. Thus an outpatient epidural baclofen infusion was performed and was successful. Based on the positive response from the epidural infusion trial, a permanent IT pump was subsequently placed and the patient has had sustained reduction of her spasticity since pump implantation 3 years ago. Limitation: Single center case report. Conclusion In patients who are reluctant to the ITB bolus trial due to previous complication such as headache, an outpatient epidural baclofen infusion trial, when done properly, can serve as an alternative approach to the ITB trial and provides needed information

Pharmacokinetic Analysis of Ziconotide (SNX-111), an Intrathecal N-Type Calcium Channel Blocking Analgesic, Delivered by Bolus and Infusion in the Dog

Ziconotide is a peptide that blocks N-type calcium channels and is antihyperalgesic after intrathecal (IT) delivery. We here characterize the spinal kinetics of IT bolus and infused ziconotide in dog. Male beagle dogs (N= 5) were prepared with chronic IT lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest-mounted pumps. Each dog received the following: 1) IT bolus ziconotide (10 µg + 1 µCi (3) H-inulin); 2) IT infusion for 48 hours of ziconotide (1 µg/100 µL/hour); 3) IT infusion for 48 hours of ziconotide (5 µg/100 µL/hour); and 4) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribution/elimination) clearance (ziconotide T(1/2-α/β) = 0.14 and 1.77 hours, and inulin T(1/2-α/β) = 0.16 and 3.88 hours, respectively). The LCSF : plasma ziconotide concentration ratio was 20,000:1 at 30 min and 30:1 at eight hours. IT infusion of 1 and then 5 µg/hour resulted in LCSF concentrations that peaked by eight hours and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48-hour infusions. Terminal elimination T(1/2) after termination of continuous infusion was 2.47 hours. Ziconotide LCSF : cisternal CSF : plasma concentration ratios after infusion of 1 and 5 µg/hour were 1:0.017:0.001 and 1:0.015:0.003, respectively. IT infusion of ziconotide at 1 µg/hour inhibited thermal skin twitch by 24 hours and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48-hour infusion period, increased in magnitude during the subsequent 5 µg/hour infusion periods, and disappeared after drug clearance. After IT bolus or infusion, ziconotide displays linear kinetics that are consistent with a hydrophilic molecule of approximately 2500 Da that is cleared slightly more rapidly than inulin from the LCSF. Behavioral effects were dose dependent and reversible.

Accidental Intoxication with 60 mg Intrathecal Baclofen: Survived

Intrathecal baclofen (ITB) is an effective and well-tolerated treatment for patients with severe spasticity. Intoxications are rare and usually iatrogenic, with reported intrathecal boluses varying between 0.050 and 30 mg. We here report the case of a 47-year-old woman with severe spastic paraplegia due to multiple sclerosis who, during a routine filling procedure, accidentally received a bolus of 60 mg ITB because of injection into the side-port instead of the reservoir of her ITB pump (Archimedes(®), Codman, Germany). After a short period of dizziness, she lost consciousness and stopped breathing. She was immediately intubated, mechanically ventilated, and admitted to the intensive care unit. As specific treatment, she received cerebrospinal fluid drainage through a newly implanted lumbar catheter. A series of generalized and complex partial seizures were treated with levetiracetam and lacosamide. Acute autonomic dysfunction with episodic arterial hypo- and hypertensions was controlled by catecholamines and clonidine, respectively. Recurrent hyperthermia, however, responded neither to drugs nor to physical treatment. After 3 weeks, the patient was discharged without any relevant new neurologic signs or symptoms. This case demonstrates that even excessive doses of ITB can let the patients survive without sequelae if treated promptly and offensively. A pertinent problem during detoxification is the question of when to restart ITB to avoid drug withdrawal.

Use of Intrathecal Ziconotide for Frequent Severe and Intractable Sickle Cell Disease-Related Pain

Abstract 1062Many patients with sickle cell disease (SCD) have recurrent, severe vaso-occlusive pain crises, with profound consequences for their quality of life. These pain crises are sometimes responsive to medical management of the underlying disease or to palliative opioid or nonopioid therapies, but in other cases, the pain is intractable. In addition, patients with SCD are prone to chronic, debilitating pain from related conditions.We decided to test intrathecal (IT) ziconotide therapy using an implantable pump with the addition of a Personal Therapy Manager (PTM) patient control accessory in patients with SCD and severe, intractable pain. Ziconotide is a direct and selective inhibitor of N-type calcium channels, believed to reduce signaling in spinal pain pathways. In randomized, controlled trials, ziconotide has been shown to reduce severe chronic pain of various etiologies. We identified 2 patients with SCD and a history of prolonged, intractable pain as suitable candidates. After successful IT ziconotide bolus dose trials demonstrated the utility of ziconotide, these patients were implanted with programmable IT infusion pumps with PTM. Ziconotide was titrated to effect over several weeks.Patient 1 was a 29-year-old female with a history of SCD and hemoglobin of 7, MCV of 83, and platelet count of 297. She had been treated at major academic centers and by private practice hematologists with maximal medical therapy including hydroxyurea and folic acid. She was hospitalized about once a month in the previous 12 months for administration of IV opioids with patient-controlled analgesia (PCA). Currently she has evidence of aseptic necrosis of both hips, not improved by intra-articular steroid injections; she is not a candidate for joint replacements in view of her youth. She underwent a 1-mcg fluoroscopically directed IT bolus trial of ziconotide, with a reduction in her average visual analog scale (VAS) pain score of 9/10 to 0/10 for 48 hours, which was an unusual occurrence for her. She was able to sleep without difficulty and had improvement in her bilateral lower extremity, hip, rib, and back pain. A pump was then implanted for continuous IT infusion of ziconotide. She has not required emergency room visits or hospitalization for sickle cell crises since pump implantation. She is currently at 3.75 mcg/d of ziconotide with a PTM dose of 0.350 mcg every 3 hours and is interested in returning to work. She has not experienced any significant adverse events during the ziconotide titration phase.Patient 2 was a 31-year-old female with a history of hemoglobin S and thalassemia trait. She had bilateral avascular necrosis of the shoulders and hips and had been treated with chronic opioid therapy (fentanyl 50 mcg) but was still being hospitalized monthly for pain management. She had been treated at 2 major academic institutions as well as multiple community hospitals. The patient admitted to previous use of marijuana and cocaine in an effort to control her pain, as well as to obtaining pain medications from multiple physicians. She responded to a 7-mcg IT ziconotide trial with pain reduction from 8/10 to 0/10 for several days and then underwent implantation of a programmable pump with PTM. Following pump implantation she had satisfactory analgesia and did not require any emergency room visits for pain at a stable ziconotide dose of 1.5 mcg/d with a PTM dose of 0.150 mcg every 3 hours. This patient was receiving home refills and developed a pump pocket infection, requiring explantation of her IT infusion pump. Currently, she is poorly controlled on long-acting opioids and has requested reimplantation of her pump with ziconotide monotherapy.Here we describe 2 cases of successful pain management in SCD with IT ziconotide. While receiving continuous IT infusion of ziconotide, both patients were able to be titrated off of high-dose, long-acting opioids. In addition, the PTM proved useful for dosage finding during the titration phase as well as for aborting pain flares. We are in the process of studying a larger number of patients to better define the improvements achieved in functional status, analgesia, and healthcare savings with improved pain management using ziconotide in patients with SCD. Disclosures:McDowell:Azur Pharma: Speakers Bureau.

Cardiovascular alterations heralded by intrathecal baclofen bolus

We describe two patients in whom serious bradycardia and arterial hypotension occurred after a small intrathecal baclofen (ITB) test bolus. Both patients suffered from severe spasticity (one due to brain injury, one due to spinal cord injury). Medical history and diagnostic examinations revealed no previous cardiological problems. Ten minutes following a 50 μg ITB bolus, patient 1 developed bradycardia (58 bpm) and incomplete right branch block, lasting for 3 hours. In patient 2, a 20 μg ITB bolus was followed after 5 minutes by severe bradycardia (30 bpm) and hypotension (60/30 mmHg), without loss of consciousness, lasting for 10 minutes. Exaggerated muscle tone was alleviated in both patients after 2 hours by the applied doses. Neither patient underwent implantation of a permanent pump system, both were continued on oral baclofen. Despite numerous unremarkable repeat cardiological exams, both patients suffered fatal cardiac arrest one and two months later, respectively. Our observations suggest that ITB may herald cardiovascular dysfunction in predisposed patients. Careful cardiological examination before ITB treatment, and close monitoring during ITB testing in particular, is advised.

Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome

Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome

Recent advances in the treatment of pain

Cancer pain and chronic non-malignant pain can be difficult to manage and may not respond satisfactorily to standard analgesics. Sequential empiric analgesic trials are usually done to manage individual patients. Experimental human pain models have helped to clarify mechanisms of opioid and adjuvant analgesic actions. Combinations of opioids and adjuvant analgesics better relieve pain than either opioids or adjuvant analgesics alone, as demonstrated in randomized controlled trials. The analgesic activity of antidepressants is largely dependent upon norepinephrine reuptake and activation of alpha 2 adrenergic receptors. Corticosteroids reduce postoperative orthopedic incident pain, which may allow patients to ambulate earlier and with less pain. Spinal corticosteroids reduce lower hemibody pain. Gabapentinoids as single high doses reduce postoperative pain and certain acute pain syndromes. Individuals who experience flares of pain while on spinal opioids benefit from intrathecal boluses of levobupivicaine or sublingual ketamine. Interventional approaches to pain management are often necessary due to the limitations of systemic analgesics. Electronics stimulators (peripheral, spinal and motor cortex) improve difficult to manage chronic pain syndromes. Pulsed radiofrequency reduces pain without tissue damage, which could be an advantage over chemical or radiofrequency neurotomy. Botulinum toxin A reduces focal neuropathic pain that is durable. Interventional related successes in relieving pain are operator dependent. Most reported benefits of systemic and regional analgesics and interventional approaches to pain relief are not based on randomized trials and are subject to selection bias, sampling error, and placebo responses, which may over-inflate reported benefits. Randomized controlled trials are needed to confirm reported benefits.

Effects of intrathecal bolus administration of morphine on postoperative hyperalgesia in rats

Effects of intrathecal bolus administration of morphine on postoperative hyperalgesia in rats

Spinal antinociception of synthetic omega-conotoxin SO-3, a selective N-type neuronal voltage-sensitive calcium channel blocker, and its effects on morphine analgesia in chemical stimulus tests in rodent

SO-3, a novel Omega-superfamily conotoxin derived from Conus striatus, selectively inhibits N-type neuronal voltage-sensitive calcium channels. In current study, antinociception of SO-3 compared with MVIIA or morphine and its effects on morphine analgesia were investigated in rodent chemical stimulus tests after acute or repeated intrathecal administration. In mice acetic acid writhing test, similar to MVIIA, SO-3 caused dose- and time-dependent spinal antinociception with ED(50) of 0.25 microg/kg and t(1/2) of 4h, which was more potent and longer-acting than morphine. In rat formalin test after intrathecal bolus injection, SO-3 produced dose- and time-dependent antinociception by suppressing acute (ED(50), 1.79 microg/kg) and tonic phases (ED(50), 0.41 microg/kg), which was similar to MVIIA and approximately 10-fold potency and twice longer-acting of morphine in blocking tonic phase responses. After repeated intrathecal injections twice daily for 5 consecutive days, SO-3 produced analgesia without loss of potency whereas morphine produced analgesia tolerance in rat formalin test; further, SO-3 still produced potent analgesia in morphine-tolerant rats. SO-3 co-administered with morphine left-shift the dose-response curve of morphine in mice acetic acid writhing test and significantly potentiated morphine analgesia in rat formalin test. No changes in motor function were seen in mice or rats receiving antinociceptive doses of SO-3 whereas MVIIA caused motor dysfunction at doses of 1.0-2.0 microg/kg in rats. This study showed that (1) novel SO-3 produced potent and long-acting spinal antinociception without observable motor dysfunction, (2) SO-3 significantly potentiated morphine analgesia, (3) After repeated intrathecal administration, SO-3 produced neither tolerance nor cross-tolerance to morphine analgesia.

Pharmacological profile of intrathecal fadolmidine, a α2-adrenoceptor agonist, in rodent models

The present experiments compared the peripheral and central pharmacological effects of three alpha(2)-adrenoceptor agonists: fadolmidine, clonidine, and dexmedetomidine after single intrathecal bolus injections at analgesic dose level in rats. Effects on mydriasis and cardiovascular functions were studied in anaesthetised rats, the effects on sedation/motor performance, body temperature, and gastrointestinal motility were evaluated in conscious rats, and also the effects on brain biogenic amines were studied. All compounds caused dose-dependent mydriasis, a decrease in blood pressure and heart rate, sedation, hypothermia, and inhibition of gastrointestinal transit, but in contrast to the analgesic effects, dexmedetomidine and clonidine were much more potent than fadolmidine. In accordance with the other systemic effects, dexmedetomidine and clonidine, but not fadolmidine, reduced the turnover of the monoamine neurotransmitters, noradrenaline and serotonin, in brain at the analgesic dose. The difference in the systemic effect profile between fadolmidine and clonidine or dexmedetomidine is most probably explained by differences in their ability to spread from the site of administration at the lumbar level into the periphery and/or the brain and further the concentrations of the compounds in the side of action. These results supports that intrathecally administered fadolmidine could have potential to be used as an analgesic agent with less subraspinal or spinal adverse effects at analgesic doses than dexmedetomidine and clonidine.

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Acidic fibroblast growth factor (aFGF; also known as FGF-1) is a potent neurotrophic factor that affects neuronal survival in the injured spinal cord. However, the pathological changes that occur with spinal cord injury (SCI) and the attribution to aFGF of a neuroprotective effect during SCI are still elusive. In this study, we demonstrated that rat SCI, when treated with aFGF, showed significant functional recovery as indicated by the Basso, Beattie, and Bresnahan locomotor rating scale and the combined behavior score (p < 0.01-0.001). Furthermore proteomics and bioinformatics approaches were adapted to investigate changes in the global protein profile of the damaged spinal cord tissue when experimental rats were treated either with or without aFGF at 24 h after injury. We found that 51 protein spots, resolvable by two-dimensional PAGE, had significant differential expression. Using hierarchical clustering analysis, these proteins were categorized into five major expression patterns. Noticeably proteins involved in the process of secondary injury, such as astrocyte activation (glial fibrillary acidic protein), inflammation (S100B), and scar formation (keratan sulfate proteoglycan lumican), which lead to the blocking of injured spinal cord regeneration, were down-regulated in the contusive spinal cord after treatment with aFGF. We propose that aFGF might initiate a series of biological processes to prevent or attenuate secondary injury and that this, in turn, leads to an improvement in functional recovery. Moreover the quantitative expression level of these proteins was verified by quantitative real time PCR. Furthermore we identified various potential neuroprotective protein factors that are induced by aFGF and may be involved in the spinal cord repair processes of SCI rats. Thus, our results could have a remarkable impact on clinical developments in the area of spinal cord injury therapy.