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Intrathecal Administration (intrathecal + administration)
Selected AbstractsChemical Stability of an Admixture Combining Ziconotide and Bupivacaine During Simulated Intrathecal AdministrationNEUROMODULATION, Issue 2007David Shields PhD ABSTRACT Objective., To determine the stability of an admixture combining ziconotide with bupivacaine hydrochloride during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods., An admixture containing ziconotide (25 µg/mL) and bupivacaine hydrochloride (5 mg/mL) was stored in SynchroMed® II pumps at 37° and in control vials at either 37° or 5°. Using high-performance liquid chromatography, drug concentrations were determined from samples obtained at varying intervals during the 30-day study. Results., After 30 days, pump ziconotide and bupivacaine hydrochloride concentrations measured an average of 86.9% and 99.4% of their initial concentrations, respectively. Control vials displayed similar degradation rates for both drugs. Statistical evaluation of the ziconotide 95% confidence interval indicated that the ziconotide concentration would meet or exceed 90% and 80% of initial concentration for 22 days and 45 days, respectively. Conclusions., An admixture containing 25 µg/mL ziconotide and 5 mg/mL bupivacaine hydrochloride was 90% stable for 22 days and 80% stable for 45 days (extrapolated) in SynchroMed® II infusion pumps. [source] Chemical Stability of Ziconotide-Clonidine Hydrochloride Admixtures With and Without Morphine Sulfate During Simulated Intrathecal AdministrationNEUROMODULATION, Issue 2007David Shields PhD ABSTRACT Objective., To determine the stability of ziconotide,clonidine hydrochloride admixtures with and without morphine sulfate during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods., Admixtures of ziconotide (25 µg/mL) and clonidine hydrochloride (2 mg/mL) with and without morphine sulfate (35 mg/mL) were stored in Medtronic SynchroMed® II pumps at 37°. Pumps were sampled immediately after filling and at four additional time points over the course of 28 (ziconotide,clonidine hydrochloride admixture) or 20 (ziconotide,clonidine hydrochloride,morphine sulfate admixture) days. Drug concentrations were determined using high-performance liquid chromatography. Results., Ziconotide concentration exceeded 97% of initial at all time points when combined with clonidine alone; statistical evaluation indicated that both ziconotide and clonidine concentrations would remain above 90% of initial for more than 60 days. When compounded with both clonidine and morphine, ziconotide and clonidine concentrations declined; statistical evaluation indicated that the ziconotide concentration was 70% of initial after 20 days, and that clonidine would remain 90% stable for 42 days. Morphine was stable in the presence of ziconotide and clonidine. Conclusions., A ziconotide-clonidine admixture was 90% stable for 60 days (extrapolated), and a ziconotide-clonidine-morphine admixture was 70% stable for 20 days. [source] GDNF hyperalgesia is mediated by PLC,, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versicanEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2008Oliver Bogen Abstract The function of the isolectin B4 (IB4+)-binding and GDNF-dependent Ret (Ret+)-expressing non-peptidergic subpopulation of nociceptors remain poorly understood. We demonstrate that acute administration of GDNF sensitizes nociceptors and produces mechanical hyperalgesia in the rat. Intrathecal IB4,saporin, a selective toxin for IB4+/Ret+ -nociceptors, attenuates GDNF but not NGF hyperalgesia. Conversely, intrathecal antisense to Trk A attenuated NGF but not GDNF hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides targeting mRNA for versican, the molecule that renders the Ret-expressing nociceptors IB4-positive (+), also attenuated GDNF but not NGF hyperalgesia, as did ADAMTS-4, a matrix metalloprotease known to degrade versican. Finally, inhibitors for all five signaling pathways known to be activated by GDNF at GFR,1/Ret: PLC,, CDK5, PI3K, MAPK/ERK and Src family kinases, attenuated GDNF hyperalgesia. Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype. [source] Cross-sample entropy statistic as a measure of complexity and regularity of renal sympathetic nerve activity in the ratEXPERIMENTAL PHYSIOLOGY, Issue 4 2007Tao Zhang In this study, we employed both power spectral analysis and cross-sample entropy measurement to assess the relationship between two time series, arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA), during a mild haemorrhage in anaesthetized Wistar rats. Removal of 1 ml of venous blood decreased BP (by 7.1 ± 0.7 mmHg) and increased RSNA (by 25.9 ± 2.4%). During these changes, the power in the RSNA signal at heart rate frequency was reduced but coherence between the spectra at heart rate frequency in RSNA and ABP remained unchanged. Cross-sample entropy was significantly increased (by 10%) by haemorrhage, revealing that there was greater asynchrony between ABP and the RSNA time series. Intrathecal administration of the glutamate receptor antagonist kynurenic acid (2 mm) almost halved (P < 0.01) the reflex increase in RSNA. Also during kynurenic acid block, haemorrhage failed to change total power, power at heart rate frequency, coherence at heart rate frequency, or the cross-sample entropy measurements. We conclude that the increase in asynchrony between ABP and RSNA during the reflex increase in RSNA was a consequence of an increase in synaptic input to the spinal renal neurones. The data show that the cross-sample entropy calculations can characterize the non-linearities of neural mechanisms underlying cardiovascular control and have a potential to reveal how some aspects of homeostatic regulation of kidney function is achieved by the autonomic nervous system. [source] Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injuryGLIA, Issue 7 2008Hirokazu Katsura Abstract Mitogen-activated protein kinase (MAPK) plays an important role in the induction and maintenance of neuropathic pain. Transforming growth factor-activated kinase 1 (TAK1), a member of the MAPK kinase kinase family, is indispensable for the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We now show that TAK1 induced in spinal cord astrocytes is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in the expression of TAK1 in the ipsilateral dorsal horn, and TAK1 was increased in hyperactive astrocytes, but not in neurons or microglia. Intrathecal administration of TAK1 antisense oligodeoxynucleotide (AS-ODN) prevented and reversed nerve injury-induced mechanical, but not heat hypersensitivity. Furthermore, TAK1 AS-ODN suppressed the activation of JNK1, but not p38 MAPK, in spinal astrocytes. In contrast, there was no change in TAK1 expression in primary sensory neurons, and TAK1 AS-ODN did not attenuate the induction of transient receptor potential ion channel TRPV1 in sensory neurons. Taken together, these results demonstrate that TAK1 upregulation in spinal astrocytes has a substantial role in the development and maintenance of mechanical hypersensitivity through the JNK1 pathway. Thus, preventing the TAK1/JNK1 signaling cascade in astrocytes might provide a fruitful strategy for treating intractable neuropathic pain. © 2008 Wiley-Liss, Inc. [source] BMP inhibition enhances axonal growth and functional recovery after spinal cord injuryJOURNAL OF NEUROCHEMISTRY, Issue 4 2008Iichiro Matsuura Abstract Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor-, superfamily. BMPs regulate several crucial aspects of embryonic development and organogenesis. The reemergence of BMPs in the injured adult CNS suggests their involvement in the pathogenesis of the lesion. Here, we demonstrate that BMPs are potent inhibitors of axonal regeneration in the adult spinal cord. The expression of BMP-2/4 is elevated in oligodendrocytes and astrocytes around the injury site following spinal cord contusion. Intrathecal administration of noggin , a soluble BMP antagonist,leads to enhanced locomotor activity and reveals significant regrowth of the corticospinal tract after spinal cord contusion. Thus, BMPs play a role in inhibiting axonal regeneration and limiting functional recovery following injury to the CNS. [source] Spinal administration of lipoxygenase inhibitors suppresses behavioural and neurochemical manifestations of naloxone-precipitated opioid withdrawalBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003Tuan Trang This study investigated the role of spinal lipoxygenase (LOX) products in the induction and expression of opioid physical dependence using behavioural assessment of withdrawal and immunostaining for CGRP and Fos protein expression in the spinal cord. Administration of escalating doses (5,50 mg kg,1; i.p.) of morphine for 5 days markedly elevated CGRP-like immunoreactivity in the dorsal horn of the rat spinal cord. Naloxone (2 mg kg,1; i.p.) challenge precipitated a robust withdrawal syndrome that depleted CGRP-like immunoreactivity and increased the number of Fos-like immunoreactive neurons in the dorsal horn. Intrathecal administration of NDGA (10, 20 ,g), a nonselective LOX inhibitor, AA-861 (1.5, 3 ,g), a 5-LOX selective inhibitor, or baicalein (1.4, 2.8 ,g), a 12-LOX selective inhibitor, concurrently with systemic morphine for 5 days or as a single injection immediately preceding naloxone challenge, blocked the depletion of CGRP-like immunoreactivity, prevented increase in the number of Fos-like immunoreactive neurons in the dorsal horn, and significantly attenuated the morphine withdrawal syndrome. The results of this study suggest that activity of LOX products, at the spinal level, contributes to the expression of opioid physical dependence, and that this activity may be expressed through increased sensory neuropeptide release. British Journal of Pharmacology (2003) 140, 295,304. doi:10.1038/sj.bjp.0705440 [source] Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signalingGLIA, Issue 4 2008Makoto Tsuda Abstract Painful neuropathy is one of the most common complications of diabetes, one hallmark of which is tactile allodynia (pain hypersensitivity to innocuous stimulation). The underlying mechanisms of tactile allodynia are, however, poorly understood. Emerging evidence indicates that, following nerve injury, activated microglia in the spinal cord play a crucial role in tactile allodynia. However, it remains unknown whether spinal microglia are activated under diabetic conditions and whether they contribute to diabetes-induced tactile allodynia. In the present study, using streptozotocin (STZ)-induced diabetic rats that displayed tactile allodynia, we found several morphological changes of activated microglia in the dorsal horn. These included increases in Iba1 and OX-42 labeling (markers of microglia), hypertrophic morphology, the thickness and the retraction of processes, and in the number of activated microglia cells. Furthermore, in the dorsal horn of STZ diabetic rats, extracellular signal-regulated protein kinase (ERK) and an upstream kinase, Src-family kinase (SFK), both of which are implicated in microglial functions, were activated exclusively in microglia. Moreover, inhibition of ERK phosphorylation in the dorsal horn by intrathecal administration of U0126, an inhibitor of ERK activation, produced a striking alleviation of existing, long-term tactile allodynia of diabetic rats. We also found that a single administration of U0126 reduced the expression of allodynia. Together, these results suggest that activated dorsal horn microglia may be a crucial component of diabetes-induced tactile allodynia, mediated, in part, by the ERK signaling pathway. Thus, inhibiting microglia activation in the dorsal horn may represent a therapeutic strategy for treating diabetic tactile allodynia. © 2008 Wiley-Liss, Inc. [source] Remote pharmacological post-conditioning by intrathecal morphine: cardiac protection from spinal opioid receptor activationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2010J. LING LING Background: Intrathecal morphine pre-conditioning attenuates cardiac ischemia,reperfusion injury via activation of central opioid receptors. We hypothesized that intrathecal morphine also post-conditions the myocardium in the rat. Methods: Intrathecal morphine at 0.3 ,g/kg (LMPC), 3 ,g/kg (MMPC) or 30 ,g/kg (HMPC) was administered for 5 min before 120-min reperfusion following 30-min ischemia. Infarct size as a percentage of area at risk (IS/AAR) was determined using triphenyltetrazolium staining. MMPC was repeated following the intrathecal administration of nor BNI, NTD, CTOP, or naloxone methiodide (NM), kappa, delta, mu and non-specific opioid receptor antagonists, respectively. The role of peripheral opioid, adenosine and calcitonin gene-related peptide (CGRP) receptors was examined by the intravenous administration of NM, 8-,-sulfophenyl theophylline (8-SPT) and human CGRP fragment (CGRP8,37), respectively. Results: Morphine post-conditioning at all three doses was cardioprotective (IS/AAR of LMPC=37±4%, MMPC=35±5%, HMPC=32±4%, control=50±5%, P<0.01). The prior administration of opioid receptor antagonists intrathecally, as well as intravenous 8-SPT and CGRP8,37 receptor antagonists, abolished this effect (nor BNI+MMPC=47±7%, NTD+MMPC=49±7%, CTOP+MMPC=45±9%, NM+MMPC=47±6% 8-SPT+MPC=46±5% & CGRP8,37+MPC=53±6%, P=0.63). However, the intravenous administration of NM did not prevent the protective effect (34±4%, P<0.01). Conclusions: Intrathecal morphine administration can induce pharmacological cardiac post-conditioning as it involves opioid receptor centrally but non-opioid receptors peripherally. [source] Post-operative pain relief following intrathecal injection of acetylcholine esterase inhibitor during lumbar disc surgery: a prospective double blind randomized studyJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2008Z. H. Khan MD Summary Background:, As spinal cholinergic receptors participate in the control of somatic pain, this effect could be potentiated by intrathecal injection of a cholinesterase inhibitor, neostigmine. Objective:, This study was designed to evaluate the effectiveness of intrathecal administration of neostigmine on pain relief after single level lumbar disectomy. Methods:, Sixty-six patients with unilateral extruded lumbar disc were randomly allocated into two groups, neostigmine (,N'), and control (,C'); the former received 100 ,g of neostigmine methylsulphate, whereas the latter received placebo intrathecally after termination of the surgery. Visual Analogue Scale was employed to measure post-operative pain, which was a primary outcome of the study. Opiate dosage consumed was also recorded as a primary outcome during the first 24 h following surgery. Nausea and vomiting although important were considered as secondary outcomes. Results:, Mean Visual Analogue Scale scores post-operatively at 1, 4 and 8 h were 2·24, 1·82 and 1·88 in group ,N' and 5·36, 5·61 and 4·88 in group C. Mean morphine used intravenously in the first 24 h was 0·9 mg in group ,N' and 4·7 mg in group C. All results were found to be significantly different in the two groups. The frequency of nausea and vomiting was not significantly different in the two groups ,C' (24%) and ,N' (18%). Conclusion:, Injection of 100 ,g hyperbaric neostigmine intrathecally was effective for pain relief, and reduced post-operative opiate demand. [source] Functional characterization of prostaglandin F2, receptor in the spinal cord for tactile pain (allodynia)JOURNAL OF NEUROCHEMISTRY, Issue 2 2003Tadatoshi Muratani Abstract Prostaglandin F2, (PGF2,) binds to its receptor (FP) to increase the intracellular-free calcium concentration ([Ca2+]i) by coupling of FP with Gq protein. Spinal intrathecal administration of PGF2, to mouse induces touch-evoked pain (mechanical allodynia), in which capsaicin-insensitive primary afferent A,-fibres and N -methyl- d -aspartate receptor ,4 subunit are involved. FP in the spinal cord, however, was not well characterized. Here, we showed constitutive expression of FP mRNA in mouse spinal cord, and functionally characterized spinal FP-expressing cells which were involved in PGF2, -induced mechanical allodynia. The method for repetitive administration of oligodeoxyribonucleotides through tubing to conscious mice was established for mechanical allodynia evaluation. We identified an antisense oligodeoxyribonucleotide targeting FP mRNA, causing both disappearance of PGF2, -induced mechanical allodynia and decrease of FP mRNA. With saline-administered mice, PGF2, rapidly increased [Ca2+]i of the cells in the deeper layer of the dorsal horn. In contrast, when the FP antisense oligodeoxyribonucleotide was repeatedly administered, the population of PGF2, -responsive cells in the slices reduced, and PGF2, -induced [Ca2+]i increase of these cells diminished. These data strongly suggested that, in the dorsal horn of the spinal cord, there are the FP-expressing cells which are involved in PGF2, -induced mechanical allodynia. [source] The Management of Pain From Collapse of Osteoporotic Vertebrae With Continuous Intrathecal Morphine InfusionNEUROMODULATION, Issue 2 2007Maria Rita Saltari MD ABSTRACT Objectives., Vertebral fractures are the most common consequences of severe osteoporosis. The chronic pain from collapse of osteoporotic vertebrae affects quality of life (QoL) and autonomy of patients. The management of pain with oral or transdermal opiates can cause severe side-effects. Continuous intrathecal administration of morphine through an implantable pump might represent an alternative therapy to conventional oral or transdermal administration of opioids and has some advantages and disadvantages for pain relief and improvement in QoL when compared to conventional opioid delivery. It is our objective to report our experience using intrathecal delivery of analgesics in a population of patients with refractory pain due to vertebral fractures. Materials and Methods., In 24 patients, refractory to conventional delivery of opioids, we used intrathecal analgesic therapy. To test for efficacy and improvement in QoL, we administered the visual analog scale (VAS) for pain and the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO). Before patients were selected for pump implantation, an intraspinal drug delivery trial was performed to monitor side-effects and responses to intrathecal therapy. Results., Significant pain relief was obtained in all implanted patients. Using the QUALEFFO, we observed significant improvement of all variables such as QDL (quality of daily life), DW (domestic work), ambulation, and PHS (perception of health status), before and after one year after pump implantation. With intrathecal morphine infusion, none of the 24 patients required additional systemic analgesic medication. The mean morphine dose during the spinal trial was 11.28 mg/day, 7.92 mg/day at pump implantation, and 16.32 mg/day at one-year follow-up. Conclusions., Our results show that intrathecal administration of morphine efficiently relieves the symptoms of pain and improves QoL. Continuous intrathecal administration of morphine appears to be an alternative therapy to conventional analgesic drug delivery and has advantages in those patients who have severe side-effects with systemic administration of analgesics. [source] Lentiviral gene delivery to CNS by spinal intrathecal administration to neonatal miceTHE JOURNAL OF GENE MEDICINE, Issue 4 2006Elena Fedorova Abstract Background Direct injection of lentivectors into the central nervous system (CNS) mostly results in localized parenchymal transgene expression. Intrathecal gene delivery into the spinal canal may produce a wider dissemination of the transgene and allow diffusion of secreted transgenic proteins throughout the cerebrospinal fluid (CSF). Herein, we analyze the distribution and expression of LacZ and SEAP transgenes following the intrathecal delivery of lentivectors into the spinal canal. Methods Four weeks after intrathecal injection into the spinal canal of newborn mice, the expression of the LacZ gene was assessed by histochemical staining and by in situ polymer chain reaction (PCR). Following the spinal infusion of a lentivector carrying the SEAP gene, levels of enzymatically active SEAP were measured in the CSF, blood serum, and in brain extracts. Results Intrathecal spinal canal delivery of lentivectors to newborn mice resulted in patchy, widely scattered areas of ,-gal expression mostly in the meninges. The transduction of the meningeal cells was confirmed by in situ PCR. Following the spinal infusion of a lentivector carrying the SEAP gene, sustained presence of the reporter protein was detected in the CSF, as well as in blood serum, and brain extracts. Conclusions These findings indicate that intrathecal injections of lentivectors can provide significant levels of transgene expression in the meninges. Unlike intracerebral injections of lentivectors, intrathecal gene delivery through the spinal canal appears to produce a wider diffusion of the transgene. This approach is less invasive and may be useful to address those neurological diseases that benefit from the ectopic expression of soluble factors impermeable to the blood-brain barrier. Copyright © 2006 John Wiley & Sons, Ltd. [source] Review of case reports of inadvertent intrathecal administration of vincristine: Recommendations to reduce occurrenceASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2 2007Peter J GILBAR Abstract Vincristine has been in clinical use for over 40 years with initial publication of the results from successful trials in 1962. Catastrophic neurotoxicity has been associated with the administration of vincristine directly into the cerebrospinal fluid (CSF). Since the first case in 1968 there have been numerous other instances, of which 23 have been reported in the literature. Of these cases 18 resulted in death. The most prominent damage on autopsy was generally in the spinal cord, brain stem and cerebellum, with severity tending to be greater in the neurons adjacent to the CSF. Fatalities appeared due to a progressive ascending myeloencephalopathy. Early recognition and immediate treatment with CSF drainage and intrathecal exchange appears to be the only intervention that has improved patient survival. The volume of injection, dose and time from the incident until the ventriculo-lumbar washout appear critical, as these factors might contribute to the extent of drug distribution in the CNS. Although several antidotes for vincristine have been suggested, including folinic acid and glutamic acid, supportive evidence for their effectiveness is scant. Several recommendations regarding prevention of this catastrophic event have been proposed. [source] | |||||||||||||