In utero Exposure to Anesthetics Alters Neuronal Migration Pattern in Developing Cerebral Cortex and Causes Postnatal Behavioral Deficits in Rats.

During fetal development, cerebral cortical neurons are generated in the proliferative zone along the ventricles and then migrate to their final positions. To examine the impact of in utero exposure to anesthetics on neuronal migration, we injected pregnant rats with bromodeoxyuridine to label fetal neurons generated at embryonic Day (E) 17 and then randomized these rats to 9 different groups receiving 3 different means of anesthesia (oxygen/control, propofol, isoflurane) for 3 exposure durations (20, 50, 120 min). Histological analysis of brains from 54 pups revealed that significant number of neurons in anesthetized animals failed to acquire their correct cortical position and remained dispersed within inappropriate cortical layers and/or adjacent white matter. Behavioral testing of 86 littermates pointed to abnormalities that correspond to the aberrations in the brain areas that are specifically developing during the E17. In the second set of experiments, fetal brains exposed to isoflurane at E16 had diminished expression of the reelin and glutamic acid decarboxylase 67, proteins critical for neuronal migration. Together, these results call for cautious use of anesthetics during the neuronal migration period in pregnancy and more comprehensive investigation of neurodevelopmental consequences for the fetus and possible consequences later in life.

Peripheral nerve stimulator for the treatment of supraorbital neuralgia: a retrospective case series.

Peripheral nerve blocks of the supraorbital, supratrochlear or occipital nerve have been utilized for the relief of headaches, although relief may be short-lasting. The purpose of this study was to evaluate the efficacy of supraorbital nerve stimulation for treatment of intractable supraorbital neuralgia. Patients presenting to the pain clinic with refractory frontal headaches who responded to a diagnostic supraorbital nerve block were selected for this case series. Patients underwent a trial of supraorbital nerve stimulation, and efficacy was assessed after 5-7 days (n = 16). From the trial, 10 patients consented to undergo permanent implantation of the stimulator. Opioid consumption and headache scores were monitored preoperatively and at timed intervals for 30 weeks. Headache scores decreased, and opioid consumption was reduced in half, and these beneficial accomplishments were maintained up to 30 weeks after implantation. In selected patients, supraorbital nerve stimulation for the treatment of chronic frontal headaches appears to be efficacious.

Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases.

Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF results in widespread retrograde transport throughout the CNS. BDNF has also been shown to be transported anterogradely within the CNS. Infusion of GDNF into the CNS results in retrograde transport limited to the nigrostriatal pathway. Hippocampal injections of NT-3 retrogradely label mainly basal forebrain neurons. Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve. Following intraventricular and intraparenchymal infusion of radiolabeled bFGF, retrograde neuronal labeling was found in the telecephalon, diencephalon, mesencephalon and pons. In contrast retrograde labeling for aFGF was found only in the hypothalamus and midbrain. Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Effect of a template-located 2',2'-difluorodeoxycytidine on the kinetics and fidelity of base insertion by Klenow (3'-->5'exonuclease-) fragment.

Gemcitabine [2',2'-difluorodeoxycytidine (dFdCyd)], a potent antitumor agent, inhibits DNA synthesis and is incorporated internally into DNA. The effect of a template-incorporated dFdCyd molecule (dFdCyd-) on DNA polymerase function was examined. Two 25-base deoxyoligonucleotides were synthesized with either a single dFdCyd- or template-incorporated deoxycytidine molecule (dCyd-) at the same position. Each was annealed separately to an identical complementary 5'-32P-labeled primer and extended by the Klenow fragment (3'-->5' exo-) of DNA polymerase I. "Correct" insertion of dGMP was 80-fold less efficient opposite dFdCyd- than dCyd-. A comparison of misinsertion efficiencies opposite template dFdCyd gave values of 2.7 x 10(-2) for dAMP insertion, 1.1 x 10(-3) for dTMP insertion, and 5.9 x 10(-4) for dCMP insertion. A similar measurement opposite template dC gave values of 1.8 x 10(-4), 1.7 x 10(-4), and 2.9 x 10(-6) for dAMP, dTMP, and dCMP insertion, respectively. Thus, the presence of dFdCyd on the template strand inhibited "normal" DNA synthesis and increased deoxyribonucleotide misinsertion frequencies. Pausing during DNA synthesis occurred directly opposite template dFdCyd suggesting that dFdC.dG base pairs might be less stable than normal dC.dG pairs, resulting in a decreased rate of primer extension beyond this site. Consistent with kinetic data, thermal denaturation measurements using comparable surrounding sequences showed that dFdC.dG "correct" pairs were less stable than dC.dG base pairs. Measurements on base mispairs showed that dFdC.dC was more stable than dC.dC, while no measurable Tm differences were found between polymers containing dFdC.dA and dC.dA or dFdC.dT, and dC.dT.

Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine).

A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.

Retrograde transport of brain-derived neurotrophic factor (BDNF) following infusion in neo- and limbic cortex in rat: relationship to BDNF mRNA expressing neurons.

Brain-derived neurotrophic factor (BDNF) was the second member of the nerve growth factor (NGF) family to be isolated. The ability of BDNF to be retrogradely transported following intraparenchymal infusion represents a unique neurobiological tool to determine the location of putative neuron-specific BDNF-responsive neuronal systems. In the present study, we infused recombinant human (rh) BDNF into the rodent neo- and limbic cortex and used a turkey anti-BDNF antibody to determine specific populations of neurons which retrogradely transport this neurotrophin. Frontal cortex infusion retrogradely labeled neurons within the ipsilateral and contralateral frontal cortex, basal forebrain, lateral hypothalamus, centrolateral, mediodorsal, ventrolateral, ventromedial, ventral posterior, rhomboid, reuniens, and medial geniculate thalamic nuclei, and locus coeruleus. Occipital cortex infusion retrogradely labeled neurons in the frontal, temporal, occipital, and perirhinal cortices as well as the claustrum, basal forebrain, thalamus, epithalamus, hypothalamus, and raphe nuclei. Dorsal hippocampal infusion retrogradely labeled neurons within the septal diagonal band, supramammillary nucleus, and entorhinal cortex and was also transported within various hippocampal subfields. Entorhinal cortex infusion retrogradely labeled neurons within the perirhinal cortex, endopiriform nucleus, piriform cortex, dentate gyrus, presubiculum, parasubiculum, CA1-CA4 fields, amygdaloid nuclei, basal forebrain, thalamus, hypothalamus, periaqueductal gray, raphe nuclei, and locus coeruleus. Amygdala infusion labeled neurons in the endopiriform nucleus, temporal cortex, piriform cortex, paralimbic cortex, hippocampus, subiculum, entorhinal cortex, amygdala, basal forebrain, thalamus, hypothalamus, substantia nigra, pars compacta, raphe, and pontine parabrachial nuclei. In situ hybridization experiments demonstrated that virtually all areas which retrogradely transport BDNF also express its message. Neuroanatomical distributional studies of BDNF will unravel specific central nervous system neurotrophic-responsive systems.

Evaluation of cervical stimulation for chronic treatment of spasticity.

Electrical stimulation of the spinal cord (SCS) to reduce spasticity was evaluated in seven patients who, along with their physicians, perceived significant and prompt benefit from stimulation. In two 24-hour test periods, on or off stimulation, we used two independent methods of evaluation: quantitative measures of joint compliance and stretch reflexes, and a standardized neurologic examination. Neither method did better than chance in determining whether SCS was actually being received. Problems with the experimental protocol are discussed, but the results cannot be interpreted as supporting the efficacy of SCS as a treatment for spasticity.

Stereotactic pallidotomy for the treatment of Parkinson's disease. Efficacy and adverse effects at 6 months in 26 patients.

We evaluated the safety and efficacy of microelectrode-guided stereotactic pallidotomy in patients with advanced Parkinson's disease (PD). Using diagnostic criteria and evaluations outlined in the Core Assessment Programme in Transplantation (CAPIT) protocol, we studied unilateral pallidotomy in 26 patients with advanced idiophatic PD, motor fluctuations, and peak dose dyskinesias. All underwent unilateral stereotactic pallidotomy. Assessments conducted in the "practically defined off" and "best on" states at baseline and at 1 and 6 months postoperatively included Unified Parkinson's Disease Rating Scale (UPDRS) parts II, III, and IV and timed motor testing as outlined in CAPIT. Motor UPDRS in the "off" state improved at 1 and 6 months after surgery (p = 0.002, p = 0.008) Likewise, the sum of individual "off" contralateral motor UPDRS items improved (p = 0.0002, p = 0.0005). The duration (p = 0.0001 at 1 and p = 0.001 at 6 months) and severity (p = 0.003 at 1 and p = 0.0005 at 6 months) of dyskinesia improved, but other aspects of the "on" function were unchanged. Serious adverse effects occurred in eight patients and included one fatal deep and three nonfatal frontal lobe hemorrhages with resultant language or behavioral deficits. Nonhemorrhagic complications included one hemiparesis and three frontal lobe syndromes. Pallidotomy improves PD motor disability in the "off" state. Peak dose dyskinesias are reduced, although other aspects of "on" motor function are unchanged. Although morbidity may limit its use, pallidotomy is effective in targeting particular symptoms such as unremitting dyskinesia and severe "off" motor disability in advanced PD.

Intrastriatal and intraventricular infusion of brain-derived neurotrophic factor in the cynomologous monkey: distribution, retrograde transport and co-localization with substantia nigra dopamine-containing neurons.

The distribution and retrograde transport of brain-derived neurotrophic factor was examined using magnetic resonance imaging guided stereotaxic intracerebroventricular and intrastriatal infusion in the cynomologous monkey. Two intracerebroventricular animals were infused with brain-derived neurotrophic factor at a dose of 3 micrograms/h for 21 and 28 days. A third intracerebroventricular animal received sequential infusions of 15, 30 and 60 micrograms/h brain-derived neurotrophic factor each for seven days using an Alzet 2002 minipump. For the multiple intrastriatal animals (n = 5) a dose of 3 micrograms/h was infused into each site. One intrastriatal monkey was infused with vehicle solution of 10 mM phosphate-buffered saline pH 7.4 for 14 days resulting in no brain-derived neurotrophic factor immunoreactivity. Following the lower dose intracerebroventricular infusion, brain-derived neurotrophic factor immunoreactivity was confined to the ventricular ependymal layer. In the sequential higher dose intracerebroventricular case, the cannula was located mainly within the lateral ventricle, although there was damage to the ependymal wall and adjacent caudate nucleus. Brain-derived neurotrophic factor immunoreactivity revealed spread of injectate within the ipsilateral and to a lesser extent the contralateral caudate nucleus, septum, orbital cortex and ventricular ependymal wall. In this case, retrogradely labelled brain-derived neurotrophic factor neurons were found within the parafascicular thalamus and substantia nigra, pars compacta, as well as within cortex, vertical limb of the diagonal band and nucleus basalis. Brain-derived neurotrophic factor intrastriatal infusion retrogradely labelled perikarya within sensory motor cortex, parafascicular thelamus and substantia nigra, pars compacta. Sections from these cases dual-immunoreacted for brain-derived neurotrophic factor and tyrosine hydroxylase, the synthesizing enzyme for dopamine, revealed a subpopulation of pars compacta dopaminergic neurons which contained retrogradely transported brain-derived neurotrophic factor. These findings indicate that a select subgroup of nigral dopamine neurons retrogradely transport brain-derived neurotrophic factor in the primate. Furthermore it remains to be determined whether select nigral cells are responsive to the trophic influences of brain-derived neurotrophic factor in the normal and neuropathologic condition.

Chronic access to endoneurial space using an arterial autograft.

A technique for direct chronic infusion of compounds onto peripheral axons has been investigated in the rat sciatic nerve. A 2 cm segment of the femoral artery was removed and one end inserted into the endoneurial space of the contralateral peroneal nerve fascicle of the same animal. The other end of the artery was connected to a catheter system to allow infusion into the endoneurium, thus bypassing the barrier that the perineurium presents to hydrophilic compounds. The patency of this arterial access system was evaluated by the ability of 20 microliters of 2% lidocaine to inhibit the toe-spreading reflex. The results of the study were that the infusion system remained operational for 3-7 days after transplantation. There were histologic changes in the nerve but there were no functional deficits due to the surgery. Although a long-term endoneurial infusion was not achieved, the limited access time to the axons might be long enough for applications such as the delivery of nerve growth factors to injured nerve.

Pharmacological characterization of LY335979: a potent cyclopropyldibenzosuberane modulator of P-glycoprotein.

The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.

Intracerebral chemotherapy: chronic microinfusion of cisplatin.

Cisplatin, a chemotherapeutic agent used to treat tumors in many parts of the body, does not reach brain tissue during systemic injection because of the blood-brain barrier and protein binding in the blood. To allow hydrophilic drugs, such as cisplatin, to reach brain neoplasms with minimal body toxicity, we tested chronic intracerebral microperfusion into the extracellular space of the brain in normal rats. Small stainless steel cannulas connected to osmotic minipumps were stereotactically placed in the midline cerebellum or frontal cortex, and cisplatin was pumped into the brain at the rate of 0.9 microgram/hour for periods of up to 7 days. Brain tissue was then analyzed for the total platinum content, at 1-mm intervals from the cannula tip, using atomic absorption spectroscopy. The results of the animal studies show that a platinum concentration of 2 ng/mg of tissue, wet weight, can be maintained over a 1-cm region of brain. If all of the extracellular platinum has remained in the active cisplatin form, then this would be equivalent to a drug concentration of 10 microM. Cisplatin at this constant level has been shown to have a therapeutic effect against various tumor lines in vitro. To extend these results to human brain neoplasms, we estimate that one cannula would be sufficient to treat a 1-cm tumor or a larger tumor that could be surgically reduced. For inoperable tumors of up to 2 cm in diameter, a multiple cannula system would be required to yield the 10 microM concentration throughout. For larger inoperable tumors, local infusion will not produce high enough drug levels. In conclusion, chronic intracerebral microinfusion can be used to produce adequate and sustained therapeutic drug levels over a considerable region of tissue without the problem of systemic toxicity.

The distribution of medication along the spinal canal after chronic intrathecal administration.

Chronic intrathecal drug infusion for the treatment of neurological diseases, such as spasticity and chronic pain, has become an accepted method of therapy in recent years. Concurrent pharmacokinetic studies have shown that the cisternal cerebrospinal fluid (CSF) drug level is considerably lower than the lumbar CSF level during continuous infusion into the lumbar subarachnoid space. One factor that makes analysis of this decline in drug level difficult to quantify is that it is only feasible to sample CSF at the two extremes of the spinal subarachnoid space. Using a radionuclide technique, we have examined the distribution along the spinal canal of a hydrophilic compound, indium-111 diethylenetriamine pentaacetic acid, that was delivered over 72 hours into the lumbar subarachnoid space in five patients with implanted drug pumps. Over a 20-cm distance of the thoracic cord, radionuclide counts decreased gradually so that the indium-111 diethylenetriamine pentaacetic acid concentration surrounding the cord at the T2 vertebral level was 43% of that at the T12 level in four patients. Therefore, it appears that even with a hydrophilic compound, which minimizes spinal cord capillary losses, there is still a considerable reduction of CSF drug concentration along the spinal canal. The clinical implication of this gradual decline in drug level is that for intrathecal infusion of relatively hydrophilic compounds there may not be any advantage in placing the catheter tip at more rostral locations, such as at the midthoracic or cervical cord.

Intrathecal octreotide for relief of intractable nonmalignant pain: 5-year experience with two cases.

Somatostatin is distributed in the substantia gelatinosa in the dorsal horn of the spinal cord, and its application has been found to produce an inhibitory effect on nociceptive neurons. Although intraspinal administration of somatostatin-14 produces pain relief in patients with cancer and in postoperative patients, its short half-life limits its clinical usefulness. Octreotide, a synthetic analog of somatostatin, is more stable and not been associated with neurodegenerative changes when administered intrathecally in dogs. Intrathecal octreotide provides analgesia without adverse drug effects when administered chronically for cancer pain; however, treatment periods have been limited. This article describes the 5-year clinical course of two patients receiving intrathecal octreotide for severe, intractable nonmalignant pain. Included in this description are the results of blinded, randomized "N of 1" trials conducted in each of these patients.

Chronic intrathecal administration of dexamethasone sodium phosphate: pharmacokinetics and neurotoxicity in an animal model.

OBJECTIVE: Although corticosteroids have been used intraspinally for many years, long-term intrathecal administration has not been examined. We have assessed the stability, bioavailability, and safety of continuously delivering the prodrug dexamethasone sodium phosphate into the lumbar subarachnoid space. METHODS: High-performance liquid chromatography studies were performed to determine whether dexamethasone sodium phosphate is degraded either in vials or in an infusion pump at 37 degrees C during a period of weeks. Rats then received implants with a combined intrathecal delivery and microdialysis sampling catheter to determine whether the prodrug is converted to free dexamethasone. A neurotoxicity study was performed in which rats received implants with an intrathecal catheter and were continuously infused with the corticosteroid during a 2-week period. RESULTS: Dexamethasone sodium phosphate, diluted in saline, is stable at body temperature in vials and implantable infusion pumps for at least 2 weeks. When delivered into the cerebrospinal fluid as a bolus, virtually all of the prodrug is converted to free dexamethasone within 40 minutes. When administered continuously, most of the corticosteroid is in its active form at steady state. Low doses of corticosteroid (< or =12.5 ng/h) produced no side effects or neuropathology in the rats, but a higher dose (125 ng/h) was associated with inflammation in the lumbar subarachnoid space. CONCLUSION: Dexamethasone sodium phosphate is a stable prodrug that is efficiently converted to free dexamethasone when delivered intrathecally. Low continuous intrathecal doses seem safe, but higher doses may lead to increased inflammation.

Effects of 2',2'-difluorodeoxycytidine (Gemcitabine) on wild type and variant mouse leukemia L1210 cells.

2',2'-Difluorodeoxycytidine (Gemcitabine, dFdCyd) is a cytotoxic agent which is active toward a variety of tumor cells. It has been shown that there are multiple intracellular sites of action which include ribonucleotide reductase and DNA polymerase. In these studies, the effects of dFdCyd on wild-type mouse leukemia L1210 cells and variant L1210 cell lines which had alterations at the ribonucleotide reductase site or at the deoxyribonucleoside kinase site were studied. For cell growth, the IC50 value for dFdCyd in wild-type L1210 cells was 3.1 nM. In the variant cell lines, the IC50 values were: hydroxyurea-resistant (HU), 3.3 nM; deoxyadenosine-resistant (Y8), 1.8 nM; pyrazoloimidazole/deoxyadenosine-resistant (ED2), 1.9 nM; and deoxyguanosine-resistant (dGuo-R), 44.7 nM. The dGuo-R cell line had a relatively specific loss of the deoxyribonucleoside kinase responsible for phosphorylating deoxyguanosine and cytosine arabinoside with little loss of the deoxycytidine kinase activity. DFdCyd had no effect on the total uptake of [14C]cytidine into the cells or incorporation into RNA. DFdCyd inhibited the conversion of [14C]cytidine to deoxycytidine nucleotides and incorporation into DNA. However, the incorporation of cytidine into DNA was inhibited to a greater extent than was the inhibition of in situ ribonucleotide reductase activity. Ribonucleotide reductase activity in cell-free extracts prepared from L1210 cells treated with dFdCyd (20 nM) overnight was reduced by 50%. These results show that cell lines which have increased levels of ribonucleotide reductase activity (HU and ED2) or loss of feedback inhibition by dATP (ED2 and Y8) are still sensitive to dFdCyd. The findings indicate that ribonucleotide reductase is not the primary site of inhibition by dFdCyd.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct delivery of medication into a brain tumor through multiple chronically implanted catheters.

A recurrent malignant glioma was treated with cisplatin delivered directly into the tumor. The drug was delivered via 68 small catheters distributed evenly throughout the tumor area. Each catheter was connected to an osmotic minipump that delivered 0.5 microliter of drug solution each hour for 10 days. There were no side effects from the catheter implantation, chemotherapy, or catheter removal. Although the chemotherapy halted progression of the tumor, it recurred, and the patient died 6 months after treatment.

Distribution of a somatostatin analog after continuous intraventricular administration.

Decreased somatostatin in the brains of patients with Alzheimer's disease has led to an investigation of the efficacy of neurotransmitter replacement therapy. The distribution of a somatostatin analog, octreotide, was determined after 2 to 6 days of continuous intraventricular infusion at 40 micrograms/h in dogs. The tissue concentration was greater than 100 ng/g wet weight in all parts of the brain, which is greater than the normal concentration of native somatostatin. There was no reduction in native somatostatin production because of the infusion of the analog. The cerebrospinal fluid octreotide concentration was 1000 times greater than the plasma concentration. The results demonstrate that neurotransmitter replacement for somatostatin can be achieved by chronic intraventricular infusion of a metabolically stable analog.

Intrathecal ciliary neurotrophic factor delivery for treatment of amyotrophic lateral sclerosis (phase I trial).

OBJECTIVE: This Phase I trial of ciliary neurotrophic factor (CNTF) delivered intrathecally for the treatment of patients with amyotrophic lateral sclerosis was designed to determine the safety of this new mode of administration as well as the pharmacokinetics and drug distribution. METHODS: CNTF was administered using a drug pump implanted into the lumbar subarachnoid space in each of four patients with amyotrophic lateral sclerosis. Escalating doses (0.4, 0.8, 1.6, 4, and 8 micrograms/h) were infused for 48 hours per week in 2-week cycles until the highest tolerated dose was achieved. Patients were observed for side effects, and standardized muscle and respiratory function tests were performed. Cerebrospinal fluid (CSF) levels of CNTF were determined using simultaneous lumbar and cervical taps. Plasma and CSF levels of antibodies, CSF cells and protein, and routine blood chemistries were monitored, as were weight and vital signs. RESULTS: Pharmacokinetic studies of four patients demonstrated that the distribution and clearance of recombinant human (rH)CNTF are similar to those of many small, water-soluble agents (morphine, baclofen, clonidine) and that the steady-state concentration of rHCNTF at the cervical level was 18 to 36% of that at the lumbar level. Lumbar CSF levels were in the range of 44 to 1230 ng/ml. Intrathecally administered rHCNTF had different adverse effects than the systemically delivered drug. With intrathecal administration, no asthenia, fever, chills, nausea, weight loss, increased cough, or sputum production was found. All patients who received rHCNTF intrathecally experienced dose-related CSF pleocytosis (primarily lymphocytic) and rises in protein levels. No clinical signs of meningeal irritation, such as stiff neck, photophobias, or nausea, were seen. However, one patient who had lumbar spinal stenosis developed severe burning and cramping leg pain. A second patient developed a severe headache and leg and back cramping. No abnormal clinical chemistry or hematological findings were encountered. Plasma levels of rHCNTF were below detection. Antibodies to rHCNTF were found in the systemic circulation of only one patient. The gradual decline in motor strength and performance of standard skills did not improve or worsen. CONCLUSIONS: In this first trial of a recombinant neurotrophic factor to be administered intrathecally by drug pump, the CNTF was well distributed along the spinal canal. Pain syndromes (headache, radicular pain) that were dose-related occurred in two patients, but systemic side effects, which had been observed with subcutaneous rHCNTF, did not occur. Intrathecal drug pump delivery of neurotrophic factors may be the most appropriate way in which to test the efficacy of these high-molecular weight proteins, because high CSF levels can be achieved without significant systemic side effects.