RESUMO
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.
Assuntos
Anestésicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Córtex Somatossensorial/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Feminino , Isoflurano/toxicidade , Neurônios/efeitos dos fármacos , Gravidez , Propofol/toxicidade , Ratos , Proteína Reelina , Córtex Somatossensorial/embriologiaRESUMO
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.
Assuntos
Terapia por Estimulação Elétrica , Transtornos da Cefaleia/terapia , Neuralgia/terapia , Adulto , Analgésicos Opioides/administração & dosagem , Terapia Combinada , Eletrodos Implantados , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Neuralgia/tratamento farmacológico , Estudos RetrospectivosRESUMO
INTRODUCTION AND METHOD: The prototypic motor feature of Huntington's disease (HD) is chorea, but parkinsonism and involuntary movements such as dystonia and myoclonus can also be present. Pallidotomy has been shown to be an effective treatment for medically refractory Parkinson's disease (PD). We performed bilateral microelectrode guided-stereotactic pallidotomies targeted at globus pallidum internus (GPi) to treat a 13-year-old patient diagnosed with Westphal variant of HD with intractable generalized dystonia and parkinsonism. RESULTS: Intraoperative microelectrode recordings of GPi cells showed a relatively low firing rate, 29 +/- 14 Hz, with most neurons showing pauses. Acutely, after surgery, limb dystonia mildly improved but trunk dystonia persisted. Postoperative follow up 3 months later showed minimal clinical improvement in dystonic features with marked worsening of spasticity. CONCLUSION: In our case, bilateral pallidotomy produced modest palliative functional improvement in dystonic features. Cellular firing patterns were markedly different than in PD and were similar to those found in dystonia.
Assuntos
Distonia/cirurgia , Globo Pálido/cirurgia , Doença de Huntington/complicações , Adolescente , Distonia/etiologia , Distonia/fisiopatologia , Evolução Fatal , Feminino , Humanos , Doença de Huntington/fisiopatologia , Doença de Huntington/cirurgia , Microcirurgia/métodos , Índice de Gravidade de Doença , Técnicas EstereotáxicasRESUMO
OBJECT: Long-term monitoring of intracranial pressure (ICP) is limited by the lack of an implantable sensor with low drift. The goal of this study was to demonstrate that a new capacitive transducer system will produce accurate and stable ICP records over extended periods. METHODS: Intracranial pressure sensors were implanted into the frontal white matter of four dogs. In addition, a fluid-filled catheter was placed in the cisterna magna (CM) to measure cerebrospinal fluid (CSF) pressure. The animals were tested using standard physiological maneuvers such as jugular vein compression, head elevation, and CSF withdrawal from and saline injection into the CM to verify that the ICP sensor precisely matched CSF pressure changes. The mean ICP pressure and CM pressure were compared for months to demonstrate that the transducer system produced minimal drift over time. The change in the ICP sensor record closely duplicated that of the CSF waveform in the CM in response to well-known physiological stimuli. More important, mean ICP pressure remained within 3 mm Hg of CM pressure for months, with a mean difference of less than 0.3 mm Hg. Histological examination of the dog brains revealed only minimal tissue reaction to the presence of the sensor. CONCLUSIONS: The authors demonstrate a new implantable solid-state sensor that reliably measures ICP for months, with minimal drift. The clinical application of this sensor and its telemetry is for long-term monitoring of patients with head injury, mass lesions, and hydrocephalus.
Assuntos
Lesões Encefálicas/diagnóstico , Hidrocefalia/diagnóstico , Pressão Intracraniana , Monitorização Fisiológica/instrumentação , Animais , Lesões Encefálicas/líquido cefalorraquidiano , Cisterna Magna , Cães , Feminino , Hidrocefalia/líquido cefalorraquidiano , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Reprodutibilidade dos Testes , Telemetria/instrumentação , Telemetria/normas , Fatores de TempoRESUMO
UNLABELLED: Intrathecal magnesium sulfate coinfusion with morphine increases antinociception in normal rats; however, because magnesium also delays the onset of tolerance, it is not clear whether this additional antinociception is a result of potentiated analgesia or tolerance abatement. We examined the antinociceptive interaction of intrathecal (IT) bolus magnesium sulfate and morphine in morphine naive rats and those with mechanical allodynia after a surgical incision. After intrathecal catheter implantation, rats were given preinjections of magnesium or saline, followed by injections of morphine or saline. In morphine naïve rats, IT bolus magnesium sulfate 281 and 375 microg followed by IT morphine 0.25 or 0.5 nmol enhanced peak antinociception and area under the response versus time curve two-to-three-fold in the tail-flick test as compared with morphine alone. Likewise, in rats with incisional pain, IT bolus magnesium sulfate 188 and 375 microg followed by morphine 0.5 nmol reduced mechanical allodynia, whereas morphine 0.5 nmol alone did not. This study suggests that IT magnesium sulfate potentiates morphine at a spinal site of action. IMPLICATIONS: Magnesium sulfate potentiates morphine analgesia when coadministered intrathecally in normal rats, and in an animal model of mechanical allodynia after a surgical incision. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.
Assuntos
Analgésicos Opioides/farmacologia , Sulfato de Magnésio/farmacologia , Morfina/farmacologia , Medula Espinal/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Dexametasona/análogos & derivados , Animais , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/farmacocinética , Bombas de Infusão Implantáveis , Masculino , Ratos , Ratos Sprague-Dawley , Coluna Vertebral , Fatores de TempoRESUMO
The benzothiophene LY329146 reverses the drug resistance phenotype in multidrug resistance protein (MRP1)-overexpressing cells when dosed in combination with MRP1-associated oncolytics doxorubicin and vincristine. Additionally, LY329146 inhibited MRP1-mediated uptake of the MRP1 substrate LTC4 into membrane vesicles prepared from MRP1-overexpressing cells.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/genética , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Antineoplásicos/farmacologia , Transporte Biológico , Membrana Celular/metabolismo , Células HL-60 , Células HeLa , Humanos , Leucotrieno C4/antagonistas & inibidores , Leucotrieno C4/metabolismo , Proteínas Associadas à Resistência a Múltiplos MedicamentosRESUMO
The authors present a case of Hallervorden-Spatz disease (HSD) in a 10-year-old boy treated with stereotactic pallidotomy for control of severe dystonia. Hallervorden-Spatz disease is a rare type of neuraxonal dystrophy that can be familial or sporadic. This is the first case of HSD reported in the literature in which a pallidotomy was performed. The patient had progressively worsening dystonias and spasms that prevented useful function of his entire right side and eventually threatened his respiratory ability. Pre- and postoperative magnetic resonance images are presented along with electrophysiological recordings made in the globus pallidus at the time of surgery. Functional improvement in the use of the patient's limbs and relief from the painful dystonia were observed. Stereotactic pallidotomy should be considered as a potential treatment in the management of HSD.
Assuntos
Globo Pálido/cirurgia , Neurodegeneração Associada a Pantotenato-Quinase/cirurgia , Técnicas Estereotáxicas , Criança , Distonia/etiologia , Distonia/fisiopatologia , Eletrofisiologia , Extremidades/fisiopatologia , Globo Pálido/fisiopatologia , Humanos , Período Intraoperatório , Imageamento por Ressonância Magnética , Masculino , Dor/fisiopatologia , Neurodegeneração Associada a Pantotenato-Quinase/complicações , Neurodegeneração Associada a Pantotenato-Quinase/diagnóstico , Resultado do TratamentoRESUMO
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.
Assuntos
Transporte Axonal , Sistema Nervoso Central/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/terapia , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/patologia , Fatores de Crescimento de Fibroblastos/administração & dosagem , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Fatores de Crescimento Neural/administração & dosagem , Fatores de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso/administração & dosagem , Proteínas do Tecido Nervoso/farmacologia , Doenças Neurodegenerativas/metabolismo , Receptores de Fator de Crescimento Neural/metabolismoAssuntos
Agonistas GABAérgicos/uso terapêutico , Globo Pálido/cirurgia , Muscimol/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Adulto , Agonistas GABAérgicos/administração & dosagem , Humanos , Injeções Intralesionais/métodos , Masculino , Muscimol/administração & dosagem , Tremor/tratamento farmacológico , Tremor/etiologiaRESUMO
UNLABELLED: N-methyl-D-aspartate (NMDA) antagonists, such as MK801, delay the development of morphine tolerance. Magnesium, a noncompetitive NMDA antagonist, reduces postoperative morphine requirements. The present study was designed to evaluate the effects of intrathecal co-administration of magnesium sulfate with morphine on antinociceptive potentiation, tolerance, and naloxone-induced withdrawal signs. Magnesium sulfate (40-60 microg/h) co-administration for 7 days, similar to MK801 (10 nmol/h), prevented the decline in antinociceptive response compared with morphine (20 nmol/h). Magnesium sulfate (60 microg/h) produced no antinociception, but co-infused with morphine (1 nmol/h), it resulted in potentiated antinociception compared with morphine throughout the 7-day period. Probe morphine doses after 7-day infusions demonstrated a significantly greater 50% effective dose value for morphine 1 nmol/h (109.7 nmol) compared with saline (10.9 nmol), magnesium sulfate 60 microg/h (10.9 nmol), and magnesium sulfate 60 microg/h plus morphine 1 nmol/h (11.2 nmol), which indicates that magnesium had delayed morphine tolerance. Morphine withdrawal signs after naloxone administration were not altered by the co-infusion of magnesium sulfate. Cerebrospinal fluid magnesium levels after intrathecal magnesium sulfate (60 microg/h) for 2 days increased from 17.0 +/- 1.0 microg/mL to 41.4 +/- 23.6 microg/mL, although serum levels were unchanged. This study demonstrates antinociceptive potentiation and delay in the development of morphine tolerance by the intrathecal coinfusion of magnesium sulfate and morphine in the rat. IMPLICATIONS: The addition of magnesium sulfate, an N-methyl-D-aspartate antagonist, to morphine in an intrathecal infusion provided better analgesia than morphine alone in normal rats. These results suggest that intrathecal administration of magnesium sulfate may be a useful adjunct to spinal morphine analgesia.
Assuntos
Analgésicos Opioides/farmacologia , Analgésicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Sulfato de Magnésio/farmacologia , Morfina/farmacologia , Analgesia , Analgésicos/administração & dosagem , Analgésicos/sangue , Analgésicos/líquido cefalorraquidiano , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Analgésicos Opioides/líquido cefalorraquidiano , Animais , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Interações Medicamentosas , Sinergismo Farmacológico , Tolerância a Medicamentos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/sangue , Antagonistas de Aminoácidos Excitatórios/líquido cefalorraquidiano , Injeções Espinhais , Sulfato de Magnésio/administração & dosagem , Sulfato de Magnésio/sangue , Sulfato de Magnésio/líquido cefalorraquidiano , Masculino , Morfina/administração & dosagem , Morfina/sangue , Morfina/líquido cefalorraquidiano , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia , Fatores de TempoRESUMO
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.
Assuntos
Globo Pálido/cirurgia , Atividade Motora , Doença de Parkinson/cirurgia , Técnicas Estereotáxicas , Atividades Cotidianas , Hemorragia Cerebral/etiologia , Seguimentos , Lateralidade Funcional , Hemiplegia/etiologia , Humanos , Transtornos da Linguagem/etiologia , Microeletrodos , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Complicações Pós-Operatórias , Índice de Gravidade de Doença , Técnicas Estereotáxicas/efeitos adversos , Fatores de TempoRESUMO
Compound LY335979 is a P-glycoprotein inhibitor currently entering phase I clinical trials for potential reversal of multidrug resistance to cancer chemotherapy. In early exploratory studies, LY335979 was found to be rapidly transformed in incubations with liver microsomes from rats, dogs, monkeys, and humans. Although the parent compound was completely metabolized, no prominent metabolite peaks were observed. One peak did appear early in the time course, but it did not increase over time. In another preliminary experiment, rats were treated iv with [3H]LY335979 (prepared for pharmacology studies), and urine and bile fractions were collected. Analysis of the urine by reverse-phase HPLC with UV and radioactivity detection revealed that almost all of the material eluted with the solvent front. More than half the radioactivity in bile was accounted for by two peaks eluting earlier than the parent compound (the rest eluted at the solvent front). With both bile and the incubations with microsomes, initial attempts to isolate metabolites were not successful. There was also evidence in both systems of products derived from cleavage of LY335979 (by both further metabolism and degradation). LC/NMR was thus used to analyze materials directly in their respective matrices. An N-oxide metabolite (LY389551) formed by oxidation of the quinoline nitrogen was identified in the microsomal incubations; in bile, three glucuronide metabolites were identified, all of which were conjugates of products formed by oxidation of the quinoline ring of LY335979. There have been few reports in the literature of LC/NMR analysis of bile, which is a more complex matrix than either urine or microsomal suspensions. However, the HPLC techniques developed in this work for the HPLC/UV and LC/MS analyses of LY335979 metabolites in the microsomal matrix and in bile proved readily adaptable for LC/NMR. Using a 500-MHz instrument, basic 1H NMR spectra could be obtained in 2-3 hr with approximately 100 ng of material in the LC/NMR microprobe. With approximately 1.5 microg of material injected onto the column, 1H-1H correlation spectroscopy spectra could be acquired overnight. Along with LC/MS data, the LC/NMR technique facilitated direct identification of a number of metabolites of LY335979 at a point at which their identification by traditional methods would not have been pursued.
Assuntos
Bile/metabolismo , Dibenzocicloeptenos/química , Dibenzocicloeptenos/metabolismo , Resistência a Múltiplos Medicamentos , Microssomos Hepáticos/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Animais , Bile/química , Cateterismo , Cromatografia Líquida , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Microssomos Hepáticos/química , Ratos , Ratos Endogâmicos F344 , Fatores de TempoRESUMO
The effects of the intrathecal alpha 2-agonists tizanidine and clonidine and the somatostatin analog octreotide on an experimental rat model of tactile allodynia were investigated to determine the therapeutic potential for treating chronic neuropathic pain. Allodynia was induced by ligating the rat sciatic nerve. The mechanical threshold for paw withdrawal was assessed by applying von Frey hairs to quantify analgesic actions. Mean 50% paw withdrawal thresholds were converted to the percentage of maximum possible effect (%MPE) where %MPE = (postdrug threshold-predrug threshold) divided by (15 g-predrug threshold) x 100. Dose-response curves were plotted for suppression of paw withdrawal 30 minutes after intrathecal injection of various doses of tizanidine, clonidine, and octreotide. Thresholds on the non-lesioned side were greater than 15 g. The lesioned side had baseline thresholds of less than 4.5 g. Dose-response curves were established for the antiallodynia effects of each drug. Tizanidine and clonidine at a 25-micrograms dose increased the threshold to greater than 97% of the MPE, but caused transient hindpaw weakness or sedation. No side effect was observed at a 10-micrograms dose, at which the threshold was 88-96% of MPE. Intrathecal octreotide modestly increased the threshold to only 49-67% of MPE, showing a lesser analgesic effect, although no side effect was observed at a 4-micrograms dose. The antiallodynic effects of intrathecal tizanidine and clonidine were more potent than that of octreotide.
Assuntos
Clonidina/análogos & derivados , Clonidina/farmacologia , Octreotida/farmacologia , Dor/tratamento farmacológico , Somatostatina/análogos & derivados , Animais , Injeções Espinhais , Masculino , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacosRESUMO
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.
Assuntos
Esclerose Lateral Amiotrófica/terapia , Fatores de Crescimento Neural/administração & dosagem , Proteínas do Tecido Nervoso/administração & dosagem , Atividades Cotidianas/classificação , Esclerose Lateral Amiotrófica/diagnóstico , Fator Neurotrófico Ciliar , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Bombas de Infusão Implantáveis , Injeções Espinhais , Taxa de Depuração Metabólica/fisiologia , Fatores de Crescimento Neural/efeitos adversos , Fatores de Crescimento Neural/farmacocinética , Proteínas do Tecido Nervoso/efeitos adversos , Proteínas do Tecido Nervoso/farmacocinética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinéticaRESUMO
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.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Dibenzocicloeptenos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Quinolinas/farmacologia , Tetra-Hidroisoquinolinas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Dibenzocicloeptenos/farmacocinética , Dibenzocicloeptenos/uso terapêutico , Humanos , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/tratamento farmacológico , Quinidina/metabolismo , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Verapamil/metabolismo , Verapamil/farmacologiaRESUMO
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.
Assuntos
Mapeamento Encefálico , Fator Neurotrófico Derivado do Encéfalo/farmacocinética , Córtex Cerebral/metabolismo , Sistema Límbico/metabolismo , Neurônios/química , RNA Mensageiro/análise , Animais , Transporte Biológico/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/citologia , Lobo Frontal/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Infusões Parenterais , Sistema Límbico/citologia , Masculino , Lobo Occipital/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacocinéticaRESUMO
Gemcitabine 2',2'-difluoro 2'-deoxy cytosine (GEM) is a novel nucleoside which has demonstrated broad preclinical anti-cancer activity and appears promising in early stage human clinical trials. One purpose of this study was to characterize the energetically favored conformational modes of GEM by means of ab initio quantum mechanical studies with comparison to a novel X-ray crystallographic structure, and to determine the performance of ab initio quantum mechanical theory by comparison with X-ray structural data for GEM and 2'-deoxy cytosine (CYT). Another objective of this study was to attempt to determine key structural and electronic atomic interactions relating to the 2',2'-difluoro substitution in GEM by the application of ab initio quantum mechanical methods. To our knowledge, these are the first reported ab initio quantum mechanical geometry optimizations of nucleosides using large (e.g. 6-31G*) slit valence function basis sets. The development of accurate physicochemical models on a small scale enables us to extend our studies of GEM to more complex studies including DNA incorporation, deamination, ribonucleotide reductase inhibition, and triphosphorylation.
Assuntos
Antimetabólitos Antineoplásicos/química , Citosina/análogos & derivados , Desoxicitidina/análogos & derivados , Fenômenos Químicos , Físico-Química , Cristalografia por Raios X , Citosina/química , Desoxicitidina/química , Modelos Moleculares , GencitabinaRESUMO
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.