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Biomedical subjects

R D Penn

Publications and source records attributed to R D Penn.

At least 37 records · Page 2Linked to original sources
PubMed1996

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.

Animals↗
PubMed1996

Intraspinal morphine for chronic pain: a retrospective, multicenter study.

Intraspinal opioids are frequently used in the treatment of cancer and noncancer pain, but few studies have evaluated the efficacy of this technique. This multicenter, retrospective study surveyed physicians in the United States regarding their standard practices when using intraspinal opioids delivered via an implanted drug administration device. Thirty-five physicians (50.0%) responded, providing 429 usable patient forms (52.4%), which sought information about screening, outcomes, dosing, and adverse effects. Patients with malignant (32.7%) and noncancer (67.3%) pain had been treated for an average of 14.6 +/- 0.57 months (range, 8-94 months) at the time of form completion. For all patients, the mean percent relief was 61.0% +/- 1.35%. Patients with somatic pain tended to have greater relief, as measured by a global rating of pain relief, than did patients with other types of pain (Mann-Whitney test, P = 0.0003). After titration during the first 3 months, intrathecal morphine doses increased only twofold from 6.84 +/- 0.65 mg/day at 3 months to 13.19 +/- 1.76 mg/day at 24 months. Compared to those with noncancer pain, malignant pain patients had a higher average initial dose. The average dose used by cancer patients escalated quickly and then stabilized, whereas the average doses used by noncancer pain patients exhibited a more gradual, linear increase in dose. Long-term adverse drug effects were uncommon, but system malfunction, usually catheter related, occurred in 21.6% of patients. Prospective, randomized, controlled clinical studies of long-term efficacy and adverse effects are warranted.

Adolescent↗
PubMed1996

Intrathecal clonidine and tizanidine in conscious dogs: comparison of analgesic and hemodynamic effects.

Intrathecal delivery of alpha(2)-adrenergic agonists produces an analgesic effect. However, hemodynamic side effects limit their clinical usage. To more fully characterize the effects on heart rate and arterial blood pressure of alpha(2)-adrenergic agonists, clonidine and tizanidine were injected intrathecally in conscious dogs. Both compounds produced a potent inhibition of thermal foot-withdrawal latencies at 1000 micrograms, which was blocked by the alpha(2)-adrenergic antagonist yohimbine. Tizanidine (250-500 micrograms) did not change heart rate. Clonidine (500 -2000 micrograms) and tizanidine (1000-2000 micrograms) decreased heart rate. The tizanidine effect was inhibited by yohimbine and the alpha(2)/imidazoline antagonist idazoxan, as well as the parasympathetic blocker glycopyrrolate. No drug completely inhibited the clonidine-induced bradycardia. Clonidine had a biphasic effect on arterial blood pressure, a decrease at 500 micrograms and an increase at 2000 micrograms. Tizanidine decreased arterial blood pressure at all doses. The results indicate that, while the analgesic effects of both drugs are similar, the hemodynamic responses differ. While the decrease in heart rate with tizanidine is consistent with alpha(2)-adrenergic binding and vagal action, the bradycardia induced by clonidine is more complex. In addition, the increased arterial blood pressure with high doses of clonidine, which is suggestive of a peripheral vasoconstrictive effect, does not occur with tizanidine.

Adrenergic alpha-Agonists↗
PubMed1996

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.

Adult↗
PubMed1996

Deep brain stimulation for essential tremor.

We examined the effects and safety of deep brain stimulation (DBS) as a treatment for essential tremor (ET). Ten ET patients with disabling medication-refractory tremor underwent stereotactic implantation of a DBS lead in the left Vim thalamic nucleus and completed a 6-month follow-up. The Clinical Tremor Rating Scale and disability assessments were performed at baseline, 1-, 3-, and 6-month follow-up. There were significant improvements in dressing, drinking, eating, bathing, and handwriting as reported by the subjects. Tremor severity, writing, pouring, and spiral and line drawing were significantly improved as rated by the examiner. Improvements persisted through the 6-month follow-up period. Although global disability significantly lessened in the group as a whole, one subject with hand-finger tremor accentuated by writing had no change in disability status. In this 6-month open-label study, DBS was effective and safe in reducing tremor and functional disability in ET.

Aged↗
PubMed1995

Intrathecal baclofen for motor disorders.

To test the efficacy of intrathecal baclofen in various movement disorders, 18 patients with dystonia, head trauma, cerebral palsy, rigidity, or painful spasms underwent a trial of intrathecal baclofen. Ten went on to permanent implantation with an infusion pump to provide long-term treatment. Patients with a component of spasticity, painful spasms, or focal dystonias did best, and no response was seen in patients with rigidity due to anoxic encephalopathy. A videotape of responses is provided.

Adolescent↗
PubMed1995

The effects of intrathecally administered baclofen on function in patients with spasticity.

The purpose of this article is to review the literature on the effects of intrathecally administered baclofen on impairment in spasticity and muscle activation patterns, on functional limitations in mobility and self-care, and on disability in daily life roles. We found plentiful evidence of improvement in spasticity, spasms, and bladder function and some reports of improved patterns of muscle activation and kinematics of single-joint movement. Improved ability to accomplish transfers, self-care, and locomotion is less consistently studied but has also been reported in about 60% to 70% of patients. Evidence of improved quality of life is primarily anecdotal but may be found in 10% to 30% of patients. We conclude that research protocols should be developed to clarify effects on control of voluntary movement, functional limitations, and quality of life.

Activities of Daily Living↗
PubMed1995

Catheter systems for intrathecal drug delivery.

A prospective study of intrathecal catheter reliability was performed at Rush-Presbyterian-St. Luke's Medical Center. All 102 patients who had baclofen administered chronically for spasticity via an implanted drug pump were included. Sixty percent of the patients had no catheter complications; the remaining patients had one to five complications over their course of treatment. Survival analysis demonstrated a steady rate of malfunction up to 80 months, with the mean time to first failure recorded at 20 months. Kinks, holes, breaks, dislodgments, and disconnections were the most common complications. On the basis of their research the authors conclude that the thin-walled silastic catheter does not perform well and that larger, thick-walled catheters should be used.

Adolescent↗
PubMed1994

Intrastriatal infusions of brain-derived neurotrophic factor: retrograde transport and colocalization with dopamine containing substantia nigra neurons in rat.

The pattern of retrogradely transported BDNF, a member of the nerve growth family of neurotrophins, following intrastriatal infusion was immunohistochemically visualized within the rodent central nervous system. Human recombinant BDNF was infused at a rate of 3 micrograms/h for 7 days with an Alzet 2002 minipump prior to sacrifice. Tissue immunohistochemically processed using a turkey anti-BDNF antibody revealed retrogradely transported BNDF within neurons located mainly within the ipsilateral frontoparietal cortex (predominantly layer V), parafascicular and posterior thalamic nuclei, and substantia nigra, pars compacta. Sections dual immunoreacted for BNNF and tyrosine hydroxylase revealed a subpopulation of dopaminergic neurons (approximately 28%) within the pars compacta which contained retrogradely transported BDNF. Experiments in which a mixture of BDNF and the retrograde tracer fluorogold were simultaneously infused for 7 days into the striatum revealed BDNF and fluorogold single-labeled neurons as well as BDNF and fluorogold dual-labeled cells within the substantia nigra, pars compacta. These observations indicate that only a subpopulation of neurons within the substantia nigra retrogradely transport BDNF following intrastriatal infusion and thus only a subpopulation of cells may be responsive to the trophic influences of BDNF. The retrograde transport of trophins, such as BDNF, represents a unique neuroanatomical tool to selectivity map the location of specific neurotrophin-responsive systems. Unraveling the trophic anatomy of BDNF will aid in understanding its role in development, degeneration, and experimental animal models of regeneration providing essential data for its use in clinical neurodegenerative disorders including Parkinson's disease.

Animals↗
PubMed1994

Altered sexual function and decreased testosterone in patients receiving intraspinal opioids.

Altered sexual function has been reported in individuals addicted to opioids or on methadone maintenance, yet little literature is available regarding the effect of intraspinal opioids on libido or sex hormone levels. We evaluated sexual function and plasma sex hormone levels in six men treated with chronic intraspinal opioids. All patients had some reduction in libido and four patients had difficulty obtaining or maintaining an erection. These changes were noted within 1 month of beginning intraspinal opioid therapy. Serum testosterone levels ranged from 26 to 367 ng/dL (normal, 350-1500 ng/dL); the mean serum level was 197.7 ng/dL (SD = 119.8). Serum testosterone levels and other sex hormones, including follicle-stimulating hormone, luteinizing hormone, sex-hormone-binding globulin, and prolactin, should be measured prior to and at various points during intraspinal opioid therapy. Patients should be queried regarding sexual function and should be cautioned regarding the possibility of these adverse effects prior to initiating spinal opioids. Supplemental testosterone should be considered to treat this dysfunction.

Adult↗
PubMed1993

Spinal cord transection produces a long-term increase in GABAB binding in the rat substantia gelatinosa.

Quantitative autoradiography was used to determine changes in GABAB receptor binding in the substantia gelatinosa of the lumbar spinal cord at 4 days and at 6 weeks after a midthoracic spinal transection in rats. In the 4 day lesion animals, there was no significant change in either the density or the affinity of the GABAB binding. At 6 weeks, however, there was a 35% increase in binding density, with no significant change in affinity. The results suggest that alterations in spinal synaptic mechanisms can slowly evolve following loss of descending input to the spinal cord.

Animals↗
PubMed1993

Neurosurgical horizons in Parkinson's disease.

Based on recent neuroanatomic and physiologic discoveries, neurosurgical therapies may increasingly complement and extend pharmacologic management of Parkinson's disease. Procedures showing promise include subthalamotomy and pallidotomy; thalamic electrical stimulation may also offer application for tremor control. Transplantation of adrenal chromaffin cells has not been associated with consistent long-term improvement in most patients, and fetal mesencephalic transplantation remains controversial. Trophic factors that may be pivotal to cellular repair and survival of transplanted tissue have potential therapeutic roles when purified and perfused centrally or when the cells that produce the factors are transplanted.

Adrenal Glands↗
PubMed1993

Intrathecal baclofen down-regulates GABAB receptors in the rat substantia gelatinosa.

At present, it is not clear why drug tolerance develops in patients receiving intrathecal baclofen for the chronic treatment of spasticity of spinal origin. To investigate the mechanisms of tolerance to the gamma-aminobutyric acid (GABAB) agonist baclofen, rats were implanted with intrathecal catheters and continuously infused with either the drug or saline for 1, 3, or 7 days. The dose chosen, 1 microgram/hr, initially caused profound hindlimb motor weakness, but by Day 7 the rats had adapted to the drug and exhibited only minimal motor impairment. The animals were sacrificed on Day 1, 3, or 7 and quantitative autoradiography was used to determine the binding density and affinity of the GABAB receptors in the substantia gelatinosa of the lumbar spinal cord. After 1 day of drug infusion there was no change in binding parameters, but after 3 and especially after 7 days there was a significant decrease in the GABAB binding density (74% and 66%, respectively) in baclofen-treated rats as compared to saline-treated control rats. This GABAB receptor down-regulation correlated with tolerance to the motor weakness in the baclofen-treated animals and suggests that similar mechanisms contribute to drug tolerance in patients.

Animals↗