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Biomedical subjects

T P Jacobs

Publications and source records attributed to T P Jacobs.

At least 55 records · Page 3Linked to original sources
PubMed1983

Dynorphin induces partially reversible paraplegia in the rat.

Endogenous opioids have previously been implicated in the pathophysiology of spinal cord injury, but the specific opioid(s) involved has not been determined. Here we report that dynorphin administered intrathecally causes dose-related, partially reversible, hindlimb paralysis in the unanesthetized rat. Other opioids, including mu-selective and delta-selective synthetic enkephalins or beta-endorphin, failed to induce motor dysfunction. These findings suggest that dynorphin or dynorphin-related peptides may play a role in spinal cord injury.

Animals↗
PubMed1983

Comparison of naloxone and a delta-selective antagonist in experimental spinal stroke.

A highly predictive spinal "stroke" model in the unanesthetized rabbit was utilized to compare the effects of naloxone and the delta-selective opiate antagonist M154,129 on neurological recovery following ischemic injury to the central nervous system. Naloxone treatment protected against both moderate (20 min aortic occlusion) and severe (25 min aortic occlusion) degrees of ischemic spinal injury, whereas treatment with M154,129 failed to improve recovery in either model. These findings confirm that naloxone therapy can alter the pathophysiological sequelae caused by a critical reduction in blood flow to the central nervous system and suggests that its beneficial effects do not relate to actions at the delta-opiate receptor.

Animals↗
PubMed1983

Comparison of thyrotropin-releasing hormone (TRH), naloxone, and dexamethasone treatments in experimental spinal injury.

We have shown that early treatment with either naloxone or thyrotropin-releasing hormone (TRH) significantly improves neurologic outcome after experimental spinal injury. Because these previous studies used different injury variables, no conclusion could be made about the relative effectiveness of the two drugs. In the present study naloxone and TRH treatment (each 2 mg per kilogram bolus, 2 mg per kilogram per hour for 4 hours) were directly compared; other cats received either dexamethasone (0.5 mg per kilogram bolus, 0.5 mg per kilogram per hour) or saline. The spinal cord was traumatized at C-7, using the Allen method; treatment was begun 1 hour after injury. Neurologic function was graded between 0 and 10, using an ordinal rating scale. Both TRH- and naloxone-treated animals had significantly better functional scores than saline controls at 6 weeks postinjury. Moreover, TRH-treated cats also showed significantly better neurologic recovery than either naloxone- or dexamethasone-treated animals. These findings confirm the therapeutic benefit of TRH and naloxone in experimental spinal injury and indicate that TRH treatment is most effective. In contrast, corticosteroid treatment was of no benefit in the present model.

Animals↗
PubMed1983

Combined PGI2, indomethacin, and heparin improves neurological recovery after spinal trauma in cats.

Anesthetized cats were subjected to standardized cervical spinal trauma produced by a modification of the Allen weight-dropping method. One hour after injury, animals were randomly allocated to one of three treatment groups, in which they received 1) saline, 2) naloxone, or 3) combined treatment, consisting of indomethacin, heparin, and prostacyclin (PGI2). Treatment was continued for 4 hours. Neurological function was evaluated weekly by a neurologist unaware of the treatment group, and was graded by means of a scale modified from that of Tarlov. Functional recovery in animals receiving combined drug therapy was significantly better than in saline-treated control animals, and was similar to that observed in naloxone-treated animals. The findings are discussed with respect to "blood-damaged tissue interaction" and may have implications both with regard to the pharmacological management of acute spinal injury and to the mechanism of action of opiate antagonists.

Animals↗
PubMed1982

Therapy of hypercalcemia due to parathyroid carcinoma with intravenous dichloromethylene diphosphonate.

Dichloromethylene diphosphonate (Cl2MDP) a potent inhibitor of osteoclast-mediated bone resorption, lowers serum calcium in hypercalcemia associated wit malignancies and with primary hyperparathyroidism, and reduces excess calcium mobilization from bone in multiple myeloma and in Paget's disease. We have evaluated the effectiveness of intravenously administered Cl2MDP in five patients with parathyroid carcinoma, a disorder characterized by severe hypercalcemia, very high parathyroid hormone (PTH) levels, and marked osteoclast-mediated bone resorption. All patients had biopsy-proved metastatic parathyroid carcinoma and hypercalcemia which persisted after multiple surgical procedures and other attempts at management. During a three-day observation period, each patients continued to demonstrate stable or progressive hypercalcemia despite infusion with saline solution and furosemide. Cl2MDP was administered over 2 hours at 2.5 mg/kg on day 1 and 5 mg/kg on days 2 through 7. Response was noted in all five patients; there was a gradual decline in the average serum calcium from 16.0 +/- 1.1 mg/dl (SEM) to 11.1 +/- 0.9 mg/dl by the eighth day (p less than 0.01). There were concomitant reductions in urinary calcium excretion, from 798 +/- 153 mg/g creatinine to 350 +/- 96 mg/g creatinine (p less than 0.05) and in the urinary hydroxyproline excretion, from 155 +/- 38 mg/g creatinine to 94 +/- 29 mg/g creatinine (p less than 0.02). Serum PTH levels remained markedly elevated (460 +/- 141 micrograms eq/ml to 493 +/- 169 micrograms eq/ml). In three patients, all indices returned to pretreatment levels by 10 days after the last infusion. In two of these patients there was a response to retreatment with Cl2MDP with a fall in calcium from 16.9 +/- 0.5 mg/dl to 12.4 +/- 1.5 mg/dl. There was no response in one patient. No adverse reactions to Cl2MDP were observed. The decrease in serum calcium and concomitant declines in urinary calcium and hydroxyproline suggest that Cl2MDP can effectively inhibit the excessive bone resorption associated with parathyroid carcinoma.

Aged↗
PubMed1982

Comparison of early and late naloxone treatment in experimental spinal injury.

The effects of early (1 hour posttrauma) and late (4 hours posttrauma) naloxone treatment on neurologic recovery were compared after experimental cervical spinal injury. Neurologic scores did not differ significantly between the early and late naloxone-treatment groups, and both naloxone groups showed significantly better neurologic recovery than saline-treated controls during a 6-week follow-up. These findings confirm the therapeutic benefit of opiate antagonists in experimental spinal injury and indicate that even delayed naloxone treatment is effective in improving neurologic outcome.

Animals↗
PubMed1981

Thyrotropin-releasing hormone improves neurologic recovery after spinal trauma in cats.

Naloxone treatment improves neurologic outcome after experimentally induced spinal trauma, but this opiate-receptor antagonist may increase post-traumatic pain. In contrast, thyrotropin-releasing hormone appears to act in vivo as a partial physiologic opiate antagonist that spares analgesic systems; this activity prompted us to evaluate its effect in spinal injury. Cervical-spine trauma was produced in anesthetized cats by the Allen method. Six animals each received thyrotropin-releasing hormone, saline, or dexamethasone as an intravenous infusion over four hours, beginning one hour after injury. Neurologic recovery was significantly better after treatment with thyrotropin-releasing hormone than after saline or dexamethasone (P less than 0.01): at six weeks, the average animal given thyrotropin-releasing hormone was normal, whereas average control animals had marked spasticity. The beneficial effect of thyrotropin-releasing hormone in experimental spinal injury and its lack of effect on nociception indicate that it may have unique therapeutic potential in spinal trauma in human beings.

Animals↗
PubMed1981

Dopamine partially mediates the cardiovascular effects of naloxone after spinal injury.

Following spinal injury, the opiate antagonist naloxone selectively elevates plasma dopamine levels, with the dopamine changes significantly correlated with improved cardiovascular function. Moreover, the cardiovascular effects of naloxone are significantly attenuated by pretreatment with the dopamine antagonist domperidone. From these data, it is concluded that the cardiovascular effects of naloxone after spinal injury are in part dopamine mediated.

Animals↗
PubMed1981

Opiate antagonist improves neurologic recovery after spinal injury.

The opiate antagonist naloxone has been used to treat cats subjected to cervical spinal trauma. In contrast to saline-treated controls, naloxone treatment significantly improved the hypotension observed after cervical spinal injury. More critically, naloxone therapy significantly improved neurologic recovery. These findings implicate endorphins in the pathophysiology of spinal cord injury and indicate that narcotic antagonists may have a therapeutic role in this condition.

Animals↗
PubMed1981

Endorphins in experimental spinal injury: therapeutic effect of naloxone.

An experimental model of cat spinal injury was used to investigate the hypotheses that endorphins are involved in the pathophysiology of spinal cord injury and that the opiate antagonist naloxone, by blocking the effects of endorphins, may improve physiological and neurological recovery. Experimental trauma to the cervical spine caused a reduction in blood pressure and spinal cord blood flow (SCBF) associated with increased plasma levels of beta-endorphin-like immunoreactivity; both blood pressure and SCBF were significantly improved by naloxone treatment. Naloxone-treated animals also showed less prominent spinal cord abnormalities and significantly improved neurological recovery compared with saline controls. Moreover, both the pathological and clinical findings correlated significantly with the blood pressure changes following treatment. The data support a pathophysiological role for endorphins in experimental spinal cord injury and suggest that opiate antagonists might improve the treatment of spinal trauma in humans.

Animals↗
PubMed1981

Clinical and biochemical effects of EHDP in Paget's disease of bone: patterns of response to initial treatment and to long-term therapy.

Studies regarding the efficacy of EHDP in the treatment of Paget's disease of bone conducted at our institution are described. An initial placebo-controlled clinical trial established that doses of 5 mg/kg/day for 6 months produced symptomatic improvement and a 50% lowering of serum alkaline phosphatase and urinary hydroxyproline. A subsequent study indicated that the biochemical suppression was maintained during the ensuing 6 months without therapy. Current results of long-term intermittent EHDP treatment in 40 patients studied for 5-8 years demonstrate that a small minority of individuals experience a sustained remission after a single six-month course of therapy, while a majority require repeated courses of 5 mg/kg/day for 6 of every 12 months to maintain their initial improvement. Data are also presented describing the successful use of EHDP at a dose of 20 mg/kg/day for 1 of every 4 months in patients refractory to conventional low doses of therapy. The possible role of parathyroid hormone in the expression of Paget's disease is also discussed, and recommendations regarding the pharmacologic management of patients with this disorder are provided.

Calcitonin↗
PubMed1981

Hypercalcemia of malignancy: treatment with intravenous dichloromethylene diphosphonate.

Twelve patients with hypercalcemia associated with various malignancies were treated with intravenous dichloromethylene diphosphonate (Cl2MDP), a potent inhibitor of osteoclastic bone resorption, in doses of 2.5 mg/kg of body weight initially and 5.0 mg/kg thereafter for up to 7 days. Mean serum calcium concentration fell from 13.8 +/- 0.6 mg/dL (SEM) before Cl2MDP to 9.8 +/- 0.7 mg/dL (SEM) (p less than 0.001) after 7 days. Urine calcium excretion fell from 775 +/- 95 mg/g creatinine (SEM) to 272 +/- 70 mg/g creatinine (SEM) (p less than 0.005), and urine hydroxyproline excretion fell from 144 +/- 28 mg/g creatinine (SEM) to 78 +/- 18 mg/g creatinine (SEM) (p less than 0.05) after treatment with Cl2MDP. The Cl2MDP was well tolerated, and adverse effects were limited to asymptomatic hypocalcemia in two patients. The ability of Cl2MDP to correct hypercalcemia and reduce urine calcium and hydroxyproline excretion in these patients is consistent with the hypothesis that increased bone resorption is primarily responsible for this complication of malignancy and suggests that Cl2MDP may be highly useful in managing this condition.

Adult↗
PubMed1980

Long-term therapy of Paget's disease of bone with EHDP.

Forty patients with Paget's disease of bone were treated with intermittent courses of the diphosphonate, EHDP. Seven individuals had prolonged remissions after their initial course of therapy, nineteen responded to retreatment with 5 mg/kg of EHDP for 6 months of each year, while 14 patients required cycles of 20 mg/kg for 1 month of every 4. Improvement was indicated by alleviation of symptoms and reduction in serum alkaline phosphatase and urinary hydroxyproline. Data suggesting a possible role for parathyroid hormone in the expression of Paget's disease are also discussed.

Aged↗
PubMed1980

Endorphin-parasympathetic interactions in spinal shock.

We have recently shown that the opiate antagonist naloxone can partially reverse the hypotension which accompanies spinal cord transection, through actions on opiate receptors in the central nervous system. In the present studies we demonstrate that either vagotomy or atropine prevents the ability of naloxone to reduce the hypotension caused by spinal transection in the rat and cat. Since the peripherally acting methyl-atropine blocks the cardiovascular effects of centrally administered naloxone in this model, these findings imply an interaction between endorphin systems and central parasympathetic centers in spinal shock. This interaction results in a depression of cardiovascular function which is mediated through cholinergic vagal efferent pathways. Furthermore, the fact that naloxone reduces the hypotension following spinal transection, along with the role of the parasympathetic system in this process, appears to question the classic conception that such hypotension results entirely from interruption of descending sympathetic pressor pathways. Finally, the beneficial cardiovascular effects of naloxone in spinal shock may have important therapeutic implications in the management of spinal cord injury.

Animals↗
PubMed1979

Giant cell tumor in Paget's disease of bone: familial and geographic clustering.

Four patients with benign giant cell tumor and one patient with probable benign giant cell tumor associated with Paget's disease of bone are reported. The familial and geographic clustering of these cases is unique in that three patients were related and all patients traced ancestral roots to the same area of southern Italy. Tumors arose from the cranial or facial bones in three patients and from vertebral bodies in two patients. All caused symptoms by local compression, and treatment by curettage or radiotherapy was successful in all patients. Three separate tumors in one patient shrank dramatically in response to treatment with high doses of dexamethasone, and one patient whose tumor caused spinal cord compression showed marked improvement in neurologic function on therapy with dexamathasone.

Bone Neoplasms↗