Protective effect of a new hypothalamic peptide against cobra venom and trauma-induced neuronal injury.

A study of separate and combined actions of cobra venom (CV) and a new hypothalamic proline-rich polypeptide (PRP) isolated from magnocellular cells (NPV and NSO) on intoxication- and trauma-induced neuronal injury (during 3-4 weeks after hemisection with and without PRP treatment) was carried out. The registration of background and evoked impulse activity flow, changes in spinal cord (SC) inter- and motoneurons, responding to flexor, extensor, and mixed nerve stimulation in both acute and chronic experimental neurodegeneration was performed. The facilitating effect of PRP on the abovementioned neurons was revealed. High doses of CV that evoked the neurodegenerative changes demonstrated an inhibitory effect. In this case PRP treatment both before and after intoxication restored electrical neuronal activity to baseline level and higher. These results are evidence of protective action of PRP. The low doses of CV induced a facilitating effect. The combination of CV and PRP displayed an additive facilitating effect; in a number of cases the repeated administration of CV led to decrease of significant PRP effect till baseline level (for example, the inhibition after primary response prior to secondary late discharge). Greater liability of the secondary early and late long-time discharges of poststimulus responses, differently expressed in various neuron types of SC to chemical influences is of interest. PRP-induced inhibition of the paroxysmal activity related with CV action is also very interesting. Morpho-functional experiments with SC injury demonstrated the abolition of difference in the background and evoked SC neuronal activity below the section and on intact symmetric side after daily PRP administration for 3 weeks. PRP hindered the scar formation and activated neuroglia proliferation; it promoted white matter element growth, hampered the degeneration of cellular elements, and protected against tissue stress. Our results favor the combined use of PRP and CV in clinical practice for the treatment of neurodegeneration of toxic and traumatic origin, as well as specific neurodegenerative diseases such as Alzheimer's.

Protection against snake venom-induced neuronal injury by the new hypothalamic neurohormone.

The action of PRP is characterized by the pronounced activation of the background activity (BA) of the brain spinal cord, and the degree of the activity depends on BA initial level. The typical peculiarity of Vipera raddei venom influence is the initial increase in frequency of BA with subsequent depression. A preliminary injection of PRP has a protective effect at subsequent influence of venom. In animals with hemisection the PRP increases the decreased activity of neurons on injury side. Taking into consideration the protective peculiarities of PRP in the relationship to snake venom and the possibility of the latter to stabilize and prolong the action of drugs (in the case of PRP) combined with them, it is supposed that the mentioned use of the combination in clinical practice will be perspective. The data obtained testify the PRP to be a neuroprotector against many toxic compounds formed in organism (glutamate, ceramid, beta-amyloid neurotoxisity, etc.). Investigations in this aspect are still in the process.

Comparison of the protection against neuronal injury by hypothalamic peptides and by dexamethasone.

The comparative study has been carried out on hypothalamic neurohormone (proline-rich polypeptides-PRP) and synthetic glucocorticoid dexamethasone (DEX) protective properties at the systemic (i/m) administration. Both background and evoked electrical activity (on n.ischiadicus stimulation) of single neurons in the lumbo-sacral part (laminae II-VI and VII-VIII by Rexed) and field potentials (FP) of spinal cord were recorded during acute experiments on intact spinal rats, subjected to Vipera Raddei (VR) venom intoxication, and chronic spinal cord trauma (hemisection). The action of PRP was characterized by the pronounced activation of the background activity (BA) with adaptive effect, depending on dose and initial level of BA, by results of the statistical analysis. A high effect is received from comparatively small doses. For comparison it was used strong glucocorticoid DEX, possessing single-directed but less expressed excitative action on investigated spinal cord neurons. The initial increase of BA frequency with subsequent depression was the typical symptom of venom influence. A protective effect of preliminary PRP injection is revealed on the succeeding VR venom influence. Use of PRP and DEX causes the increase of reduced activity of neurons on the injury side of animals with spinal cord hemisection. It provides the possibility of the therapeutic utilization. It was revealed considerably more expressed PRP action on neurodegenerative process connected to spinal cord injury (in comparison with DEX). The influence of hormones was compared in identical conditions of experiments on non-injured (control) and injured sides. Taking into consideration revealed protection characteristic of PRP and also the ability of snake venom to stabilize and to prolong its action combined with these preparations, the assumption is made on prospective use of the specified combination in clinical practice.

Effect of beta-adrenergic agents on intracellular potential of rabbit ciliary epithelium.

PURPOSE: To study the effects of beta-adrenergic agents on intracellular potential (Vm) of the isolated and intact rabbit ciliary epithelium. METHODS: Vm was measured on the isolated intact ciliary epithelium superfused with adrenergic agents and cyclic AMP modulators. RESULTS: The nonselective beta-adrenergic agonist isoproterenol depolarized Vm in a dose-dependent fashion. beta-adrenergic antagonists alone had no effect on baseline Vm. The isoproterenol response was blocked by the nonselective antagonist timolol (5 x 10(-5) M). The selective beta 2-antagonist ICI 118-551 caused a greater inhibition (IC50 approximately 7 x 10(-7)) than the selective beta 1-antagonist betaxolol (IC50 approximately 6 x 10(-6)). The isoproterenol response was also significantly (p < 0.03) blocked by the non-selective alpha-antagonist phentolamine. Cyclic AMP and phosphodiesterase inhibitors significantly decreased Vm. Pretreatment with these inhibitors potentiated the agonist-induced depolarization. Barium, a blocker of Ca(2+)-sensitive K+ channels, significantly decreased baseline Vm. Barium pretreatment blocked the beta-agonist and cAMP induced depolarization of Vm, suggesting that the K+ current is necessary for the observed isoproterenol response. Pretreatment with the cotransport inhibitor bumetanide had no effect on the isoproterenol-induced response. CONCLUSIONS: The beta-adrenergic agonist isoproterenol affects ionic transport processes across the ciliary epithelium (beta 2 > beta 1). This effect is likely mediated through adenylate cyclase coupled to adrenoreceptors and requires the presence of the K+ current. Blockage of the isoproterenol-induced decrease in Vm by a nonselective alpha-adrenergic antagonist indicates an interaction between the two adrenergic systems in the ciliary epithelium.

Individual variability in concentrations of urinary sulindac sulfide.

Among 70 patients with arthritis who were receiving satisfactory maintenance therapy with sulindac (300 to 400 mg daily), 64% had no detectable sulindac sulfide (active metabolite) in one to four random urine specimens. However, 36% had 1.0 to 7.8 (mean, 2.2 +/- 1.4) micrograms/ml sulindac sulfide in urine, similar to the therapeutically effective concentrations found in 24 concurrent plasma specimens (1.4 to 9.0 micrograms/ml). Ten patients had sulindac sulfide in only one or two of two to four urine specimens. Thus, 36% of the patients had pharmacodynamically significant concentrations of sulindac sulfide in urine, presumably capable of suppressing the cyclooxygenase pathway responsible for prostaglandin synthesis in the kidney and elsewhere. The findings suggest individual variability in the capacity for renal oxidation of sulindac sulfide to inactive metabolites, perhaps related to genetic or environmental factors or both. These findings may help to explain conflicting reports on the effects of sulindac on urinary prostaglandins and renal function.

Serum concentration and dose-response relationships for carprofen in rheumatoid arthritis.

Thirty-eight patients with active, definite, or classical rheumatoid arthritis were tested in a double-blind, 3-week-per-arm, multiple-crossover, randomized, block-design comparison of 100, 300, 600, and 800 mg/day carprofen given b.i.d. A linear dose-response relationship was demonstrated for six of nine efficacy measures (p less than 0.052). A plasma concentration to therapeutic response relationship was shown just before or 1 to 2 hours after a dose (p less than 0.05) for seven efficacy parameters for the patients with at least three serum carprofen concentrations. By nonparametric analysis, with the patients divided into three equal groups, the percent of responders rose from 38.1% to 50% to 59.1%. Sixty-nine percent of patients responded when carprofen concentrations were greater than 10 micrograms/ml, whereas only 9% responded when they were below 1.9 micrograms/ml. Although only seven patients had limiting side effects, there was a tendency toward a dose-toxicity relationship through 600 mg daily carprofen.

Serum concentrations of salicylate and naproxen during concurrent therapy in patients with rheumatoid arthritis.

The kinetic interaction between salicylate and naproxen was investigated in 25 rheumatoid arthritis patients. Kinetic interactions were tested in serum after patients had been on each drug regimen for 1 month. Salicylate decreased serum naproxen concentration from 89.5 mg/liter to 65.9 mg/liter (P less than 0.001) and increased serum naproxen clearance by 56%. Naproxen had minimal effect on serum salicylate concentrations.

Serum enzyme abnormalities in juvenile rheumatoid arthritis.

Elevated serum transaminases, particularly SGOT, as a result of acetylsalicylic acid (ASA) therapy have been reported in patients with juvenile rheumatoid arthritis (JRA). In order to evaluate the possibilities that these elevated transaminases may result from JRA itself or from concomitant muscle injury, we correlated liver function tests and a specific test for muscle damage, creatine phosphokinase (CPK), with ASA therapy in 37 patients. These JRA patients were evaluated serially; 20 took ASA continuously, 6 took it intermittently, and 11 were on no therapy. Thirty-five healthy children were also studied to establish normal control values for the serum enzyme tests. Mean SGOT and SGPT in the 11 untreated subjects were significantly (P less than.001) higher than normal controls while CPK and alkaline phosphatase (AP) were not elevated. Mean SGOT and SGPT were also significantly (P less than .001) elevated in 20 children receiving ASA continuously; CPK was normal and AP less (P less than .05) than normal. CPK was elevated in 13 patients. Elevation of enzymes was sporadic and there was no correlation with serum salicylate, sex, age, disease duration, type, or activity. We conclude that mild abnormalities of SGOT and SGPT in JRA patients are common, but that they occur sporadically and elevated values appear to be unrelated to ASA therapy.

Correlation of plateau serum salicylate level with rate of salicylate metabolism.

The range of plateau serum salicylate concentrations was 4.4 to 33 mg/100 ml in patients with rheumatoid arthritis after they were treated with 50 mg/kg of aspirin daily for 5 days. Individual plateau serum levels correlated better with urinary excretion rates of the metabolite, salicylurate (whose maximum production is capacity-limited), than with total urinary excretion of salicylates. These observations suggest that large intersubject variations in plateau serum salicylate levels are determined, at least in part, by similar differences in the maximum rates of capacity-limited metabolic reactions. For optimal therapeutic responses, individualization of aspirin dosage by following serum salicylate levels is recommended.