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Purpose: Resolvin E1 (RvE1; RX-10001) belongs to a new class of endogenous immunoregulating mediators, originally identified as a metabolite of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid. Based on its proven efficacy in models of chronic inflammation, this study investigated the efficacy of resolvin E1 in a murine model of dry eye., Methods: C57/B6 mice, aged 6 to 8 weeks, were treated with systemic scopolamine and exposed to air draft and low humidity for 16 hours/day for 5 days and allocated to the following groups: unexposed controls, disease controls, treatment with vehicle or RvE1 delivered topically as its methyl ester prodrug, RX-10005, to enhance corneal surface penetration. Treatment was initiated at the time of desiccating stress induction. Treatment efficacy was assessed by corneal permeability using Oregon Green Dextran and by conjunctival goblet cell density using periodic acid-Schiff reagent., Results: RvE1 reduced the increase in corneal staining by 80% compared with untreated disease controls. Goblet cell density was reduced by 20% in disease controls but fully maintained in the group receiving RvE1., Conclusions: RvE1, delivered as its methyl ester prodrug, improved the outcome measures of corneal staining and goblet cell density in this murine model of dry eye, indicating the potential utility of endogenous resolvins and resolvin analogues in the treatment of dry eye.

Background: A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS)., Objective: To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status., Design and Methods: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging., Results: Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138)., Conclusions: In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

The synthetic immunomodulator Linomide, a quinoline-3-carboxamide, has a profound inhibitory influence in several experimental autoimmune diseases, including acute and chronic experimental allergic encephalomyelitis. In a double-blind trial, 31 patients with relapsing-remitting multiple sclerosis were randomized to oral doses of 2.5 mg Linomide or placebo once a day for six months. Fourteen patients receiving Linomide and 14 receiving placebo completed the trial, and the results were based on this population. The mean number of active (new and enlarged T2 weighted) lesions per monthly MRI scan was 1.37 in the patients receiving Linomide and 4.22 in the patients receiving placebo (p = 0.043). The percentage of scans with active MRI lesions was lower in the Linomide-treated group (p = 0.0064). When neurologic deficit was assessed by the Regional Functional Scoring System (RFSS), the Linomide group showed an improvement of 1% of the maximal RFSS range and the placebo group a deterioration of 0.2% (p = 0.14). There were three patients with relapses in the Linomide-treated group and six in the placebo group (p = 0.22). A slightly decreased proportion of natural killer cells in cerebrospinal fluid and peripheral blood was noted in the Linomide group. A severe adverse event of pleuropericarditis occurred in one of the Linomide-treated patients. The most frequent adverse event was musculoskeletal pain, of mild to severe degree, which tended to diminish after three months on Linomide therapy.

Amylase secretion from dispersed lobules of the parotid gland of the rabbit was studied in response to isoprenaline (10(-8)-10(-5) M) and to carbachol (10(-8)-10(-5) M). The effects of each agent were investigated along and in combination at certain concentrations. Isoprenaline produced a dose-related amylase secretion with an average maximum of 688 units/100 mg, at 10(-5) M. The amylase secretion produced by submaximal concentrations of isoprenaline could be further increased by carbachol, already in low concentrations (10(-8)-10(-7) M), that were subthreshold for amylase secretion. This potentiating effect was seen not only as a larger secretion but also as a greater depletion of amylase from the tissue. In contrast to what is known from experiments in vivo, carbachol in a high concentration (10(-5) M), by activating muscarinic receptors only, released amylase to the same extent as that released by isoprenaline. This concentration of carbachol regularly decreased the amylase secretion evoked by isoprenaline, and may be regarded as unphysiologically high. The increase in isoprenaline evoked amylase secretion, brought about by carbachol in lower concentrations, may be due to an improved transport of amylase, because of secretion of fluid, but could also be caused by augmentation of the beta-adrenoceptor mediated effects.

In rabbits under urethane anaesthesia parotid secretion of fluid and amylase in response to electrical stimulation of the sympathetic and parasympathetic nerves was measured before and after injections of various agents acting on alpha-adrenoceptors. Amylase secretion in response to sympathetic nerve stimulation at 0.5 and 1 Hz was markedly reduced by clonidine, 0.5-30 micrograms/kg, in a dose related manner. The effect was not due to an altered responsiveness of the gland, since isoprenaline still caused a large release of amylase. Phenylephrine, 10 micrograms/kg, and prazosine, 300 micrograms/kg, had no effect on the sympathetically evoked amylase secretion. Yohimbine in a dose of 0.5 mg/kg increased the amylase output in response to sympathetic nerve stimulation at 0.5 Hz by 70%, while the response at 1 Hz, which is close to maximum for the gland, was not significantly increased. The fluid and amylase secretion produced by parasympathetic nerve stimulation at 1.5, 5.0 and 10 Hz remained unchanged after clonidine, 1.0-30 micrograms/kg, or yohimbine 0.5 mg/kg. In rabbits provided with chronic parotid fistulae fluid and amylase secretion were studied after injections of clonidine, 30 micrograms/kg, and yohimbine, 1 mg/kg. In the conscious animal clonidine reduced not only amylase but also fluid secretion, by around 50 and 30%, respectively, indicating an effect on the activity in both the sympathetic and parasympathetic secretory nerves. Yohimbine increased the output of amylase during feeding, seen as an increased mean output of amylase due to an increased concentration of amylase in the saliva, while fluid secretion remained unchanged. The various experiments suggest that amylase secretion in response to sympathetic activation may be influenced by prejunctional control of transmitter release via alpha-2-adrenoceptors, and that this control may be of physiological significance. Parasympathetically evoked secretion does not seem to be under the influence of a similar control.

After extirpation of the superior cervical ganglion in the rat a degeneration secretion of amylase occurs in an in vitro preparation of the parotid gland. It can be detected about 14 h after the sympathectomy, reaches a maximum after about 17 h and then slowly subsides. It is abolished by atenolol, but not by dihydroergotamine or atropine, nor by tetrodotoxin. From this it is concluded that the phenomenon is due to an action mainly on beta 1-adrenoceptors exerted by noradrenaline, which is released from the degenerating sympathetic nerves at the neuro-glandular junctions, independently of propagated nerve impulses.

Cat myocardium was used to investigate muscarinic receptor function in atria and ventricles. Carbachol and oxotremorine were used to determine agonist binding to the muscarinic receptors. It was found that carbachol was bound with almost the same characteristics in atria (KdH 1 microM; KdL 150 microM) as in ventricles (KdH 3 microM; KdL 150 microM). However, in the presence of guanylylimidodiphosphate Gpp(NH)p a difference was apparent so that the ventricular curve was shifted to a majority of low affinity sites whereas in atria two affinity sites remained even if the guanine nucleotide concentration was increased to 10 mM. Oxotremorine was bound with almost equal affinity in both atria and ventricles. The addition of Gpp(NH)p left all the receptors in the low affinity state irrespective of receptor localisation. The two agonists were also used to determine inhibition of adenylate cyclase activity. It was shown that the magnitude of adenylate cyclase inhibition was more pronounced in ventricles than in atria whether it was induced by oxotremorine or carbachol. When the effects of muscarinic agonists were determined on phosphatidylinositol metabolism it was shown that carbachol mediated a greater effect in atria than in ventricles. Almost no effect was seen with oxotremorine on phosphatidylinositol breakdown. Pirenzipine binding showed the presence of M1 receptors both in atria and ventricles. On the basis of diversity of muscarinic agonists on function and receptor occupancy it is suggested that heterogeneity exists for muscarinic receptors in both atria and ventricles.

H 160/51 is a calcium agonistic 1,4-dihydropyridine. Its optical isomers were now found to have opposing actions in the cat papillary muscle and rat portal vein. The inhibitory (+)-enantiomer had potencies of the same order as those of the stimulatory (-)-enantiomer. However the racemate and the (-)-enantiomer had approximately the same potencies and intrinsic activities. A model is presented to account for the fact that the effects of the inhibitory (+)-enantiomer can be concealed in the effects of the racemate of H 160/51.

The excitation of the chorda-tympani nerve caused a marked increase in the blood flow through the gland and in secretion of saliva; both phenomena had a threshold frequency of around 0.3 Hz and reached a maximum at around 20 Hz, where a 6-fold increase in the blood flow and a salivary secretion of at the most 300 microliters/min were seen. Sympathetic excitation severely retarded the blood flow, which almost ceased at frequencies as low as 3-5 Hz; mostly single shocks of sympathetic stimulation reduced the blood flow through the gland. An on-going parasympathetic activation did not alter the effects of sympathetic stimulation on the blood flow and the parasympathetically produced salivary secretion almost stopped. The experiments support previous results, which have suggested electrical excitation of the sympathetic trunk at or above 2 Hz to cause a vasoconstriction which adversely affects the fluid secretion in the rabbit salivary glands.

Sympathetic secretory responses from the parotid and the submaxillary glands of the rabbit were studied; sympathetic excitation occurred either alone or during a slow parasympathetic background secretion, imitating the resting secretion normally present. The fairly rapid sympathetically evoked flow of saliva from the parotid gland was, in the background secretion, further increased and obtained at low frequencies, which at sympathetic stimulation alone were subthreshold. The effects, which could be repeated with sympathomimetic drugs in a pilocarpine induced secretion, were abolished by alpha and beta-adrenoceptor blockade in combination. The submaxillary gland gave a very scanty secretion on sympathetic excitation, the effects being mediated via beta-adrenoceptors. The responses were not increased in a background secretion but the main effect of sympathetic activation was to retard the salivary flow. The retardation was attributed to vasoconstriction accompanying sympathetic excitation. Eliminating the vasoconstrictor responses, while retaining the sympathetic secretory effects, did not reveal any increase of the sympathetic salivary responses in the submaxillary gland.

Reflex secretion of amylase was studied in response to feeding pellets and carrots. Section of the ipsilateral glossopharyngeal nerve but not of the lingual nerve reduced the secretion of amylase with carrots but not with pellets. The fluid secretion was unaffected by the nerve sections. Larger volumes were secreted with pellets than with carrots, indicating that the hardness of the food, via chewing, is the main stimulus for fluid secretion. Sweet, salty, sour and bitter taste stimuli did not produce any fluid secretion in concentrations normally used for gustatory stimulation in rabbits. In a background flow of parasympathetically secreted saliva sweet stimuli regularly caused a large increase in the amylase output, salty stimuli usually had a small effect and sour and bitter stimuli seemed to have only exceptionally a small effect. Citric acid in a high concentration caused fluid secretion, at the most at a rate of about 50% of maximum; this saliva had a high content of amylase. The results support the view that during feeding the sympathetic secretory nerves can be activated via both taste stimulation and chewing, while the parasympathetic activity is mainly influenced by chewing.

The contribution by different autonomic receptors to the amylase secretion from the parotid gland of the anaesthetized rabbit was studied as the response to various parasympathomimetic and sympathomimetic drugs. Amylase secretion by infusions of pilocarpine and parasympathetic nerve stimulation was low, but regularly higher in response to pilocarpine than to parasympathetic nerve stimulation. These effects were reduced to the same level by beta-adrenoceptor block indicating the presence and for pilocarpine also the release of catecholamines, probably from the adrenals. Isoprenaline injections produced a high amylase secretion, that was blocked by atenolol, indicating that predominantly beta 1-adrenoceptors were activated. Phenylephrine was without amylase secretory effects. By accepting isoprenaline maximum as maximum for sympathetically produced amylase secretion, a theoretical frequency-response relationship for amylase secretion by sympathetic nerve stimulation could be calculated: ED50 was 0.9 Hz. The results indicate that under experimental conditions in vivo there are certain differences between the rat and the rabbit parotid glands in the autonomic control not only of fluid, but particularly of amylase secretion.