piperidines and Neuritis

NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NF-κB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2). The result of absorption, distribution, metabolism and excretion and Docking studies indicated that among 51 designed molecules PA-3'K showed the best binding potential in both the substrate and inhibitory binding pocket of the COX-2 enzyme with affinity values of -9.33 and -5.12 for PDB ID 1CVU and 3LN1, respectively, thereby having the potential to be developed as a therapeutic agent. The results of cell viabilities indicated that PA-3'k possesses the best cell viability property with respect to its dose (17.33 ng/ml), with 67.76% and 67.93% viable cells for CHME3 and SVG cell lines, respectively.

Topics: Alkaloids; Animals; Benzodioxoles; Biological Availability; Cell Line; Computer Simulation; Cyclooxygenase 2 Inhibitors; Drug Design; Humans; Models, Molecular; Molecular Docking Simulation; Neuritis; NF-kappa B; Nitric Oxide Donors; Piperidines; Polyunsaturated Alkamides; Protein Transport; Structure-Activity Relationship; Tissue Distribution

Interleukin 1beta (IL-1beta) is a potent mediator of neutrophil accumulation. Antidromic stimulation of the rat saphenous nerve leads to neurogenic oedema formation mediated by endogenous tachykinins. Here, we have investigated links between IL-1beta and the tachykinin 1 (NK(1)) receptors in microvascular events in rat skin. Saphenous nerve-induced plasma extravasation was not modulated by skin pretreatment with IL-1beta (3 pmol/site intradermally). In addition, the long-lasting antidromic electrical stimulation did not induce significant neutrophil accumulation in naive rat skin. By comparison, the effect of IL-1beta-induced neutrophil accumulation was significantly potentiated by co-stimulation of the ipsilateral saphenous nerve; an effect prevented by an NK(1) receptor antagonist (SR140333, 480 nmol/kg, i.v.). We conclude that IL-1beta-induced neutrophil accumulation can be influenced in a pro-inflammatory manner by ongoing neurogenic inflammation, of relevance to the sensory nerve input that occurs during ongoing inflammatory disease.

Topics: Animals; Edema; Electric Stimulation; Interleukin-1; Male; Microcirculation; Neuritis; Neurokinin-1 Receptor Antagonists; Neutrophils; Piperidines; Plasma; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Sciatic Nerve; Sensory Receptor Cells; Skin; Tachykinins

Cannabinoid receptor (CB1) agonists strongly inhibit behavioral responses to acute noxious stimuli, but their effects on behavioral responses in persistent pain states are less clear. Here, we examined the effects of intrathecal (i.t.) administration of a CB1 agonist, WIN55,212-2, on mechanical allodynia (decreased withdrawal threshold) produced by injections of complete Freund's adjuvant (CFA) in the plantar surface of the rat hindpaw. We measured mechanical thresholds with calibrated von Frey filaments before and after CFA and used Fos expression as a marker of the activity of spinal cord neurons during inflammation and in response to a CB1 antagonist. One day post CFA-induced injury, mechanical sensitivity was significantly increased in the hindpaw ipsilateral to the CFA injection, as was the number of neurons that express Fos. Intrathecal injection of WIN55,212-2, significantly, reversed the allodynia at doses that had no effect on the mechanical threshold of the contralateral paw of CFA-treated or the withdrawal thresholds in naive animals. This effect was blocked by coadministration of the CB1 antagonist, SR141716A, with WIN55212-2. By itself, SR141716A, had no effect on mechanical thresholds in normal animals. In inflamed animals, SR141716A did not further reduce mechanical thresholds in the inflamed paw, but it significantly enhanced mechanical sensitivity 'contralateral' to the inflammation. Furthermore, i.t. injection of SR141716A increased Fos expression in both normal and inflamed animals, to a different extent in different laminae. In normal animals, the increase was primarily in laminae V-VI and in the ventral horn; in animals with persistent inflammation SR141716A increased the number of Fos neurons in laminae I-II and V-VI. These results demonstrate that WIN55212-2 reverses inflammation-induced allodynia at doses that do not produce analgesia and that SR141716A differentially affects the pattern of Fos expression in the spinal cord, depending on the presence or absence of inflammation. Taken together, these results suggest that the CB1 receptor system is tonically active in the spinal cord under normal conditions and that its activity is increased in response to injury.

Topics: Analgesics; Animals; Behavior, Animal; Benzoxazines; Cannabinoids; Immunohistochemistry; Injections, Spinal; Male; Morpholines; Naphthalenes; Nerve Tissue Proteins; Neuritis; Pain Threshold; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Stress, Mechanical

1. The effect of bradykinin, capsaicin, substance P and low pH medium on plasma extravasation in the guinea-pig conjunctiva has been studied. Evans blue dye was measured in the conjunctiva after local instillation of the agents into the conjunctival sac. 2. Bradykinin (2-50 nmol), capsaicin (20-50 nmol) and substance P (0.5-5 nmol) caused a dose-dependent increase in plasma extravasation with the following order of potency: substance P > bradykinin = capsaicin. The effect of capsaicin (50 nmol) and substance P (5 nmol) was abolished by the tachykinin NK1 receptor antagonist, CP-99,994 (8 mumol kg-1, i.v.) (P < 0.01), whereas CP-100,263 (8 mumol kg-1, i.v.) the inactive enantiomer of CP-99,994 was without effect. CP-99,994 inhibited by 70% (P < 0.01) the effect of bradykinin. 3. The kinin B2 receptor antagonist, Hoe 140 (icatibant, 10 nmol kg-1, i.v.) abolished the response to bradykinin (50 nmol) (P < 0.01), but did not affect the responses to capsaicin (50 nmol) or substance P (5 nmol). Plasma extravasation induced by low pH medium (pH 1) was abolished by CP-99,994 (P < 0.01) and by Hoe 140 (P < 0.01). 4. The present findings suggest that: endogenous or exogenous tachykinins increase plasma extravasation in the guinea-pig conjunctiva by activation of NK1 receptors; bradykinin-induced plasma extravasation is mediated by tachykinin release from sensory nerve endings; low pH media cause plasma extravasation via release of kinins that by activation of B2 receptors release tachykinins from sensory nerve endings.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Capillary Permeability; Capsaicin; Conjunctiva; Guinea Pigs; Hydrogen-Ion Concentration; Male; Neuritis; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Bradykinin; Substance P; Tachykinins

Case report of polyneuritis and liver dysfunction induced by perhexiline maleate in a 64 years old male patient. The ultrastructural study of nerve, liver, muscle and skin biopsies shows polymorphous, membrane bound, often multilamellar, lysosome-like inclusions, the content of which is probably complex lipids. The histochemical study of liver reveals a lipid storage, consisting mainly of triglycerides and of smaller amount of phospholipids and free fatty acids, the pattern of which is abnormal. The biochemical study of nerve tissue shows a decrease of phospholipids levels and some qualitative disturbances in gangliosides. These changes, some of which are similar to those reported in amphiphilic drug intoxications, are prevalent in high lipid metabolism cells such as hepatic and Schwann cells.

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Humans; Inclusion Bodies; Lipidoses; Liver; Male; Middle Aged; Neuritis; Perhexiline; Piperidines; Schwann Cells

Topics: Aminopyrine; Dipyrone; Drug Combinations; Drug Evaluation; Drug Synergism; Humans; Neuritis; Piperidines; Torticollis

Topics: Analgesics; Atropine; Chlorpromazine; Female; Humans; Lumbosacral Region; Male; Neuritis; Piperidines; Procaine; Spinal Nerves

Topics: Anesthetics, Local; Anilides; Cardiovascular Diseases; Humans; Neuritis; Pain; Piperidines; Spondylitis; Surgical Procedures, Operative; Xylenes