Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Porcine small intestinal submucosa (SIS) has been recommended as a cell-free, biocompatible biomaterial for the repair of rotator cuff tendon tear. However, we have observed noninfectious edema and severe pain in patients who have undergone SIS implantation for tendon repair. The aim of this study was to conduct an independent assessment of the safety and efficacy of Restore SIS membrane. The Restore orthobiologic implant was examined by histology and the nested PCR technique using porcine immunoreceptor DAP12 gene to examine if SIS membrane contained porcine cells or DNA, respectively. The material was also implanted into mice and rabbits for the evaluation of biological reaction and inflammatory response. Restore SIS was found to contain multiple layers of porcine cells. Chloroacetate esterase staining showed that some of these cells were mast cells. Nested PCR of the DAP12 gene demonstrated that Restore SIS contained porcine DNA material. Subcutaneous implantation of Restore SIS membrane in mice, and in rabbits for rotator cuff tendon repair, showed that the membrane caused an inflammatory reaction characterized by massive lymphocyte infiltration. In conclusion, Restore SIS is not an acellular collagenous matrix, and contains porcine DNA. Our results contradict the current view that Restore SIS is a cell-free biomaterial, and that no inflammatory response is elicited by its implantation. We suggest that further studies should be conducted to evaluate the clinical safety and efficacy of SIS implant biomaterials.
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PMID:Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: possible implications in human implantation. 1573 87

Spontaneous bacterial peritonitis (SBP) is one of the main infectious complications of cirrhosis and occurs in 8-30% of hospitalized patients with ascites. SBP is characterized by infection of the ascitic fluid (AF) in the absence of any primary focus of intra-abdominal infection. The main route by which the AF becomes infected is the hematogenous route. The pathogenic mechanism by which infection develops is bacterial translocation from the intestinal flora to the mesenteric lymph nodes and from there to the bloodstream. Contributing factors are an increased growth of Gram-negative aerobic bacilli in the jejunum, changes in the intestinal barrier and in addition factors which could reduce the local flow of blood. For clinical diagnosis, patients with SBP may present signs of peritoneal irritation and pain, together with changes in gastrointestinal motility, sometimes with nausea, vomiting, diarrhea or ileus. Many patients, however, may not present any symptoms or signs as a result of the presence of SBP. Diagnostic paracentesis of the AF must be performed for every patient with cirrhosis, hospitalized with ascites. Laboratory diagnosis of SBP is carried out by polymorphonuclear count in the AF, together with a positive culture from the AF, which is characteristically monomicrobial. Escherichia coli has been the main bacterium isolated from AF as well as other Gram-negative bacteria from the Enterobacteriaceae family and Streptococcus genus. A more rapid diagnosis of SBP can be obtained via the use of leukocyte esterase, which is present in biological fluids and reacts with a component of the dipstick, changing its color. During the acute phase of SBP, antibiotics should be initiated promptly once the clinical and laboratory diagnosis of SBP has been made, before the result of AF culture. Cefotaxime or other third-generation cephalosporins have been considered the first-choice empirical antibiotics in the treatment of cirrhotic patients with SBP, and is efficacious in approximately 90% of cases. Broad-spectrum quinolones, which are almost completely absorbed after oral administration and diffuse rapidly through the AF, are currently used for oral treatment of uncomplicated SBP. Patients who have already had a previous episode of SBP, with a 69% probability of recurrence within a year, will benefit from prophylactic treatment. Cirrhotic patients with a high risk of SBP and other infections, such as those with gastrointestinal bleeding, also benefit from primary prophylaxis and norfloxacin has been used with success.
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PMID:Spontaneous bacterial peritonitis: a therapeutic update. 1659 6

In the spinal dorsal horn, activation of the nicotinic acetylcholine receptors (nAChR) by exogenously applied agonists is known to enhance inhibitory synaptic transmission, and to produce analgesia. However, it is still unknown whether endogenously released acetylcholine exerts a tonic inhibition on nociceptive transmission through the nAChRs in the spinal dorsal horn. Here, we report the presence of such a tonic inhibitory mechanism in the spinal dorsal horn in mice. In behavioral experiments, intrathecal (i.t.) injection of non-selective nAChR antagonist mecamylamine and alpha4beta2 subtype-selective antagonist dihydro-beta-erythroidine (DHbetaE) dose-dependently induced thermal and mechanical hyperalgesia in mice while the alpha7-selective antagonist methyllycaconitine (MLA) had no effect. Similarly, antisense knock-down of alpha4 subunit of nAChR, but not alpha7 subunit, in spinal cord induced thermal and mechanical hyperalgesia. In whole-cell patch-clamp experiments in spinal cord slice preparation from adult mice, the frequency of miniature inhibitory postsynaptic currents (mIPSCs) observed in substantia gelatinosa (SG) neurons was decreased by mecamylamine and DHbetaE, but not by MLA. The amplitudes of the mIPSCs were not affected. The nicotinic antagonists decreased the frequency of both GABAergic and glycinergic IPSCs. On the other hand, the nicotinic antagonists had no effect on the excitatory postsynaptic currents (EPSCs). Finally, acetylcholine-esterase inhibitor neostigmine-induced facilitation of IPSC frequencies in SG neurons was inhibited by mecamylamine and DHbetaE. Altogether these findings suggest that nicotinic cholinergic system in the spinal dorsal horn can tonically inhibit nociceptive transmission through presynaptic facilitation of inhibitory neurotransmission in SG via the alpha4beta2 subtype of nAChR.
Pain 2006 Nov
PMID:Tonic inhibitory role of alpha4beta2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice. 1678 Oct 69

The mast-cell sarcoma of a bone is described here for the first time. The tumour presented in a 4-year-old boy, with pain, oedema and deformation of his right lower leg. Radiological findings revealed a destructive tumourous mass. Histopathological examination showed the tumour to be composed of large, atypical cells, with hyperchromatic oval and polygonal nuclei. The cytoplasm around them was eosinophilic with many basophilic and toluidine-blue-positive granules. These atypical mast cells were positive for chloroacetate esterase, c-kit, tryptase and negative for myeloperoxidase. The primary disease quickly progressed to mast-cell leukaemia, and despite intensive chemotherapy the patient died 18 months after first symptoms.
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PMID:Mast-cell sarcoma of the tibia. 2177 98

Adjuvants are compounds which by themselves have undesirable side-effects or low potency but in combination with opioids allow a reduction of narcotic dosing for postoperative pain control. Adjuvants are needed for postoperative pain management due to side-effects of opioid analgesics, which hinder recovery, especially in the increasingly utilized ambulatory surgical procedures. NMDA antagonists have psychomimetic side-effects at high doses, but at moderate doses do not cause stereotypic behavior but allow reduction in opioid dose to obtain better pain control. Alpha-2 adrenergic agonists cause sedation, hypotension and bradycardia at moderate doses, but at low doses can be opioid sparing especially in spinal administration. Gabapentin-like compounds have low potency against acute pain, but in combination with opioids allow a reduction in opioid dose with improved analgesia. Corticosteroids may have only a limited role as adjuvants while acetylcholine esterase inhibitors may have too many side-effects. Newer adjuvants will be needed to reduce opioid dose and concomitant side-effects, even more as same day surgeries become more routine.
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PMID:Useful adjuvants for postoperative pain management. 1748 18

Long-acting analgesia is critical for patients suffering from long-acting pain. The purpose of this study was to develop lipid emulsions as parenteral drug delivery systems for morphine and its ester prodrugs. Morphine prodrugs with various alkyl chain lengths, including morphine propionate (MPR), morphine enanthate (MEN), and morphine decanoate (MDE), were synthesized. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were quickly hydrolyzed to the parent drug when exposed to esterase and plasma. Lipid emulsions were prepared using phosphatidylethanolamine (PE) as an emulsifier, while squalene was used as an inner oil phase. Drug release was found to be a function of the drug/prodrug lipophilicity, with a lower release rate for more-lipophilic drug/prodrugs. The inclusion of morphine and its prodrugs into lipid emulsions retarded their release. Lipid emulsions, which incorporated cholesterol, generally exhibited a drug/prodrug release comparable to that of emulsions without co-emulsifiers. Pluronic F68 (PF68) further slowed down the release of morphine and its prodrugs from the emulsions. The antinociceptive activity through the parenteral administration of these emulsions was examined using a cold ethanol tail-flick study. Compared with an aqueous solution, a prolonged analgesic duration was detected after application of the drug/prodrug emulsions. Incorporation of co-emulsifiers such as PF68 and cholesterol further increased the duration of action. The combination of prodrug strategy and lipid emulsions may be practically useful for improving analgesic therapy with morphine.
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PMID:The delivery and antinociceptive effects of morphine and its ester prodrugs from lipid emulsions. 1815 22

Lipases play key roles in nearly all cells and organisms. Potent and selective inhibitors help to elucidate their physiological functions and associated metabolic pathways. Organophosphorus (OP) compounds are best known for their anticholinesterase properties but selectivity for lipases and other targets can also be achieved through structural optimization. This review considers several lipid systems in brain modulated by highly OP-sensitive lipases. Neuropathy target esterase (NTE) hydrolyzes lysophosphatidylcholine (lysoPC) as a preferred substrate. Gene deletion of NTE in mice is embryo lethal and the heterozygotes are hyperactive. NTE is very sensitive in vitro and in vivo to direct-acting OP delayed neurotoxicants and the related NTE-related esterase (NTE-R) is also inhibited in vivo. KIAA1363 hydrolyzes acetyl monoalkylglycerol ether (AcMAGE) of the platelet-activating factor (PAF) de novo biosynthetic pathway and is a marker of cancer cell invasiveness. It is also a detoxifying enzyme that hydrolyzes chlorpyrifos oxon (CPO) and some other potent insecticide metabolites. Monoacylglycerol lipase and fatty acid amide hydrolase regulate endocannabinoid levels with roles in motility, pain and memory. Inhibition of these enzymes in mice by OPs, such as isopropyl dodecylfluorophosphonate (IDFP), leads to dramatic elevation of brain endocannabinoids and distinct cannabinoid-dependent behavior. Hormone-sensitive lipase that hydrolyzes cholesteryl esters and diacylglycerols is a newly recognized in vivo CPO- and IDFP-target in brain. The OP chemotype can therefore be used in proteomic and metabolomic studies to further elucidate the biological function and toxicological significance of lipases in lipid metabolism. Only the first steps have been taken to achieve appropriate selective action for OP therapeutic agents.
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PMID:Organophosphate-sensitive lipases modulate brain lysophospholipids, ether lipids and endocannabinoids. 1849 1

We proposed the use of opioid drug bound covalently to hyaluronan (HA) via ester linkages as a method to prolong drug delivery and to possibly increase the quality of perioperative pain management. The in vitro release profile of morphine conjugated to HA (1.3 million MW) was studied. The influence of parameters such as conjugation site and steric protection of the labile ester bonds was investigated in phosphate buffered saline (PBS) medium. HA--codeine and HA--naloxone conjugates were used as structural controls. Codeine and morphine conjugated via the allylic hydroxyl group had a release half-life of 14.0 days in PBS. Naloxone conjugated via the phenolic hydroxyl group showed a half-life of 0.3 days, and all drugs admixed in HA showed half-lives of 0.1 days. Methyl, ethyl, or n-propyl introduced in vicinal position to the ester bond prolonged release of naloxone with half-lives of 0.5, 4.0, and 4.0 days in PBS, respectively. Incorporation of a methyl group prolonged codeine release with a half-life of 55.0 days in PBS. Drugs were released chemically unaltered from the conjugates as confirmed by LC-MS/MS. Further, morphine was conjugated to divinylsulfone cross-linked HA (Hylan B) particles and the release profiles in rat plasma were studied in vitro and in vivo. Release in rat plasma was faster than in PBS with a half-life of 2.5 days, but the release was similar (ca. 12 days) when a cocktail of protease inhibitors was added to the plasma. Sustained release of morphine was observed in a rat surgical model over 30 h. Morphine was released chemically unaltered from the conjugate and morphine intermediates were not detected in significant amounts as confirmed by LC-MS/MS. These results suggest that the morphine release profile from the HA conjugates depends on the alkyl groups vicinal to the ester and the nature of the leaving group. In rat plasma, hydrolysis seems to be controlled by esterase activity.
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PMID:Hyaluronan-tethered opioid depots: synthetic strategies and release kinetics in vitro and in vivo. 1871 37

Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family. It catalyzes the hydrolysis of several endogenous biologically active lipids, including anandamide (arachidonoyl ethanolamide), oleoyl ethanolamide, and palmitoyl ethanolamide. These endogenous FAAH substrates have been shown to be involved in a variety of physiological and pathological processes, including synaptic regulation, regulation of sleep and feeding, locomotor activity, pain and inflammation. Here we describe the biochemical and biological properties of a potent and selective FAAH inhibitor, 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide (JNJ-1661010). The time-dependence of apparent IC(50) values at rat and human recombinant FAAH, dialysis and mass spectrometry data indicate that the acyl piperazinyl fragment of JNJ-1661010 forms a covalent bond with the enzyme. This bond is slowly hydrolyzed, with release of the piperazinyl fragment and recovery of enzyme activity. The lack of inhibition observed in a rat liver esterase assay suggests that JNJ-1661010 is not a general esterase inhibitor. JNJ-1661010 is >100-fold preferentially selective for FAAH-1 when compared to FAAH-2. JNJ-1661010 dose-dependently increases arachidonoyl ethanolamide, oleoyl ethanolamide, and palmitoyl ethanolamide in the rat brain. The compound attenuates tactile allodynia in the rat mild thermal injury model of acute tissue damage and in the rat spinal nerve ligation (Chung) model of neuropathic pain. JNJ-1661010 also diminishes thermal hyperalgesia in the inflammatory rat carrageenan paw model. These data suggest that FAAH inhibitors with modes of action similar to JNJ-1661010 may be useful clinically as broad-spectrum analgesics.
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PMID:Biochemical and biological properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase. 1909 68

Arterial hypertension is a very common condition. Cerebral, coronary and renal vessels are mainly affected by the deleterious effect of this condition, and both acute and chronic organ failure may ensue. Exacerbation of underlying pathophysiologic conditions or new precipitating factors can lead to hypertensive crisis, either urgencies or emergencies. During hypertensive emergencies, a quick raise in arterial pressure may lead to acute and significant organ dysfunction, such as aortic dissection, acute myocardial infarction, intracranial bleeding or acute renal failure. Perioperative hypertension often takes the shape of a crisis and it can be related to hypothermia, pain, neuro-hormonal response to surgical trauma or antihypertensive drugs withdrawal. Treatment for hypertensive crisis should achieve a progressive control of blood pressure, avoiding any abrupt decrease in organ blood supply. Therapeutic options are many and different in terms of pharmacokinetics and pharmacodynamic profiles. The best option should be based upon the characteristics of the patient and the pathophysiology of the hypertensive crisis. Of particular interest, some agents are metabolized by blood esterase and have a very short half life (e.g., clevidipine). This allows tight titration of their effect, which is advisable when carefully lowering blood pressure. This is of particular importance when treating hypertensive crisis in surgical patients both intra-operatively or in critical care.
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PMID:Acute severe arterial hypertension: therapeutic options. 1970 25


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