Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085437 (bacterial meningitis)
 4,038 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenyl N-tert-butylnitrone (PBN) is the parent of a family of nitrones used as spin-trapping agents to trap free radicals. PBN's pharmacological effects in animal models are extensive, ranging from protection against death after endotoxin shock, protection from ischemia-reperfusion injury, to increasing the life span of mice. Recent additions to the list include protection from bacterial meningitis, thalidomide-induced teratogenicity, drug-induced diabetogenesis, and choline-deficient hepatocarcinogenesis. Because PBN reacts with oxygen radicals to produce less reactive species, it has been suggested that this is the basis of its pharmacological effects. However, there has been no hard evidence for this notation. Nevertheless, many investigators have used the presence of PBN's pharmacologic effect as evidence for free radical involvement in their models. Mechanistic studies on the PBN's antisepsis action revealed that PBN inhibits expression of various pro-inflammatory genes, suggesting that the protective action involves more than a straightforward free radical-scavenging mechanism. Previous and recent developments in the investigations on the pharmacologic properties of PBN are described in this review.
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PMID:Pharmacologic properties of phenyl N-tert-butylnitrone. 1123 46

In bacterial meningitis, long-term neurological sequelae and death are caused jointly by several factors: (1) the systemic inflammatory response of the host, leading to leukocyte extravasation into the subarachnoid space, vasculitis, brain edema and secondary ischemia; (2) stimulation of resident microglia within the CNS by bacterial compounds; and (3) possible direct toxicity of bacterial compounds on neurons. Neuronal injury is mediated by the release of reactive oxygen intermediates, proteases, cytokines and excitatory amino acids, and is executed by the activation of transcription factors, caspases and other proteases. In experimental meningitis, dexamethasone as an adjunct to antibiotic treatment leads to an aggravation of neuronal damage in the hippocampal formation, suggesting that corticosteroids might not be the ideal adjunctive therapy. Several approaches that interfere selectively with the mechanisms of neuronal injury are effective in animal models, including the use of nonbacteriolytic protein synthesis-inhibiting antibiotics, antioxidants and inhibitors of transcription factors, matrix metalloproteinases, and caspases.
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PMID:Neuronal injury in bacterial meningitis: mechanisms and implications for therapy. 1180 37

In spite of improved antimicrobial therapy, bacterial meningitis still results in brain damage leading to significant long-term neurological sequelae in a substantial number of survivors, as confirmed by several recent studies. Meningitis caused by Streptococcus pneumoniae is associated with a particularly severe outcome. Experimental studies over the past few years have increased our understanding of the molecular mechanisms underlying the events that ultimately lead to brain damage during meningitis. Necrotic damage to the cerebral cortex is at least partly mediated by ischemia and oxygen radicals and therefore offers a promising target for adjunctive therapeutic intervention. Neuronal apoptosis in the hippocampus may represent the major pathological process responsible for cognitive impairment and learning disabilities in survivors. However, the mechanisms involved in causing this damage remain largely unknown. Anti-inflammatory treatment with corticosteroids aggravates hippocampal damage, thus underlining the potential shortcomings of current adjuvant strategies. In contrast, the combined inhibition of matrix metalloproteinase and tumour necrosis factor-alpha converting enzyme protected both the cortex and hippocampus in experimental meningitis, and may represent a promising new approach to adjunctive therapy. It is the hope that a more refined molecular understanding of the pathogenesis of brain damage during bacterial meningitis will lead to new adjunctive therapies.
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PMID:Current concepts in the pathogenesis of meningitis caused by Streptococcus pneumoniae. 1201 59

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.
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PMID:Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents. 1278 86

Bacterial meningitis, once almost universally fatal, remains a cause of serious neurologic illness and subsequent disability. The initial diagnosis, although sometimes clear-cut, can be subtle and difficult. Appropriate intervention may have a favorable influence on outcome. The advent of corticosteroids and brain imaging has improved management but created controversy concerning the sequence at which various interventions should be introduced. Empiric treatment with antibiotics is important in the initial stages. Complications can arise, such as seizures, increased intracranial pressure, and ischemia. The prognosis remains unfavorable for some affected individuals in spite of advances in antibiotic management and supportive care.
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PMID:Bacterial meningitis: diagnosis and treatment. 1456 99

The contribution of axonal injury to CNS damage in bacterial meningitis was studied by histology and immunohistochemistry for amyloid-beta precursor protein in humans and experimental rabbits. Axonal injury in the white matter caused predominantly but not exclusively by ischemia was detected in all autopsy cases (n = 5) and in 11 of 15 brains of rabbits 18 to 24 hours after intracisternal infection with Streptococcus pneumoniae. This suggests a substantial contribution of axonal pathology to neurologic sequelae after bacterial meningitis.
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PMID:Axonal injury, a neglected cause of CNS damage in bacterial meningitis. 1487 46

Adverse outcome in bacterial meningitis is associated with the breakdown of the blood-brain barrier (BBB). Matrix-metalloproteinases (MMPs) facilitate this process by degradation of components of the BBB. This in turn results in acute complications of bacterial meningitis including edema formation, increased intracranial pressure and subsequent ischemia. We determined the parenchymal balance of MMP-9 and TIMP-1 (tissue inhibitor of MMP) and the structural integrity of the BBB in relation to cortical damage in an infant rat model of pneumococcal meningitis. The data demonstrate that the extent of cortical damage is significantly associated with parenchymal gelatinolytic activity and collagen type IV degradation. The increased gelatinolysis was found to be associated with a brain parenchymal imbalance of MMP-9/TIMP-1. These findings provide support to the concept that MMPs mediated disruption of the BBB contributes to the pathogenesis of bacterial meningitis and that protection of the vascular unit may have neuroprotective potential.
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PMID:In bacterial meningitis cortical brain damage is associated with changes in parenchymal MMP-9/TIMP-1 ratio and increased collagen type IV degradation. 1625 22

Infarction in the genu of the internal capsule causes dementia that is characterized by abulia, lethargy and memory loss without obvious motor palsy (capsular genu syndrome). We found infarction or decreased cerebral blood flow in the genu of the internal capsule in 6 of 13 patients with severe bacterial meningitis. Four of these six patients developed post-meningitis dementia, characterized by abulia, lethargy, and memory loss. Of 24 patients with viral meningitis, none developed capsular genu ischemia or post-meningitis dementia. In patients with severe bacterial meningitis, capsular genu ischemia may play some role in the development of post-meningitis dementia. In patients with viral meningitis, absence of such ischemia may explain, at least in a part, the rarity of post-meningitis dementia.
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PMID:Dementia and capsular genu ischemia in patients with severe bacterial meningitis. 1983 22

One of the causes of sensorineural hearing loss is the loss of auditory hair cells following exposure to environmental stresses. Auditory hair cell death in response to cochlear trauma occurs via both necrosis and apoptosis. Apoptosis of hair cells involves the caspase and MAPK/JNK pathways which are activated by oxidative stress and secretion of inflammatory cytokines in response to trauma. Identification of the pathways that lead to apoptosis provides therapeutic targets for the conservation of hearing. Antioxidants reduce the level of reactive oxygen species and reactive nitrogen species generated by oxidative stress in response to acoustic trauma, aminoglycoside and platinum-based drugs. Caspase inhibitors affect both the extrinsic and intrinsic apoptotic pathways thereby reducing cisplatin, aminoglycoside, hydraulic trauma and ischemia-induced hearing losses. Corticosteroid therapy reduces inflammation and inhibits apoptosis while activating pro-survival pathways in the organ of Corti following exposure to noise, vibration, cisplatin, aminoglycoside, ischemia/reperfusion injury, bacterial meningitis and electrode insertion trauma. Inhibitors of JNK signaling pathway prevent apoptosis of auditory hair cells following electrode insertion trauma, acute labyrinthitis, acoustic trauma and aminoglycoside ototoxicity. This review provides an overview of the different pathways involved in auditory hair cell death following an environmental stress and both traditional and newly developed drugs that are currently being studied or used for the treatment of acute hearing loss. Recent patents related to otoprotective strategies to conserve hearing and auditory hair cells are also discussed in this review.
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PMID:The injured cochlea as a target for inflammatory processes, initiation of cell death pathways and application of related otoprotectives strategies. 2016 5

Laparoscopic donor nephrectomy has the advantages of less pain, early ambulation and shorter hospitalization compared to open donor nephrectomy. Kidney recipient surgery is, however, traditionally performed by open surgery. Our aim was to study feasibility and safety of laparoscopic kidney transplantation (LKT). After permission from Internal Review Board, LKT was performed in four patients. All kidneys were procured from deceased donors. Left kidney was used for LKT and transplanted in left iliac fossa while right kidney was used for standard open kidney transplantation (OKT). All transplantation procedures were performed successfully. Cold ischemia time varied between 4 h and 14 h. For LKT, mean time for anastomosis was 65 (range 62-72) min, mean operative time was 3.97 (range 3.5-5) h, mean blood loss was 131.25 mL (range 45-350) mL. Mean wound length was 7 cm in LKT group and 18.4 cm in OKT group. Delayed graft function was observed in one patient in each group. One patient was lost in OKT group due to posttransplant bacterial meningitis. At 6 months, both groups have comparable value of serum creatinine. In conclusion, LKT is technically feasible and safe. Long term outcome needs to be evaluated in a larger study.
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PMID:Laparoscopic kidney transplantation: an initial experience. 2223 53


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