Glucosephosphate Dehydrogenase Deficiency
Drug Evaluation, Preclinical
Lupus Erythematosus, Discoid
Central nervous system-mediated hyperglycemic effects of NIK-247, a cholinesterase inhibitor, and MKC-231, a choline uptake enhancer, in rats. (1/943)We investigated the effects of intracerebroventricular administration of NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclo-penta(b)-quinoline monohydrate hydrochloride; a cholinesterase inhibitor) or MKC-231 (2-(2-oxypyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofur o[2,3-b]quinolin-4-yl) acetoamide; a choline uptake enhancer) on plasma glucose level in comparison with that of neostigmine administration in rats. The extents of NIK-247- and MKC-231-induced hyperglycemia were considerably less than that by neostigmine, suggesting that the potencies of the drugs to produce the peripheral hyperglycemia may be pharmacologically negligible. (+info)
The immune response modifier imiquimod requires STAT-1 for induction of interferon, interferon-stimulated genes, and interleukin-6. (2/943)Imiquimod is an oral inducer of interferon (IFN) and several other proinflammatory cytokines and has been successfully used topically as an antiviral agent for the treatment of genital warts. We have investigated the molecular mechanisms by which imiquimod induces the expression of IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in vivo, using mice deficient in various components of the IFN signaling system. Mice deficient in the transcription factor interferon regulatory factor 1 (IRF-1) or in the serine/threonine protein kinase PKR responded normally to imiquimod, producing high levels of circulating IFN and induction of several ISGs. On the other hand, when mice deficient in STAT-1 were treated, a 32-fold reduction in the level of circulating IFN was observed, together with a lack of induction of 2-5 oligo adenylate synthetase (2-5 OAS) and IRF-1 genes. Interestingly, there was also a lack of induction of interleukin-6 (IL-6) gene expression, although tumor necrosis factor was induced and readily detected in serum. In mice deficient in the type I IFN receptor, imiquimod induced levels of IFN similar to those in control mice, but again, neither 2-5 OAS, IRF-1, nor IL-6 genes were induced in mutant mice. Our results suggest that STAT-1 plays a critical role in the mechanism of gene activation by imiquimod. Moreover, induction of IL-6 gene expression appears to be dependent on components of the IFN signaling cascade. (+info)
Nitric oxide inhibits L-type Ca2+ current in glomus cells of the rabbit carotid body via a cGMP-independent mechanism. (3/943)Previous studies have shown that nitric oxide (NO) inhibits carotid body sensory activity. To begin to understand the cellular mechanisms associated with the actions of NO in the carotid body, we monitored the effects of NO donors on the macroscopic Ca2+ current in glomus cells isolated from rabbit carotid bodies. Experiments were performed on freshly dissociated glomus cells from adult rabbit carotid bodies using the whole cell configuration of the patch-clamp technique. The NO donors sodium nitroprusside (SNP; 600 microM, n = 7) and spermine nitric oxide (SNO; 100 microM, n = 7) inhibited the Ca2+ current in glomus cells in a voltage-independent manner. These effects of NO donors were rapid in onset and peaked within 1 or 2 min. In contrast, the outward K+ current was unaffected by SNP (600 microM, n = 6), indicating that the inhibition by SNP was not a nonspecific membrane effect. 2-(4-carboxyphenyl)-4,4,5, 5-tetramethyl-imidazoline-1-oxyl-3-oxide (carboxy-PTIO; 500 microM), an NO scavenger, prevented inhibition of the Ca2+ current by SNP (n = 7), whereas neither superoxide dismutase (SOD; 2,000 U/ml, n = 4), a superoxide scavenger, nor sodium hydrosulfite (SHS; 1 mM, n = 7), a reducing agent, prevented inhibition of the Ca2+ current by SNP. However, SNP inhibition of the Ca2+ current was reversible in the presence of either SOD or SHS. These results suggest that NO itself inhibits Ca2+ current in a reversible manner and that subsequent formation of peroxynitrites results in irreversible inhibition. SNP inhibition of the Ca2+ current was not affected by 30 microM LY 83, 583 (n = 7) nor was it mimicked by 600 microM 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP; n = 6), suggesting that the effects of NO on the Ca2+ current are mediated, in part, via a cGMP-independent mechanism. N-ethylmaleimide (NEM; 2.5 mM, n = 6) prevented the inhibition of the Ca2+ current by SNP, indicating that SNP is acting via a modification of sulfhydryl groups on Ca2+ channel proteins. Norepinephrine (NE; 10 microM) further inhibited the Ca2+ current in the presence of NEM (n = 7), implying that NEM did not nonspecifically eliminate Ca2+ current modulation. Nisoldipine, an L-type Ca2+ channel blocker (2 microM, n = 6), prevented the inhibition of Ca2+ current by SNP, whereas omega-conotoxin GVIA, an N-type Ca2+ channel blocker (1 microM, n = 9), did not prevent the inhibition of Ca2+ current by SNP. These results demonstrate that NO inhibits L-type Ca2+ channels in adult rabbit glomus cells, in part, due to a modification of calcium channel proteins. The inhibition might provide one plausible mechanism for efferent inhibition of carotid body activity by NO. (+info)
Possible novel mechanism for bitter taste mediated through cGMP. (4/943)Taste is the least understood among sensory systems, and bitter taste mechanisms pose a special challenge because they are elicited by a large variety of compounds. We studied bitter taste signal transduction with the quench-flow method and monitored the rapid kinetics of the second messenger guanosine 3',5'-cyclic monophosphate (cGMP) production and degradation in mouse taste tissue. In response to the bitter stimulants, caffeine and theophylline but not strychnine or denatonium cGMP levels demonstrated a rapid and transient increase that peaked at 50 ms and gradually declined throughout the following 4.5 s. The theophylline- and caffeine-induced effect was rapid, transient, concentration dependent and gustatory tissue-specific. The effect could be partially suppressed in the presence of the soluble guanylyl cyclase (GC) inhibitor 10 microM ODQ and 30 microM methylene blue but not 50 microM LY 83583 and boosted by nitric oxide donors 25 microM NOR-3 or 100 microM sodium nitroprusside. The proposed mechanism for this novel cGMP-mediated bitter taste signal transduction is cGMP production partially by the soluble GC and caffeine-induced inhibition of one or several phosphodiesterases. (+info)
Treatment of experimental leishmaniasis with the immunomodulators imiquimod and S-28463: efficacy and mode of action. (5/943)There is a need for new, effective, and less toxic treatments for leishmaniasis, an infectious disease caused by Leishmania protozoa and is a major cause of suffering and morbidity in much of the developing world. Imiquimod, an immune-response modifier, has recently been approved by the Food and Drug Administration for the treatment of genital warts caused by human papillomaviruses. Imiquimod initiates a local immune reaction, including the stimulation of macrophages, resulting in resolution of human papillomavirus infection and regression of the viral lesion. Since imiquimod activates a number of immune cells, including macrophages, which are the only host cells of Leishmania species, an investigation was done to determine whether it induces leishmanicidal properties in infected macrophages in vitro and in vivo in a mouse model. Imiquimod and a related compound, S-28463, effectively stimulated leishmanicidal activity in macrophages; moreover, imiquimod stimulated signal transduction associated with inducing nitric oxide synthesis in macrophages. (+info)
Protection against hydrogen peroxide cytotoxicity in rat-1 fibroblasts provided by the oncoprotein Bcl-2: maintenance of calcium homoeostasis is secondary to the effect of Bcl-2 on cellular glutathione. (6/943)The oncoprotein Bcl-2 protects cells against apoptosis, but the exact molecular mechanism that underlies this function has not yet been identified. Studying H2O2-induced cell injury in Rat-1 fibroblast cells, we observed that Bcl-2 had a protective effect against the increase in cytosolic calcium concentration and subsequent cell death. Furthermore, overexpression of Bcl-2 resulted in an alteration of cellular glutathione status: the total amount of cellular glutathione was increased by about 60% and the redox potential of the cellular glutathione pool was maintained in a more reduced state during H2O2 exposure compared with non-Bcl-2-expressing controls. In our cytotoxicity model, disruption of cellular glutathione homoeostasis closely correlated with the pathological elevation of cytosolic calcium concentration. Stabilization of the glutathione pool by Bcl-2, N-acetylcysteine or glucose delayed the cytosolic calcium increase and subsequent cell death, whereas depletion of glutathione by dl-buthionine-(S, R)-sulphoximine, sensitized Bcl-2-transfected cells towards cytosolic calcium increase and cell death. We therefore suggest that the protection exerted by Bcl-2 against H2O2-induced cytosolic calcium elevation and subsequent cell death is secondary to its effect on the cellular glutathione metabolism. (+info)
Nitric oxide stimulates cGMP production and mimics synaptic responses in metacerebral neurons of Aplysia. (7/943)Nitric oxide (NO) acts as a neurotransmitter and neuromodulator in the nervous systems of many vertebrates and invertebrates. We investigated the mechanism of NO action at an identified synapse between a mechanoafferent neuron, C2, and the serotonergic metacerebral cell (MCC) in the cerebral ganglion of the mollusc Aplysia californica. Stimulation of C2 produces a decreasing conductance, very slow EPSP in the MCC. C2 is thought to use histamine and NO as cotransmitters at this synapse, because both agents mimic the membrane responses. Now we provide evidence that treatment with NO donors stimulates soluble guanylyl cyclase (sGC) in the MCC, and as a result cGMP increases. S-Nitrosocysteine (SNC, an NO donor) and 8-bromo-cGMP (8-Br-cGMP) both induced the membrane depolarization and increase in input resistance that are characteristic of the very slow EPSP. Two inhibitors of sGC, 6-anilino-5,8-quinolinequinone (LY83583) and 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxaline-1-one (ODQ), suppressed both the very slow EPSP and the membrane responses to SNC but not the histamine membrane responses. NO-induced cGMP production was determined in the MCC using cGMP immunocytochemistry (cGMP-IR). In the presence of 3-isobutyl-1-methylxanthine (IBMX), 10 microM SNC was sufficient to induce cGMP-IR, and the staining intensity increased as the SNC dose was increased. This cGMP-IR was suppressed by ODQ in a dose-dependent manner and completely blocked by 10 microM ODQ. Histamine did not induce cGMP-IR. The results suggest that NO stimulates sGC-dependent cGMP synthesis in the MCC and that cGMP mediates the membrane responses. The cotransmitter histamine induces essentially the same membrane responses but seems to use a separate and distinct second messenger pathway. (+info)
Histochemically reactive zinc in plaques of the Swedish mutant beta-amyloid precursor protein transgenic mice. (8/943)Endogenous metals such as zinc may contribute to beta-amyloid (Abeta) aggregation and hence the plaque formation. In the present study, we examined brains of four Swedish mutant amyloid precursor protein (APP) transgenic mice at 12 months of age for histochemically reactive zinc in the plaques. Here, we report that all the Congo red (+) mature plaques contained chelatable zinc, as demonstrated by staining with the zinc-specific fluorescent dye 6-methoxy-8-quinolyl-para-toluenesulfonamide (TSQ). On the other hand, Congo red (-) preamyloid Abeta deposits were not stained with TSQ. Interestingly, although cerebellum contained similar degree of preamyloid Abeta deposits as cerebral cortex, it was completely devoid of Congo red- or TSQ-stained mature plaques. Although zinc from plaques was only slowly and partially removed by a specific zinc remover, dithizone, treatment of brain sections with heparinase-III, which degrades heparan sulfate proteoglycan (HSPG), another major constituent of plaques, greatly fastened the zinc removal with dithizone. The present study has demonstrated the presence of histochemically reactive zinc in plaques, but not preamyloid Abeta deposits, of the Swedish mutant APP transgenic mice. Because preamyloid Abeta deposits fail to develop into congophilic plaques in cerebellum where synaptic vesicle zinc is deficient, the synaptic zinc may be a necessary element in the plaque formation. In holding zinc inside plaques, HSPG may contribute in addition to Abeta. (+info)
The condition is inherited in an X-linked recessive pattern, meaning that the gene for G6PD deficiency is located on the X chromosome and affects males more frequently than females. Females may also be affected but typically have milder symptoms or may be carriers of the condition without experiencing any symptoms themselves.
G6PD deficiency can be caused by mutations in the G6PD gene, which can lead to a reduction in the amount of functional enzyme produced. The severity of the condition depends on the specific nature of the mutation and the degree to which it reduces the activity of the enzyme.
Symptoms of G6PD deficiency may include jaundice (yellowing of the skin and eyes), fatigue, weakness, and shortness of breath. In severe cases, the condition can lead to hemolytic anemia, which is characterized by the premature destruction of red blood cells. This can be triggered by certain drugs, infections, or foods that contain high levels of oxalic acid or other oxidizing agents.
Diagnosis of G6PD deficiency typically involves a combination of clinical evaluation, laboratory tests, and genetic analysis. Treatment is focused on managing symptoms and preventing complications through dietary modifications, medications, and avoidance of triggers such as certain drugs or infections.
Overall, G6PD deficiency is a relatively common genetic disorder that can have significant health implications if left untreated. Understanding the causes, symptoms, and treatment options for this condition is important for ensuring appropriate care and management for individuals affected by it.
There are several different types of malaria, including:
1. Plasmodium falciparum: This is the most severe form of malaria, and it can be fatal if left untreated. It is found in many parts of the world, including Africa, Asia, and Latin America.
2. Plasmodium vivax: This type of malaria is less severe than P. falciparum, but it can still cause serious complications if left untreated. It is found in many parts of the world, including Africa, Asia, and Latin America.
3. Plasmodium ovale: This type of malaria is similar to P. vivax, but it can cause more severe symptoms in some people. It is found primarily in West Africa.
4. Plasmodium malariae: This type of malaria is less common than the other three types, and it tends to cause milder symptoms. It is found primarily in parts of Africa and Asia.
The symptoms of malaria can vary depending on the type of parasite that is causing the infection, but they typically include:
4. Muscle and joint pain
6. Nausea and vomiting
8. Anemia (low red blood cell count)
If malaria is not treated promptly, it can lead to more severe complications, such as:
3. Respiratory failure
4. Kidney failure
5. Liver failure
6. Anemia (low red blood cell count)
Malaria is typically diagnosed through a combination of physical examination, medical history, and laboratory tests, such as blood smears or polymerase chain reaction (PCR) tests. Treatment for malaria typically involves the use of antimalarial drugs, such as chloroquine or artemisinin-based combination therapies. In severe cases, hospitalization may be necessary to manage complications and provide supportive care.
Prevention is an important aspect of managing malaria, and this can include:
1. Using insecticide-treated bed nets
2. Wearing protective clothing and applying insect repellent when outdoors
3. Eliminating standing water around homes and communities to reduce the number of mosquito breeding sites
4. Using indoor residual spraying (IRS) or insecticide-treated wall lining to kill mosquitoes
5. Implementing malaria control measures in areas where malaria is common, such as distribution of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS)
6. Improving access to healthcare services, particularly in rural and remote areas
7. Providing education and awareness about malaria prevention and control
8. Encouraging the use of preventive medications, such as intermittent preventive treatment (IPT) for pregnant women and children under the age of five.
Early diagnosis and prompt treatment are critical in preventing the progression of malaria and reducing the risk of complications and death. In areas where malaria is common, it is essential to have access to reliable diagnostic tools and effective antimalarial drugs.
It is important for individuals with discoid lupus erythematosus to be aware of their condition and seek medical attention if they experience any changes in their symptoms or if new lesions develop, as the disease can lead to complications such as skin cancer, scarring, and joint pain if left untreated. Early diagnosis and treatment can help prevent these complications and improve quality of life for those affected by the condition.
Peter J. H. Scott
Martinet dioxindole synthesis
Harry L. Fisher
Mass drug administration
Stateville Penitentiary Malaria Study
History of malaria
Mizoroki-Heck vs. Reductive Heck
List of MeSH codes (D03)
Safety of 8-aminoquinoline antimalarial medicines
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Undergraduate Research - University of Evansville
- Among those with G6PD deficiency, hemolytic anemia may be triggered by bacterial or viral infections and by certain foods and drugs, including the 8-aminoquinoline (8-AQ) class of antimalarials. (health.mil)
- What do Tafenoquine, 8-Aminoquinoline and Malaria have. (hyperleap.com)
- Tafenoquine is in the 8-aminoquinoline family of medications. (hyperleap.com)
- In 2018, the US Food and Drug Administration approved the uses of a new hepatic schizontocidal and hypnozoitocidal 8-aminoquinoline called tafenoquine for the respective prevention of all malarias and for the treatment of those that relapse (P. vivax and Plasmodium ovale). (nih.gov)
- Tafenoquine, an 8-aminoquinoline antimalarial, is active against all the stages of Plasmodium species that include the hypnozoite (dormant stage) in the liver. (drugcentral.org)
- Providing radical cure for women with 8-aminoquinolines (e.g., primaquine) is hindered by gender-specific complexities. (tropmedres.ac)
- Chloroquine and hydroxychloroquine, two antimalarial medications that belong to the 4-aminoquinolines, chelate and remove hepatic-bound porphyrins by forming water-soluble complexes that are eliminated in the urine. (medscape.com)
- Trials of the use of the 4-aminoquinolines, chloroquine and hydroxychloroquine, in the treatment of people with COVID-19, exemplify the problem. (cebm.net)
- [ 42 ] However, a report by Salameh indicated that relapses are more common after 4-aminoquinoline treatment as compared with phlebotomy for PCT. (medscape.com)
- 1,2 For example, members of the 8-aminoquinoline (8-AQ) class of antimalarial drugs can cause hemolysis in the G6PD deficient population. (health.mil)
- 2014). Safety of 8-aminoquinoline antimalarial medicines. (who.int)