Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic arsenic poisoning is reported to be associated with peripheral and cardiovascular disease, arteriosclerosis, Raynaud's syndrome, hypertension, and Blackfoot disease. Monomethylarsonous acid (MMA(III)) is a reactive metabolite of inorganic arsenic and a potent inhibitor of endothelial nitric oxide synthase (eNOS). Arsenic is also reported to phosphorylate eNOS in cultured keratinocyte and Human T cell leukemia Jurkat cells, respectively. In the present study, we examined the cytotoxicity and eNOS phosphorylation by MMA(III) exposure in cultured bovine aortic endothelial cells (BAEC). Results showed that MMA(III) is more toxic than arsenite in BAEC cells. The IC(50) values for MMA(III) and arsenite were determined to be approximately 1.7 and 24.1 micromol/L, respectively. Exposure of BAEC to MMA(III) (0.75 micromol/L) caused a significant eNOS phosphorylation 15 min after MMA(III) exposure. However, a complex of MMA(III) with dithiothreitol (DTT) that lacks the reactivity with vicinal thiols unaffected eNOS phosphorylation. The present study shows that MMA(III )generated during biomethylation of arsenic is highly toxic in BAEC. Our study also suggests that MMA(III) could induce the eNOS phosphorylation through modification to cellular thiols of the eNOS enzyme. And the initial up-regulation of eNOS phosphorylation by MMA(III )seems to be an adaptive response against disruption of eNOS bioactivity during arsenic exposure.
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PMID:Monomethylarsonous acid induced cytotoxicity and endothelial nitric oxide synthase phosphorylation in endothelial cells. 1761 1

The quinazolines represent a useful natural product scaffold with demonstrated activities against disorders such as high blood pressure and benign prostatic hyperplasia. Here we report on the synthesis and biological activity of a series of quinazolines that were prepared by a one-pot synthesis of substituted cyclohexadiene enaminonitriles from methyl-ketones. The approach, which employs NaH, complements published procedures where LDA is utilized. While the NaH catalyzed reaction generates the cyclohexadiene enaminonitriles in high yields with heterocyclic substrates, the reaction fails to promote product formation of aliphatic alkyl substrates. On the contrary, the LDA mediated synthesis favors the long chain alkyl substituents while reactions involving the aromatic substrates result in low yields. The final conversion to the quinazolines is also a modification on literature protocols. In cellular assays, the quinazolines showed the most promising activity against Jurkat with CC(50) values in the low micromolar range. Weak activity was observed against microbial strains (Bacillus subtilis, Escherichia coli, and Saccharomyces cerevisiae). The substituted enaminonitrile intermediates also exhibited weak anti-microbial activity and cytotoxicity against human T-cell leukemia.
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PMID:An efficient one-pot synthesis of tethered cyclohexadiene enaminonitriles from methyl-ketones: an effective route to quinazolines. 1796 39

CYP 3A4 plays a vital role in the metabolism of many drugs including immunosuppressants. An association between a transition of A --> G at position -290 of the 5'-regulatory region of the CYP 3A4 gene and an effect on the level of transcription has been reported. The CYP 3A4-G variant frequency varies substantially in different populations. In addition it has been demonstrated in association with several disease conditions, including clinical grades of prostate cancer, breast cancer, secondary leukemia, hypercholesterolemia and diabetes. We sought to determine the frequency distributions, in African American (AFAM) and Caucasian (CAU) populations as well as patients with multiple complex diseases, such as those that had undergone cardiac or renal transplantation. Sequence-specific primers and PCR were used to determine genotype variation in 206 AFAM and 108 CAU individuals. CYP 3A4-G genotype was present with a higher frequency in AFAM individuals as compared with CAU (83% vs. 3%, p < 0.0001, RR = 3.9). The homozygous AA allele was predominantly present in CAU (97%) but only 17% in AFAM (p < 0.0001, RR = 2.5). In contrast, the homozygous GG allele was only detected in AFAM group (14.6%). The frequency distribution of homozygous GG and AA alleles were inversely present in male vs. female patients with CTx or RTx. Pre-transplantation clinical conditions demonstrated that hypertension (HTN), hyperlipidemia and to a lesser extent diabetes (DM) were present in CTx and RTx patients with homozygous GG alleles. In addition, 75% of AFAM patients with homozygous GG genotype experienced multiple rejection episodes with severity grades of 3A after cardiac transplantation, and 31.5% of homozygous GG patients with RTx suffered from rejections (p < 0.05; RR = 2.4). In conclusion, CYP 3A4 genotype demonstrated a remarkable interindividual variation between AFAM and CAU populations, and furthermore CTx patients with homozygous GG genotype were at higher risk of developing rejection as compared with RTx patients. This indicates an underlying heterogeneity with regard to the disease characteristics as well as the therapy regimen.
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PMID:Frequency distribution of cytochrome P450 3A4 gene polymorphism in ethnic populations and in transplant recipients. 1797 99

Targeted therapies, which include monoclonal antibodies and small molecule inhibitors, have significantly changed the treatment of cancer over the past 10 years. These drugs are now a component of therapy for many common malignancies, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The mechanisms of action and toxicities of targeted therapies differ from those of traditional cytotoxic chemotherapy. Targeted therapies are generally better tolerated than traditional chemotherapy, but they are associated with several adverse effects, such as acneiform rash, cardiac dysfunction, thrombosis, hypertension, and proteinuria. Small molecule inhibitors are metabolized by cytochrome P450 enzymes and are subject to multiple drug interactions. Targeted therapy has raised new questions about the tailoring of cancer treatment to an individual patient's tumor, the assessment of drug effectiveness and toxicity, and the economics of cancer care. As more persons are diagnosed with cancer and as these patients live longer, primary care physicians will increasingly provide care for patients who have received targeted cancer therapy.
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PMID:Targeted therapies: a new generation of cancer treatments. 1829 54

In this retrospective, personal review covering our research from the late 1980s until 2007, we outline nearly two-decade worth of our own work on several aspartic protease inhibitors including those affecting renin, HIV-1 protease, plasmepsins, beta-secretase, and HTLV-I protease and we report on aspartic protease inhibitors as potential drugs to treat hypertension, AIDS, malaria, Alzheimer's disease and adult T-cell leukemia, HTLV-I associated myelopathy / tropical spastic paraparesis, and various, respectively, associated diseases. Herein, we describe our methods for rational substrate-based drug design of peptidomimetics that potently inhibit the activity of renin, HIV-1 protease, plasmepsins, beta-secretase, and HTLV-I protease accordingly, using an appropriately selected inhibitory residue that contained a hydroxymethylcarbonyl isostere. Although this non-hydrolyzable isostere mimics the transition state that is formed during protein cleavage of a substrate, the isostere-containing inhibitor is not cleaved. We highlight our optimization studies in which we used various techniques and tools such as truncation studies, natural and non-natural amino acid substitution studies, various moieties to promote chemical and pharmacological stability, X-ray crystallography, computer-assisted docking and dynamic simulations, quantitative structure-activity relationship studies, and various other methods that this review can barely mention.
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PMID:Design of potent aspartic protease inhibitors to treat various diseases. 1876 14

Large granular lymphocyte (LGL) leukemia is commonly associated with poor hematopoiesis. The first case of pulmonary artery hypertension (PAH) was observed in a 57-year-old woman with natural killer (NK)-LGL leukemia and transfusion-dependent anemia. Using a genetic approach, we demonstrated that killing of pulmonary endothelial cells by patient NK cells was mediated by dysregulated balance in activating and inhibitory NK-receptor signaling. Elevated pulmonary artery pressure and erythroid differentiation improved after disrupting the NK-receptor signaling pathway with 4 courses of a farnesyltransferase inhibitor, tipifarnib. Coincidental association between PAH and LGL leukemia suggest a causal relationship between the expanded lymphocyte population and these clinical manifestations. This trial is registered at www.ClinicalTrials.gov as NCI 6823.
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PMID:Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling. 1879 Nov 65

We hypothesized an association between renal calculi and bone mineral density (BMD) deficits, shown in adults, exists in survivors of childhood acute lymphoblastic leukemia (ALL). Thus, we analyzed the associations between quantitative computed tomography (QCT)-determined renal calcifications and clinical parameters (gender, race, age at diagnosis and age at the time of QCT), BMD, treatment exposures and Tanner stage. We investigated the associations between stone formation and nutritional intake, serum and urinary calcium and creatinine levels, and urinary calcium/creatinine ratio. Exact chi(2)-test was used to compare categorical patient characteristics, and the Wilcoxon-Mann-Whitney test to compare continuous measurements. Of 424 participants, 218 (51.4%) were males; 371 (87.5%) were nonblack. Most (n=270; 63.7%) were >or=3.5 years at ALL diagnosis. Mean (s.d.) and median (range) BMD Z-scores of the entire cohort were -0.4 (1.2) and -0.5 (-3.9 to 5.1), respectively. Nineteen participants (10 males; 10 Caucasians) had kidney stones (observed prevalence of 4.5%; 19/424) with a significant negative association between stone formation and body habitus (body mass index, P=0.003). Stone formation was associated with treatment protocol (P=0.009) and treatment group (0.007). Thus, kidney stones in childhood ALL survivors could herald the future deterioration of renal function and development of hypertension. Long-term follow-up imaging may be warranted in these patients to monitor for progressive morbidity.
Leukemia 2009 Jan
PMID:Asymptomatic kidney stones in long-term survivors of childhood acute lymphoblastic leukemia. 1883 Feb 61

Large granular lymphocyte (LGL) leukemia, or LGLL, is characterized by increased numbers of circulating clonal LGL cells in association with neutropenia, anemia, rheumatoid arthritis, and pulmonary artery hypertension (PAH). Emerging evidence suggests that LGLL cells with a CD8(+)CD28(null) phenotype induce these clinical manifestations through direct destruction of normal tissue. Compared with CD8(+)CD28(null) T cells from healthy controls, CD8(+)CD28(null) T cells from LGLL patients have acquired the ability to directly lyse pulmonary artery endothelial cells and human synovial cells. Here, we show that LGLL cells from patients possess enhanced cytotoxic characteristics and express elevated levels of activating natural killer receptors as well as their signaling partners, DAP10 and DAP12. Moreover, downstream targets of DAP10 and DAP12 are constitutively activated in LGLL cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. These are the first results to show that activating NKR-ligand interactions play a critical role in initiating the DAP10 and DAP12 signaling events that lead to enhanced lytic potential of LGLL cells. Results shown suggest that inhibitors of DAP10 and DAP12 or other proteins involved in this signaling pathway will be attractive therapeutic targets for the treatment of LGLL and other autoimmune diseases and syndromes.
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PMID:A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia. 1907 87

PURPOSE Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events. PATIENTS AND METHODS We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models. Results At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001). CONCLUSION A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.
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PMID:Aortic stiffness increases upon receipt of anthracycline chemotherapy. 1990 Nov 5

This report describes four patients with acute lymphoblastic leukaemia, suffering from posterior reversible encephalopathy syndrome during the induction period of treatment. A review of the literature on posterior reversible encephalopathy syndrome in paediatric leukaemia is given. The exact mechanism of posterior reversible encephalopathy syndrome is not clear and seems to be multifactorial. Hypertension is likely to play a major role in the development but could be also secondary. All patients in this case series presented after introduction of the new induction protocol for acute lymphoblastic leukaemia. Treatment of hypertension is likely to have a favourable role and posterior reversible encephalopathy syndrome is most often reversible. It is important to consider this diagnosis during the induction phase of leukaemia treatment in the presence of neurological symptoms. The incidence of PRES in the induction scheme should be investigated, in order to optimize the ALL treatment.
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PMID:Posterior reversible encephalopathy syndrome in paediatric leukaemia. 2081 Feb 97


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