Ketamine-induced hepatoprotection: the role of heme oxygenase-1.

Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 micromol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-kappaB and PPAR-gamma analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-gamma activity, it enhanced NF-kappaB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.

Ethanol-induced gastric damage in the rat: Lack of a correlation with oxygen-derived free radicals

The present study investigated the role of oxygen-derived free radicals as mediators of acute damage to rat gastric mucosae exposed to topically applied absolute ethanol. Although a hydroxyl radical scavenger, Dimethylthiourea, was noted to exhibit profound gastroprotective properties, other pretreatment regimens employing a host of known free radical scavengers, and enzyme inhibitors failed to confirm this hypothesis. Furthermore, no change in mucosal malondialdehyde, an indicator of free radical attack to cell membranes, could be detected in ethanol exposed tissues. Taken together, the present study fails to confirm that oxygen-derived free radicals mediate the gastric damaging effects of topically applied absolute ethanol. ^

Quality of care after acute coronary syndromes in a prospective cohort with reasons for non-prescription of recommended medications

BACKGROUND Adherence to guidelines is associated with improved outcomes of patients with acute coronary syndrome (ACS). Clinical registries developed to assess quality of care at discharge often do not collect the reasons for non-prescription for proven efficacious preventive medication in Continental Europe. In a prospective cohort of patients hospitalized for an ACS, we aimed at measuring the rate of recommended treatment at discharge, using pre-specified quality indicators recommended in cardiologic guidelines and including systematic collection of reasons for non-prescription for preventive medications. METHODS In a prospective cohort with 1260 patients hospitalized for ACS, we measured the rate of recommended treatment at discharge in 4 academic centers in Switzerland. Performance measures for medication at discharge were pre-specified according to guidelines, systematically collected for all patients and included in a centralized database. RESULTS Six hundred and eighty eight patients(54.6%) were discharged with a main diagnosis of STEMI, 491(39%) of NSTEMI and 81(6.4%) of unstable angina. Mean age was 64 years and 21.3% were women. 94.6% were prescribed angiotensin converting enzyme inhibitors/angiotensin II receptor blockers at discharge when only considering raw prescription rates, but increased to 99.5% when including reasons non-prescription. For statins, rates increased from 98% to 98.6% when including reasons for non-prescription and for beta-blockers, from 82% to 93%. For aspirin, rates further increased from 99.4% to 100% and from to 99.8% to 100% for P2Y12 inhibitors. CONCLUSIONS We found a very high adherence to ACS guidelines for drug prescriptions at discharge when including reasons for non-prescription to drug therapy. For beta-blockers, prescription rates were suboptimal, even after taking into account reason for non-prescription. In an era of improving quality of care to achieve 100% prescription rates at discharge unless contra-indicated, pre-specification of reasons for non-prescription for cardiovascular preventive medication permits to identify remaining gaps in quality of care at discharge.

[The treatment of arterial hypertension in elderly men in Iceland].

The choice of antihypertensive therapy in elderly Icelanders is unknown. In the database of the Icelandic Heart Association 1145 men, aged 70-84 were alive in 1994. Eight hundred thirty-four came to the Heart Association Clinic, 429 of whom either had hypertension or were found to be hypertensive on examination. The prevalence of hypertension in elderly Icelandic men was therefore about 50%. One hundred fifty-seven men took drugs for hypertension. Ninety-five of them were treated with a single drug, 49 with two drugs and five with three drugs. The type of drugs was unknown concerning eight men. Diuretics and ß-blockers were dominant. Although the comparison between those two classes of drugs was uncontrolled the blood pressure was significantly lower in systole on diuretics. The most common combination was ß-blockers and diuretics, then angiotensin converting enzyme inhibitors and diuretics, finally ß-blockers and calcium blockers. It is suggested that the use of diuretics should be increased in this age group.

Impact of hypertension on the outcome of patients admitted with acute coronary syndrome

OBJECTIVE The role of hypertension and its impact on outcome in patients with acute coronary syndrome (ACS) is still debated. This study aimed to compare the outcomes of hypertensive and nonhypertensive ACS patients. METHODS Using data of ACS patients enrolled in the Acute Myocardial Infarction in Switzerland Plus Registry from 1997 to 2013, characteristics at presentation and outcomes in hospital and after 1 year were analyzed. Hypertension was defined as previously diagnosed and treated by a physician. The primary endpoint was mortality. Data were analyzed using multiple logistic regressions. RESULTS Among 41 771 ACS patients, 16 855 (40.4%) were without and 24 916 (59.6%) with preexisting hypertension. Patients with preexisting hypertension had a more favorable in-hospital outcome [odds ratio (OR) in-hospital mortality 0.82, 95% confidence interval (CI) 0.73-0.93; P = 0.022]. The independent predictors of in-hospital mortality for patients with preexisting hypertension were age, Killip class greater than 2, Charlson Comorbidity Index greater than 1, no pretreatment with statins and lower admission systemic blood pressure. Preexisting hypertension was not an independent predictor of 1-year mortality in the subgroup of patients (n = 7801) followed: OR 1.07, 95% CI 0.78-1.47; P = 0.68. Independent predictors of mortality 1 year after discharge for the 4796 patients with preexisting hypertension were age, male sex and comorbidities. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists and statins prescribed at discharge improved the outcomes. CONCLUSION Outcome of ACS patients with preexisting hypertension was associated with an improved in-hospital prognosis after adjustment for their higher baseline risk. However, this effect was not long-lasting and does not necessarily mean a causal relationship exists. Short-term and long-term management of patients with hypertension admitted with ACS could be further improved.

Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40

Objectives: To estimate the economic efficiency of tight blood pressure control, with angiotensin converting enzyme inhibitors or β blockers, compared with less tight control in hypertensive patients with type 2 diabetes.

Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes

Transition-state theory has led to the design of Immucillin-H (Imm-H), a picomolar inhibitor of purine nucleoside phosphorylase (PNP). In humans, PNP is the only route for degradation of deoxyguanosine, and genetic deficiency of this enzyme leads to profound T cell-mediated immunosuppression. This study reports the biological effects and mechanism of action of Imm-H on malignant T cell lines and on normal activated human peripheral T cells. Imm-H inhibits the growth of malignant T cell leukemia lines with the induction of apoptosis. Imm-H also inhibits activated normal human T cells after antigenic stimulation in vitro. However, Imm-H did not inhibit malignant B cells, colon cancer cell lines, or normal human nonstimulated T cells, demonstrating the selective activity of Imm-H. The effects on leukemia cells were mediated by the cellular phosphorylation of deoxyguanosine and the accumulation of dGTP, an inhibitor of ribonucleotide diphosphate reductase. Cells were protected from the toxic effects of Imm-H when deoxyguanosine was absent or when deoxycytidine was present. Guanosine incorporation into nucleic acids was selectively blocked by Imm-H with no effect on guanine, adenine, adenosine, or deoxycytidine incorporation. Imm-H may have clinical potential for treatment of human T cell leukemia and lymphoma and for other diseases characterized by abnormal activation of T lymphocytes. The design of Imm-H from an enzymatic transition-state analysis exemplifies a powerful approach for developing high-affinity enzyme inhibitors with pharmacologic activity.

A new strategy to decrease N-methyl-d-aspartate (NMDA) receptor coactivation: Inhibition of d-serine synthesis by converting serine racemase into an eliminase

Serine racemase is a brain-enriched enzyme that synthesizes d-serine, an endogenous modulator of the glycine site of N-methyl-d-aspartate (NMDA) receptors. We now report that serine racemase catalyzes an elimination reaction toward a nonphysiological substrate that provides a powerful tool to study its neurobiological role and will be useful to develop selective enzyme inhibitors. Serine racemase catalyzes robust elimination of l-serine O-sulfate that is 500 times faster than the physiological racemization reaction, generating sulfate, ammonia, and pyruvate. This reaction provides the most simple and sensitive assay to detect the enzyme activity so far. We establish stable cell lines expressing serine racemase and show that serine racemase can also be converted into a powerful eliminase in cultured cells, while the racemization of l-serine is inhibited. Likewise, l-serine O-sulfate inhibits the synthesis of d-serine in primary astrocyte cultures. We conclude that the synthetic compound l-serine O-sulfate is a better substrate than l-serine as well as an inhibitor of d-serine synthesis. Inhibition of serine racemase provides a new strategy to selectively decrease NMDA receptor coactivation and may be useful in conditions in which overstimulation of NMDA receptors plays a pathological role.

Desenvolvimento de uma plataforma modelo para a busca de ligantes com potencial leishmanicida baseado na inibição seletiva da enzima diidroorotato desidrogenase

As doenças tropicais negligenciadas (DTNs) causam um imenso sofrimento para a pessoa acometida e em muitos casos podem levar o indivíduo a morte. Elas representam um obstáculo devastador para a saúde e continuam a ser um sério impedimento para a redução da pobreza e desenvolvimento socioeconômico. Das 17 doenças desse grupo, a leishmaniose, incluindo a leishmaniose cutânea, tem grande destaque devido sua alta incidência, os gastos para o tratamento e as complicações geradas em processos de coinfecção. Ainda mais agravante, os investimentos direcionados ao controle, combate e principalmente a inovação em novos produtos é ainda muito limitado. Atualmente, a academia tem um importante papel na luta contra essas doenças através da busca de novos alvos terapêuticos e também de novas moléculas com potencial terapêutico. É nesse contexto que esse projeto teve como meta a implantação de uma plataforma para a identificação de moléculas com atividade leishmanicida. Como alvo terapêutico, optamos pela utilização da enzima diidroorotato desidrogenase de Leishmania Viannia braziliensis (LbDHODH), enzima de extrema importância na síntese de novo de nucleotídeos de pirimidina, cuja principal função é converter o diidroorotato em orotato. Esta enzima foi clonada, expressa e purificada com sucesso em nosso laboratório. Os estudos permitiram que a enzima fosse caracterizada cineticamente e estruturalmente via cristalografia de raios- X. Os primeiros ensaios inibitórios foram realizados com o orotato, produto da catálise e inibidor natural da enzima. O potencial inibitório do orotato foi mensurado através da estimativa do IC50 e a interação proteína-ligante foi caracterizada através de estudos cristalográficos. Estratégias in silico e in vitro foram utilizadas na busca de ligantes, através das quais foram identificados inibidores para a enzima LbDHODH. Ensaios de validação cruzada, utilizando a enzima homóloga humana, permitiram identificar os ligantes com maior índice de seletividade que tiveram seu potencial leishmanicida avaliado in vitro contra as formas promastigota e amastigota de Leishmania braziliensis. A realização do presente projeto permitiu a identificação de uma classe de ligantes que apresentam atividade seletiva contra LbDHODH e que será utilizada no planejamento de futuras gerações de moléculas com atividade terapêutica para o tratamento da leishmaniose. Além disso, a plataforma de ensaios otimizada permitirá a avaliação de novos grupos de moléculas como uma importante estratégia na busca por novos tratamentos contra a leishmaniose

Farmacogenética em toxicologia forense : estudo do gene CYP2D6 em amostras post mortem com tramadol

Tese de mestrado, Medicina Legal e Ciências Forenses, Universidade de Lisboa, Faculdade de Medicina, 2016

Report of workshop on isolation, characterization, and mechanism of action of proteases and antiproteases /

Mode of access: Internet.

Alternate enzymes for use in cholinesterase antagonist monitors : CAM's /

Mode of access: Internet.

CAM-4, a portable warning device for organophosphate hazardous material spills /

Mode of access: Internet.

Hypertension and diabetes treatments and risk of adverse outcomes among breast cancer patients

Thesis (Ph.D.)--University of Washington, 2016-06

Secondary prevention of renal and cardiovascular disease: Results of a renal and cardiovascular treatment program in an Australian aboriginal community

Australian Aborigines are experiencing an epidemic of renal and cardiovascular disease. In late 1995 we introduced a treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated ESRD of 2760 per million. Eligible for treatment were people with hypertension, diabetics with micro or overt albuminuria, and all people with overt albuminuria. Treatment centered around use of perindopril (Coversyl, Servier), with other agents added to reach BP goals; attempts to control glucose and lipid levels; and health education. Thirty percent of the adult population, or 267 people, were enrolled, with a mean follow up of 3.39 yr. Clinical parameters were followed every 6 mo, and rates of terminal endpoints were compared with those of 327 historical controls matched for baseline disease severity, followed in the pretreatment program era. There was a dramatic reduction in BP in the treatment group, which was sustained through 3 yr of treatment. Albuminuria and GFR stabilized or improved. Rates of natural deaths were reduced by an estimated 50% (P = 0.012); renal deaths were reduced by 57% (P = 0.038); and nonrenal deaths by 46% (P = 0.085). Survival benefit was suggested at all levels of overt albuminuria, and regardless of diabetes status, baseline BP, or prior administration of angiotensin converting enzyme inhibitors (ACEI). No significant benefit was apparent among people without overt albuminuria, nor among those with GFR less than 60 ml/min. An estimated 13 renal deaths and 10 nonrenal deaths were prevented, with the number-needed-to-treat to avoid one terminal event of only 11.6. Falling deaths and renal failure in the whole community support these estimates. The program was extremely cost-effective. Programs like this should be introduced to all high-risk communities as a matter of urgency.