A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases.

BACKGROUND: Mucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (ßENaC-Tg mice). METHODS: We compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G') of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in ßENaC-Tg mice to determine its mucolytic efficacy in vivo. RESULTS: In CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G', was faster in decreasing sputum G' by 50% and caused mucolysis of a larger proportion of sputum samples within 15 min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1 day in adult ßENaC-Tg mice decreased airway mucus content (16.8±3.2 versus 7.5±1.2 nL·mm-2, p<0.01) and bronchoalveolar lavage cells (73 833±6930 versus 47 679±7736 cells·mL-1, p<0.05). Twice-daily treatment with MUC-031 for 2 weeks also caused decreases in these outcomes in adult and neonatal ßENaC-Tg mice and reduced mortality from 37% in vehicle-treated ßENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05). CONCLUSION: MUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in ßENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.

Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.

BACKGROUND: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination. MAIN BODY: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS. CONCLUSIONS: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD.

Are the Cytotoxic Properties of Conjugated Unsaturated Ketones Inactivated by Thiols?

The focus of this study was to examine whether the conversion of cytotoxic conjugated unsaturated ketones (or enones) into the corresponding thiol adducts leads to a reduction or abolition of cytotoxic potencies. A number of enones and related thiol adducts were evaluated against human HCT116 and HT29 colon cancer cells. Some 63% of the IC50 values are less than 10 µM and several compounds are more toxic than 5-FU. The thiol adducts are either more potent or are equipotent with the corresponding enones. A number of compounds are far more toxic to HCT116 and HT29 neoplasms than non-malignant CRL1790 cells leading to impressive Selectivity Index figures. An additional positive feature of these compounds is that they have favorable ADME properties.

Anti-inflammatory, antioxidant, anti-fibrotic and schistosomicidal properties of plumbagin in murine schistosomiasis.

Schistosomiasis is still a major health problem affecting nearly 250 million people worldwide and causes approximately 280,000 deaths per year. The disease causes a serious granulomatous inflammatory response that produces significant mortality. Plumbagin reportedly displays anti-inflammatory, anti-fibrotic, antioxidant and anthelmintic properties. This study further elucidates these properties. Mice were infected with schistosomes and divided into five groups: non-infected untreated (C); infected untreated (IU); non-infected treated with plumbagin (P); infected treated with plumbagin (PI) and infected treated with praziquantel (PZ). Mice treated with 20 mg plumbagin/kg body weight showed reduction of 64.28% and 59.88% in male and female animals, respectively. Also, the number of eggs/g tissue was reduced 69.39%, 68.79% and 69.11% in liver, intestine and liver/intestine combined, respectively. Plumbagin alleviated schistosome-induced hepatosplenomegaly and reduced hepatic granuloma and liver collagen content by 62.5% and 35.26%, respectively while PZQ reduced hepatic granuloma and liver collagen content by 41.11% and 11.21%, respectively. Further, plumbagin treatment significantly (p < .001) reduced IL-4, IL-13, IL-17, IL-37, IFN-γ, TGF-ß and TNF-α levels and significantly (p < .001) upregulated IL-10. Plumbagin treatment restored hepatic enzymes activity to nearly normal levels and induced an increase in catalase, SOD, GSH, total thiol and GST in liver tissue homogenate. NO and LPO content was, however, decreased. Moreover, serum IgG levels significantly increased. The present study is the first to report immunomodulatory and schistosomicidal activities of plumbagin in schistosomiasis.

N-Acetyl Cysteine and Glutathione in Health and Cancer-Pharmacogenomics, Research, and Clinical Practice: Hypothesis and Review.

Context: Glutathione (GSH) is a major intracellular antioxidant capable of scavenging free radicals and detoxifying electrophiles from endogenous and exogenous sources via the free thiol group. GSH plays an important role in a multiple cellular process, including cell differentiation, proliferation, and apoptosis. Pharmacogenomics has demonstrated its important role as a key element in cellular health. Objective: The study intended to examine the benefits of using GSH pharmacogenomics as a therapy to prevent side effects and interactions with antineoplastic agents in the diagnosis and treatment of malignancies. Design: The research team performed a narrative review using the Google scholar and PubMed electronic databases. Conclusions: In summary, the involvement of GSH in the carcinogenesis and drug resistance of tumor cells is clear and well understood, but further studies, aimed at understanding the GSH-driven molecular pathways, might be crucial to designing new therapeutic strategies to fight cancer progression, overcoming chemoresistance, using in combination with immunotherapies, and preventing or minimizing their negative side effects.

Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition.

ABSTRACT: Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.

Phytochemicals in Gynecological Cancer Prevention.

Gynecological cancer confers an enormous burden among women worldwide. Accumulating evidence points to the role of phytochemicals in preventing cervical, endometrial, and ovarian cancer. Experimental studies emphasize the chemopreventive and therapeutic potential of plant-derived substances by inhibiting the early stages of carcinogenesis or improving the efficacy of traditional chemotherapeutic agents. Moreover, a number of epidemiological studies have investigated associations between a plant-based diet and cancer risk. This literature review summarizes the current knowledge on the phytochemicals with proven antitumor activity, emphasizing their effectiveness and mechanism of action in gynecological cancer.

Association of high-density lipoprotein particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). METHODS: The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. RESULTS: Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P = .81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. CONCLUSIONS: Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.

Formation of a Thiol-Ene Addition Product of Asthma Medication Montelukast Caused by a Widespread Tin-Based Thermal Stabilizer.

We report the formation and characterization of two diastereomeric thiol-ene addition products of the asthma medication Montelukast within chewing tablets. Widespread tin-based thermal stabilizers dioctyltin bis(2-ethylhexyl thioglycolate) and monooctyltin tris(2-ethylhexyl thioglycolate), used in the manufacturing process of the medication's forming foil, were identified as the source of the thiol reactant, showing that these stabilizers may play a part in the degradation of Montelukast and APIs with functionalities similar to those of Montelukast, which should be considered during development of medication. The isolation and analysis of these impurities was performed by HPLC and UV-vis spectroscopy. HRMS and NMR data were collected to characterize and determine the structures of these compounds.

Click chemistry compared to thiol chemistry for the synthesis of site-selective glycoconjugate vaccines using CRM197 as carrier protein.

Conjugation chemistry is one of the main parameters affecting immunogenicity of glycoconjugate vaccines and a rational approach toward a deeper understanding of their mechanism of action will greatly benefit from highly-defined and well-characterized structures. Herein, different conjugation methods were investigated with the aim of controlling glycosylation site and glycosylation density on the carrier protein. S. Typhimurium lipopolysaccharide O-Antigen and CRM197 carrier protein were used as models. In particular, thiol and click chemistry were examined, both involving the linkage of the terminal reducing sugar unit of the O-Antigen chain to different amino acids on the carrier protein. Thiol chemistry allowed O-Antigen conjugation only when the carrier protein was activated on the lysines and with a relative high number of linkers, while click chemistry allowed conjugate generation even when just one position on the protein was activated and to both lysine and tyrosine sites. The study highlights click chemistry as a leading approach for the synthesis of well-defined glycoconjugates, useful to investigate the relationship between conjugate design and immune response.

A thiopyran derivative with low murine toxicity with therapeutic potential on lung cancer acting through a NF-κB mediated apoptosis-to-pyroptosis switch.

Pyroptosis is a novel manner of cell death that can be mediated by chemotherapy drugs. The awareness of pyroptosis is significantly increasing in the fields of anti-tumor research and chemotherapy drugs. Invoking the occurrence of pyroptosis is an attractive prospect for the treatment of lung cancer. Here, the compound L61H10 was obtained as a thiopyran derivative to compare its activity with curcumin. It was indicated that L61H10 exhibited good anti-tumor activity both in vitro and in vivo via the switch of apoptosis-to-pyroptosis, which was associated with the NF-κB signaling pathway. In addition, L61H10 had no obvious side effects both in vitro and in vivo. In brief, L61H10 is shown to be a potential anti-lung cancer agent and research on its anti-tumor mechanism provides new information for chemotherapy drug research.

Antitumor activity of Lepidium latifolium and identification of the epithionitrile 1-cyano-2,3-epithiopropane as its major active component.

Consumption of Brassica (Cruciferae) vegetables is associated with a reduced risk of cancer, but identification of the active components and insights into the underlying molecular events are scarce. Here we found that an extract of Lepidium latifolium, a cruciferous plant native to southern Europe, Mediterranean countries and Asia, showed in vitro cytotoxic activity, inducing caspase-dependent apoptosis, in a variety of human tumor cells, and the plant juice showed in vivo antitumor activity in a HT-29 human colon cancer xenograft mouse model. The epithionitrile 1-cyano-2,3-epithiopropane (CETP) was identified as the major active cancer cell-killing principle of L. latifolium. Synthetic and plant-derived CETP displayed similar proapoptotic activities as assessed by biochemical and morphological analyses. Analysis of the antiproliferative capacity of CETP on a wide number of cancer cell lines from the NCI-60 cell line panel followed by COMPARE analysis, showed an activity profile different from known anticancer agents. Flow cytometry and biochemical analyses revealed that CETP-induced apoptosis involved mitochondria, as assessed by loss of mitochondrial transmembrane potential and generation of reactive oxygen species, while overexpression of Bcl-XL and Bcl-2 prevented CETP-induced apoptosis. Inhibition of reactive oxygen species by glutathione and N-acetyl cysteine reduced the apoptotic response induced by CETP. FADD dominant negative form, blocking Fas/CD95 signaling, and a specific caspase-8 inhibitor also inhibited CETP-induced killing. Taken together, our data suggest that the cancer cell-killing action of CETP, involving both intrinsic and extrinsic apoptotic signaling pathways, underlies the antitumor activity of L. latifolium plant, which could be of potential interest in cancer treatment.

CETP: Pharmacogenomics-Based Response to the CETP Inhibitor Dalcetrapib.

High-density lipoproteins are involved in reverse cholesterol transport and possess anti-inflammatory and antioxidative properties. Paradoxically, CETP (cholesteryl ester transfer protein) inhibitors have been shown to increase inflammation as revealed by a raised plasma level of high-sensitivity C-reactive protein. CETP inhibitors did not improve clinical outcomes in large-scale clinical trials of unselected patients with coronary disease. Dalcetrapib is a CETP modulator for which effects on cardiovascular outcomes were demonstrated in the dal-OUTCOMES trial to be influenced by correlated polymorphisms in the ADCY9 (adenylate cyclase type 9) gene (P=2.4×10-8 for rs1967309). Patients with the AA genotype at rs1967309 had a relative reduction of 39% in the risk of presenting a cardiovascular event when treated with dalcetrapib compared with placebo (95% confidence interval, 0.41-0.92). In contrast, patients with the GG genotype had a 27% increase in risk, whereas heterozygotes (AG) presented a neutral result. Supporting evidence from the dal-PLAQUE-2 study using carotid ultrasonography revealed that the polymorphisms tested in the ADCY9 linkage disequilibrium block were associated with disease regression for patients with the protective genotype, progression for the harmful genotype, and no effect in heterozygotes (P≤0.05 and ≤0.01 for 10 and 3 polymorphisms, respectively) when comparing dalcetrapib to placebo. Strikingly concordant and significant genotype-dependent effects of dalcetrapib were also obtained for changes in high-sensitivity C-reactive protein and cholesterol efflux capacity. The Dal-GenE randomized trial is currently being conducted in patients with a recent acute coronary syndrome bearing the AA genotype at rs1967309 in the ADCY9 gene to confirm the effects of dalcetrapib on hard cardiovascular outcomes.

Future of cholesteryl ester transfer protein inhibitors.

The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. Despite two failures, CETP inhibitors are still in clinical development. We review the genetics of CETP and coronary disease, preclinical data on CETP inhibition and atherosclerosis, and the effects of CETP inhibition on cholesterol efflux and reverse cholesterol transport. We discuss the two failed CETP inhibitors, torcetrapib and dalcetrapib, and attempt to extract lessons learned. Two CETP inhibitors, anacetrapib and evacetrapib, are in phase III development, and we attempt to differentiate them from the failed drugs. Whether pharmacologic CETP inhibition will reduce the risk of cardiovascular disease is one of the most fascinating and important questions in the field of cardiovascular medicine.

The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel?

BACKGROUND: According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. MATERIALS AND METHODS: This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. RESULTS: Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. CONCLUSION: These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.

Development of PEGylated Cysteine-Modified Lysine Dendrimers with Multiple Reduced Thiols To Prevent Hepatic Ischemia/Reperfusion Injury.

To inhibit hepatic ischemia/reperfusion injury, we developed polyethylene glycol (PEG) conjugated (PEGylated) cysteine-modified lysine dendrimers with multiple reduced thiols, which function as scavengers of reactive oxygen species (ROS). Second, third, and fourth generation (K2, K3, and K4) highly branched amino acid spherical lysine dendrimers were synthesized, and cysteine (C) was conjugated to the outer layer of these lysine dendrimers to obtain K2C, K3C, and K4C dendrimers. Subsequently, PEG was reacted with the C residues of the dendrimers to obtain PEGylated dendrimers with multiple reduced thiols (K2C-PEG, K3C-PEG, and K4C-PEG). Radiolabeled K4C-PEG ((111)In-K4C-PEG) exhibited prolonged retention in the plasma, whereas (111)In-K2C-PEG and (111)In-K3C-PEG rapidly disappeared from the plasma. K4C-PEG significantly prevented the elevation of plasma alanine aminotransferase (ALT) activity, an index of hepatocyte injury, in a mouse model of hepatic ischemia/reperfusion injury. In contrast, K2C-PEG, K3C-PEG, l-cysteine, and glutathione, the latter two of which are classical reduced thiols, hardly affected the plasma ALT activity. These findings indicate that K4C-PEG with prolonged circulation time is a promising compound to inhibit hepatic ischemia/reperfusion injury.

[Treatment of dyslipidemia - is here still place for CETP-inhibitors?] / Prístup k liecbe dyslipidémií - je tu este miesto pre CETP-inhibítory?

In the treatment of dyslipidemias about 5-6 years back a new class of drugs emerged, CETP (cholesteryl ester transfer protein)-inhibitors. Their benefit was due to an increase of HDL-cholesterol (HDL-C) serum levels. This treatment mode was supported by epidemiological and clinical studies, as people with high serum HDL-C levels suffered less from cardiovascular (CV) events. Three studies with CETP inhibitors (ILLUMINATE with torcetrapib, dal-OUTCOMES with dalcetrapib and ACCELERATE with evacetrapib) were unfortunately negative, and torcetrapib was even harmful to patients due to an increase of aldosterone serum levels. Treatment with dalcetrapib was safe, but without benefit. Similar it was with evacetrapib. There is still running also a study with anacetrapib (REVEAL), but a benefit is here not expected. Evacetrapib and anacetrapib in comparison to dalcetrapib can reduce serum LDL-cholesterol (LDL-C) much more, and similar results were found also in another CETP-inhibitor TA-8995 (TULIP study). Authors try to explain why there is no benefit with CETP-inhibitors (dysfunctional HDL particle, another effective mechanism than reverse cholesterol transport). A genetic analysis in dalcetrapib studies (dal-OUTCOMES and dal-PLAQUE-2) showed, that a cardiovascular benefit from this treatment is concentrated only to a subgroup of patients with a genotype AA in the gene ADCY9 on 16th chromosome. In the population there are about 20% of people with this AA genotype. A clinical study DAL-301 will test this data in a near future. Framingham Offspring study showed that the association of" HDL-C serum level - CV risk in the future" is greatly influenced by serum levels of LDL-C and triglycerides (if these are increased, than the CV future prediction with HDL-C levels is lost). HDL particles are complex and we do not know which subtype of HDL particles is for cardiovascular prognosis important. The research here continues.Key words: acute coronary syndrome - CETP-inhibitors - dalcetrapib - dysfunctional HDL particles - dyslipidemia - HDL-cholesterol - pharmacogenomics of ADCY9 gene.

Effects of dalcetrapib in patients with a recent acute coronary syndrome.

BACKGROUND: In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. METHODS: We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. RESULTS: At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons). CONCLUSIONS: In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).

[Radioprotectors: History, Trends and Prospects].

The search for ideal protective agents for use in a variety of radiation scenarios has continued for more than six decades. This review describes the history of the major discoveries, shows the chronology of the changes in attitudes, trends and paradigms. The readers are invited to meet with various classes of chemical compounds that have the potential to protect against acute and late effects of ionizing radiation when administered either before or after radiation exposure. The work represents characteristics of radioprotective agents such as a dose reduction factor, time of administration, tissue specificity, toxicity; the mechanisms of their action and practical applications are also described. A separate chapter considers the further development prospects and directions in this field of research.

Antimalarial chemotherapy: artemisinin-derived dimer carbonates and thiocarbonates.

Several 2-carbon-linked trioxane dimer secondary alcohol carbonates 14 and thiocarbonates 15, combined with mefloquine and administered in a low single oral dose, prolonged the survival times of malaria-infected mice much more effectively than the popular monomeric antimalarial drug artemether plus mefloquine. Three dimer carbonates 14 and one dimer thiocarbonate 15 partially cured malaria-infected mice.