Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

Biochemical and molecular characterisation of cubozoan protein toxins

Class Cubozoa includes several species of box jellyfish that are harmful to humans. The venoms of box jellyfish are stored and discharged by nematocysts and contain a variety of bioactive proteins that are cytolytic, cytotoxic, inflammatory or lethal. Although cubozoan venoms generally share similar biological activities, the diverse range and severity of effects caused by different species indicate that their venoms vary in protein composition, activity and potency. To date, few individual venom proteins have been thoroughly characterised, however, accumulating evidence suggests that cubozoan jellyfish produce at least one group of homologous bioactive proteins that are labile, basic, haemolytic and similar in molecular mass (42-46 kDa). The novel box jellyfish toxins are also potentially lethal and the cause of cutaneous pain, inflammation and necrosis, similar to that observed in envenomed humans. Secondary structure analysis and remote protein homology predictions suggest that the box jellyfish toxins may act as α-pore-forming toxins. However, more research is required to elucidate their structures and investigate their mechanism(s) of action. The biological, biochemical and molecular characteristics of cubozoan venoms and their bioactive protein components are reviewed, with particular focus on cubozoan cytolysins and the newly emerging family of box jellyfish toxins.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.     

The debate on DDT

The paper reviews the early toxicologic and pharmacologic studies carried out by the author and his associates from 1943 to 1947, which were largely responsible for launching DDT as an agent for the control of typhus, malaria, yellow fever, and related vector-borne diseases. After reviewing recent studies conducted at the University of Miami, which dealt with organochlorine pesticides in human tissues, the tumorigenicity of aldrin, dieldrin and endrin (rat), six-generation mouse and three-generation dog reproduction studies, synergism of DDT and aldrin (dog), and the fate of DDT and aldrin during a period of severe starvation (rat), it is pointed out that it is primarily the overuse and misuse of DDT in pest control that have caused the pollution in our ecology. It is emphasized that the requirements for pest control differ the world over and that it must therefore be left to the national regulatory agencies to legislate the safe use of DDT and related pesticides. It is recommended that future human and animal studies with DDT and its derivatives give consideration to: (a) the balance and metabolism of the various hormones, (b) reproduction (estrus, libido, mammary development, milk production, (c) hepatic microsomal enzyme activities, (d) cancer prevention and cancer production, (e) excessive body weight changes induced by disease, unbalanced diet or starvation, and (f) the effects of DDT and its derivatives when absorbed in combination with other related and even unrelated compounds.Presented at the joint meeting of the Scandinavian and German Pharmacological Societies, Copenhagen, Denmark, July 20–23, 1971.     

Recent developments in the treatment of sepsis

Despite advances in supportive care, septic shock remains a major cause of morbidity and mortality. With the identification of the systemic inflammatory response as a major component in the pathogenesis of the septic shock syndrome, much of the recent work has focused on modulating this response. This includes antiendotoxin therapies in patients with Gram-negative sepsis, and therapies to modulate the pro-inflammatory mediators produced in response to infection, such as TNF-α, platelet-activating factor and complement. High-flow haemofiltration has the potential advantage of clearing both endotoxin and pro-inflammatory mediators. Antithrombotic strategies have been investigated and have yielded the first major success in the treatment of sepsis with activated protein C. Nitric oxide produces the cardiovascular features of sepsis and investigators have looked at both reducing its production and mopping up the excess. Attempts to reduce apoptosis have been a new focus in the treatment of sepsis. There have also been recent developments in supportive care suggesting a role for vasopressin and replacement corticosteroid therapy.     

Further characterization of the discriminative stimulus properties of the atypical antipsychotic drug clozapine in C57BL/6 mice: role of 5-HT2A serotonergic and α1 adrenergic antagonism

Rationale  The discriminative stimulus properties of the atypical antipsychotic drug (APD) clozapine (CLZ) have recently been studied in C57BL/6 mice, a common background strain for genetic alterations. However, further evaluation is needed to fully characterize CLZ’s discriminative cue in this strain of mice. Objectives  The objectives of the study were to confirm the previous findings using a shorter pretreatment time and to further characterize the receptor mechanisms mediating the discriminative stimulus properties of CLZ by testing APDs, selective ligands, and N-desmethylclozapine (CLZ’s major metabolite) in C57BL/6 mice. Materials and methods  C57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ (s.c.) from vehicle in a two-lever drug discrimination task. Results  Generalization testing with CLZ yielded an ED₅₀ = 1.19 mg/kg. Substitution testing with APDs showed that the atypical APDs quetiapine, sertindole, zotepine, iloperidone, and melperone fully substituted for CLZ (≥80% CLZ-appropriate responding), but aripiprazole did not. The typical APDs chlorpromazine and thioridazine substituted for CLZ (fluphenazine and perphenazine did not). The serotonin (5-HT) _2A antagonist M100907 and the α₁-adrenoceptor antagonist prazosin fully substituted for CLZ. The H₁ histaminergic antagonist pyrilamine, dopamine agonist amphetamine, and the selective serotonin reuptake inhibitor fluoxetine did not substitute for CLZ. While N-desmethylclozapine did not substitute for CLZ when tested alone, N-desmethylclozapine plus a low dose of CLZ combined in an additive manner produced full substitution. Conclusions  CLZ’s discriminative cue in C57BL/6 mice is a “compound” cue mediated in part by antagonism of 5-HT_2A and α₁ receptors.     

‘Superbugs’: new antibacterials in the pipeline

‘Superbugs’ in the context discussed herein are Gram-positive pathogens that are multi-resistant to common antibiotic classes. Although many of these organisms were recently susceptible only to vancomycin, therapeutic options are now expanding with the recent approvals for the use of quinupristin-dalfopristin and linezolid against some of these pathogens. Compounds currently under development include cell-wall active agents, such as anti-MRSA cephalosporins, and the glycopeptide LY-333328 to treat resistant Gram-positive infections. More active topoisomerase inhibitors, such as gemifloxacin, sitafloxacin and non-fluoroquinolones, are being evaluated for treatment of multi-drug resistant streptococci, as is the penem faropenem. Novel protein synthesis inhibitors, such as new ketolides and the glycylcycline GAR-936, are also in development; in addition, the lipopeptides daptomycin and HMR-1043 are being evaluated. Safety and efficacy in the treatment of serious infections are two major issues that will determine the eventual success of these agents.     

Emerging drugs for acute ischemic stroke

Stroke is no longer an untreatable condition, and its management is changing rapidly as new developments appear for acute treatments. The objective of this article is to provide a concise introduction to the pathophysiology and existing treatments for stroke, as well as discussing current research goals and interventions under evaluation, along with potential development issues. It will end with the authors' interpretations of the presented material and their opinions about where the field is going, or should go, in the coming years. The material herein is derived from current literature and expert opinion. Overall, the most important findings are that future advances in stroke treatment will probably include combination therapies that will be administered in specialized stroke care units to maximize patient outcome.