Current opinion in pharmacology
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Curr Opin Pharmacol · Feb 2011
ReviewThe role of serotonin receptors in the action of atypical antipsychotic drugs.
The main class of atypical antipsychotic drugs (APDs) in current use includes the protypical atypical APD, clozapine, as well as aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone. At clinically effective doses, these agents produce extensive blockade of serotonin (5-HT)(2A) receptors, direct or indirect stimulation of 5-HT(1A) receptors, and to a lesser extent, reduction in dopamine (DA) D(2) receptor-mediated neurotransmission. This contrasts with typical APDs, for example haloperidol and perphenazine, which are mainly DA D(2/)D(3) receptor antagonists and have weaker, if any, potency as 5-HT(2A) receptor antagonists. ⋯ There is considerable preclinical and some clinical evidence that effects on 5-HT receptors contribute to the low risk of producing extrapyramidal side effects, which is the defining characteristic of an atypical APD, the lack of elevation in plasma prolactin levels (with risperidone and 9-hydroxyrisperidone being exceptions), antipsychotic action, and ability to improve some domains of cognition in patients with schizophrenia. The serotonergic actions of the atypical APDs, especially 5-HT(2A) receptor antagonism, are particularly important to the differential effects of typical and atypical APDs to overcome the effects of acute or subchronic administration of N-methyl-d-aspartate (NMDA) receptor antagonists, such as phencyclidine, ketamine, and dizocipline (MK-801). 5-HT(1A) receptor stimulation and 5-HT(6) and 5-HT(7) receptor antagonism may contribute to beneficial effects of these agents on cognition. In particular, 5-HT(7) receptor antagonism may be the basis for the pro-cognitive effects of the atypical APD, amisulpride, a D(2)/D(3) receptor antagonist, which has no effect on other 5-HT receptor. 5-HT(2C) receptor antagonism appears to contribute to the weight gain produced by some atypical APDs and may also affect cognition and psychosis via its influence on cortical and limbic dopaminergic activity.
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Early treatment of invasive fungal infections (IFIs) is essential for optimal clinical outcomes. Standard antifungal drugs (polyenes, azoles and echinocandins) are not predictably effective against emerging yeasts and filamentous fungi and may cause undesirable side effects. ⋯ Appropriate dosing and consideration of pharmacokinetic parameters (including therapeutic drug monitoring) are important with newer triazoles. New therapies such as addition of the iron chelator, deferasirox, in the treatment of zygomycosis in diabetic patients, appear promising but additional agents with new targets of action are urgently needed.
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Severe asthma is a complex and heterogeneous phenotype where management can be challenging. While many patients with severe asthma respond to high-dose inhaled corticosteroids in combination with a long-acting beta-agonist, there remains a significant subset of patients that require oral corticosteroids to control symptoms. Alternative therapies are needed to help reduce the need for continuous oral corticosteroids; however, there are currently very few effective options. ⋯ These include macrolide antibiotics, omalizumab, tumor necrosis factor-alpha inhibitors, cytokine receptor antagonists, and bronchial thermoplasty. The challenge with these entities is determining the appropriate phenotype of severe asthma where effectiveness is demonstrated, given the significant heterogeneity of the disease. Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge.
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Curr Opin Pharmacol · Jun 2010
ReviewOsmolytes and ion transport modulators: new strategies for airway surface rehydration.
Mucociliary clearance (MCC) in CF lung disease is limited by airway dehydration, leading to persistent bacterial infection and inflammation in the airways. Agents designed to rehydrate the airway mucosa lead to improved MCC. ⋯ Combinations of these therapies may result in a synergistic improvement in airway hydration, and thus, restore MCC. Active ongoing phase II and III trials of new pharmacotherapeutics are covered in this review.
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Staphylococcus aureus is a major health problem worldwide and the leading cause of bacterial infections in the United States. Historically, the success of S. aureus as a human pathogen has been facilitated by a strong propensity to develop antibiotic resistance and multidrug resistant strains are endemic in hospitals. ⋯ The pathogen is characterized by its ability to spread rapidly and cause infections in otherwise healthy individuals. This review focuses on current progress toward understanding the enhanced virulence properties of CA-MRSA, with an emphasis on Panton-Valentine leukocidin, alpha-hemolysin, and the recently discovered alpha-type phenol-soluble modulins.