Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used during the 1950s and 1960s as an experimental drug in psychiatric research for producing so-called "experimental psychosis" by altering neurotransmitter system and in psychotherapeutic procedures ("psycholytic" and "psychedelic" therapy). From the mid 1960s, it became an illegal drug of abuse with widespread use that continues today. With the entry of new methods of research and better study oversight, scientific interest in LSD has resumed for brain research and experimental treatments. Due to the lack of any comprehensive review since the 1950s and the widely dispersed experimental literature, the present review focuses on all aspects of the pharmacology and psychopharmacology of LSD. A thorough search of the experimental literature regarding the pharmacology of LSD was performed and the extracted results are given in this review. (Psycho-) pharmacological research on LSD was extensive and produced nearly 10,000 scientific papers. The pharmacology of LSD is complex and its mechanisms of action are still not completely understood. LSD is physiologically well tolerated and psychological reactions can be controlled in a medically supervised setting, but complications may easily result from uncontrolled use by layman. Actually there is new interest in LSD as an experimental tool for elucidating neural mechanisms of (states of) consciousness and there are recently discovered treatment options with LSD in cluster headache and with the terminally ill.

The cinnamon extract seems to have a moderate effect in reducing fasting plasma glucose concentrations in diabetic patients with poor glycaemic control.

The selective induction of PGE2 synthesis in inflammation suggests that a PGE synthase may be linked to an inducible pathway for PG synthesis. We examined the expression of the recently cloned inducible microsomal PGE synthase (mPGES) in synoviocytes from patients with rheumatoid arthritis, its modulation by cytokines and dexamethasone, and its linkage to the inducible cyclooxygenase-2. Northern blot analysis showed that IL-1β or TNF-α treatment induces mPGES mRNA from very low levels at baseline to maximum levels at 24 h. IL-1β-induced mPGES mRNA was inhibited by dexamethasone in a dose-dependent fashion. Western blot analysis demonstrated that mPGES protein was induced by IL-1β, and maximum expression was sustained for up to 72 h. There was a coordinated up-regulation of cyclooxygenase-2 protein, although peak expression was earlier. Differential Western blot analysis of the microsomal and the cytosolic fractions revealed that the induced expression of mPGES protein was limited to the microsomal fraction. The detected mPGES protein was catalytically functional as indicated by a 3-fold increase of PGES activity in synoviocytes following treatment with IL-1β; this increased synthase activity was limited to the microsomal fraction. In summary, these data demonstrate an induction of mPGES in rheumatoid synoviocytes by proinflammatory cytokines. This novel pathway may be a target for therapeutic intervention for patients with arthritis.

Abstract-Aging is associated with an increased risk for atherosclerosis. A possible cause is low numbers and dysfunction of endothelial progenitor cells (EPC) which insufficiently repair damaged vascular walls. We hypothesized that decreased levels of insulin-like growth factor-1 (IGF-1) during age contribute to dysfunctional EPC. We measured the effect of growth hormone (GH), which increases endogenous IGF-1 levels, on EPC in mice and human subjects. We compared EPC number and function in healthy middle-aged male volunteers (57.4Ϯ1.4 years) before and after a 10 day treatment with recombinant GH (0.4 mg/d) with that of younger and elderly male subjects (27.5Ϯ0.9 and 74.1Ϯ0.9 years). Middle-aged and elderly subjects had lower circulating CD133 ϩ /VEGFR-2 ϩ EPC with impaired function and increased senescence. GH treatment in middle-aged subjects elevated IGF-1 levels (126.0Ϯ7.2 ng/mL versus 241.1Ϯ13.8 ng/mL; PϽ0.0001), increased circulating EPC with improved colony forming and migratory capacity, enhanced incorporation into tube-like structures, and augmented endothelial nitric oxide synthase expression in EPC comparable to that of the younger group. EPC senescence was attenuated, whereas telomerase activity was increased after GH treatment. Treatment of aged mice with GH (7 days) or IGF-1 increased IGF-1 and EPC levels and improved EPC function, whereas a two day GH treatment did not alter IGF-1 or EPC levels. Ex vivo treatment of EPC from elderly individuals with IGF-1 improved function and attenuated cellular senescence. IGF-1 stimulated EPC differentiation, migratory capacity and the ability to incorporate into forming vascular networks in vitro via the IGF-1 receptor. IGF-1 increased telomerase activity, endothelial nitric oxide synthase expression, phosphorylation and activity in EPC in a phosphoinositide-3-kinase/Akt dependent manner. Small interference RNA-mediated knockdown of endothelial nitric oxide synthase in EPC abolished the IGF-1 effects. Growth hormone-mediated increase in IGF-1 reverses age-related EPC dysfunction and may be a novel therapeutic strategy against vascular disorders with impairment of EPC. Patients with reduced EPC levels are at increased risk for cardiovascular events and death. 3,4 Recent studies suggest augmentation of circulating EPC to result in improved coronary collateral development in coronary artery disease. 5 Increasing age is associated with decreased number 6 and impaired function of EPC, 7 which may facilitate atherosclerotic processes. Regulation of EPC mobilization, differentiation and function is complex, but specific growth hormones and cytokines are explicitly involved. 8 Insulin-like growth factor-1 (IGF-1) enhances migration, tube formation and angiogenesis of mature endothelial cells 9 and increases te- Low serum IGF-1 levels, common in the elderly, are associated with an increased risk for ischemic heart disease. 12 Restoration of IGF-1 in elderly individuals by growth hormone therapy may have significant beneficial health effects. 13 In growth hormone de...

Nitric oxide (NO) is synthesized from L-arginine by the NO synthases. At present, mainly three NO synthase isoenzyme groups are differentiated: two constitutive NO synthases, responsible for homeostatic cardiovascular and neuronal functions of NO, and an inducible NO synthase. After induction by certain cytokines or endotoxin, this latter isoform produces large quantities of NO with cyto- and bacteriotoxic effects. High amounts of NO, synthesized systemically and intra-articularly, play an important role in inflammatory joint diseases, as shown in animal models of arthritis and in patients with rheumatoid arthritis or spondyloarthropathies. In experimental arthritis, administration of NO synthase inhibitors profoundly reduced disease activity. In humans, beneficial effects of NO synthesis inhibition are inferred from indirect evidence: glucocorticoids, inhibiting induction of the inducible NO synthase, reduce enhanced NO synthesis and disease activity. Thus, selective inhibition of the pathologically enhanced NO synthesis emerges as a new experimental therapeutic approach in the treatment of inflammatory joint diseases.

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SUMMARYMechanisms regulating the balance of T-helper 1 ( Th1) and T-helper 2 ( Th2) immune responses are of great interest as they may determine the outcome of allergic and infectious diseases. Recently, in mice, nitric oxide ( NO), a powerful modulator of inflammation, has been reported to preferentially down-regulate Th1-mediated immune responses. In the present study, we investigated the effect of NO on the production of Th1-and Th2-associated cytokines by activated human T cells and human T-cell clones. Cytokine secretion was measured in the presence of the NO-donating agents 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). Both NO-donors markedly inhibited the release of interferon-c (IFN-c), interleukin-2 (IL-2 ), IL-5, IL-10 and IL-4 by anti-CD3 activated T cells. A preferential inhibition of Th1-associated cytokines was not observed. Neither was nitrite found in the supernatants of activated T cells, nor was specific mRNA for inducible and constitutive NO synthase detectable, indicating that T cells themselves did not contribute to the observed effect of the NO donors. Costimulation with anti-CD28 monoclonal antibodies (mAb) prevented SIN-1/SNAP-mediated down-regulation of cytokine production only in part. In contrast, when T cells were stimulated by phorbol-ester and ionomycin, they were refractory to SIN-1-induced inhibition of cytokine production. When SIN-1 was added after the onset of anti-CD3 stimulation, the inhibitory effect was found to be less pronounced, indicating that SIN-1 may interfere with early signal transduction events. The addition of superoxide dismutase (SOD) and catalase did not restore the effects of SIN-1, demonstrating that the inhibition of cytokines was due to NO and not to oxygen intermediates. Furthermore, 8-Br-cGMP-mediated increase of intracellular cGMP caused the same pattern of cytokine inhibition as observed with SIN-1 and SNAP. Using a single cell assay, these agents were shown to reduce the frequency of IFN-c-producing T cells, suggesting that not all T cells are susceptible to SIN-1/SNAP. However, cytokine production by purified T-cell subpopulations (CD4+, CD8+, CD45RA+, and CD45RO+) was equally impaired by NO donors. In conclusion, in contrast to the murine system, our results do not provide evidence that NO preferentially inhibits Th1-cytokine secretion of activated human T cells in vitro.

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