Induction of sister chromatid exchanges in vivo in bone marrow cells of AKR mice]

Induction of sister chromatid exchanges (SCEs) in bone-marrow cells of AKR Mice receiving in vivo four drugs well-known for their mutagenesis activity has been tested. A decreasing activity in SCE was shown by the drugs tested in the order cyclophosphamide, procarbazine, methylmethane sulfonate and diethylnitrosamine. This technique presents an encouraging method for testing the effect of chemical agents in vivo.     

Profound hypothermia in golden hamsters (Mesocricetus auratus) induced by serotonergic potentiating and noradrenergic inhibiting drugs

Summary Profound hypothermia (6°C) was induced in cold exposed golden hamsters (Mesocricetus auratus) by a combination of drugs that potentiate brain serotonergic activity (fluoxetine and pargyline) and inhibit noradrenergic activity (alpha-methyl-p-tyrosine). Individual drugs and combinations of 2 were ineffective.Acknowledgements. We acknowledge the support of a research grant PCM74-05158 A01 to A.H.M. from the National Science Foundation (USA) and thank Lilly Research Laboratories, Indianapolis, Indiana, for the gift of fluoxetine (Lilly 110140).     

Interaction of smooth muscle relaxant drugs with calmodulin and cyclic nucleotide phosphodiesterase

Some smooth muscle relaxant drugs with an unknown mechanism of action have been tested for their interaction with calmodulin and with calmodulin-induced cyclic nucleotide phosphodiesterase (PDE) activity. The affinity of these drugs for calmodulin does not parallel their inhibitory effect on the calmodulin activation of PDE. The lack of parallelism could be due to a binding of the drugs to different sites on calmodulin; furthermore a binding of papaverine, octylonium bromide and felodipine to PDE molecule might also be considered to explain their inhibitory effect on PDE basal activity. The myolytic effect of octylonium bromide and pinaverium bromide may be due to their interaction with calmodulin-dependent systems.     

Interaction of smooth muscle relaxant drugs with calmodulin and cyclic nucleotide phosphodiesterase

Summary Some smooth muscle relaxant drugs with an unknown mechanism of action have been tested for their interaction with calmodulin and with calmodulin-induced cyclic nucleotide phosphodiesterase (PDE) activity. The affinity of these drugs for calmodulin does not parallel their inhibitory effect on the calmodulin activation of PDE. The lack of parallelism could be due to a binding of the drugs to different sites on calmodulin; furthermore a binding of papaverine, octylonium bromide and felodipine to PDE molecule, might also be considered to explain their inhibitory effect on PDE basal activity. The myolytic effect of octylonium bromide and pinaverium bromide may be due to their interaction with calmodulin-dependent systems.     

Antibacterial properties of several drug categories

Summary Several drugs of various pharmacological classes were tested for antimicrobial activity by the agar diffusion technique and minimal inhibitory concentration (MIC) estimation. Among them diclofenac sodium, haloperidol, meclastine fumarate, chlorpromazine, chlorimipramine and promethazine were the more active.     

Antimicrobial activity of metal derivatives of sulfonamides

Antimicorbial activities of a series of metal derivatives of some sulfa drugs were examined. Such metal derivatives showed higher antimicorbial activity than the parent sulfa drugs, and among the metals, gold derivatives are seen to be the most effective.     

Hemmung des durch blutdrucksenkende Pharmaka bei Ratten ausgelösten Trinkens durch Nephrektomie

Summary The drinking response of rats seen after the hypotensive drugs phentolamine, isoproterenol and hydralazine/bretylium can be abolished by nephrectomy. It is postulated, that the dipsogenic activity of these drugs is mediated by renin.     

Activity of sulfa drugs and dihydrofolate reductase inhibitors againstCandida albicans

Summary Growth ofCandida albicans can be inhibited by sulfa drugs which prevent biosynthesis of folic acid. The dihydrofolate reductase (E.C. 1.5.1.3) inhibitors aminopterin and methotrexate also exhibit anticandidal activity, but trimethoprim does not. Kinetic evaluations withC. albicans dihydrofolate reductase indicate that methotrexate and aminopterin are tight-binding inhibitors whereas trimethoprim binds poorly.     

The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication

Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression.     

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.     

Antimicrobial activity of metal derivatives of sulfonamides

Summary Antimicrobial activities of a series of metal derivatives of some sulfa drugs were examined. Such metal derivatives showed higher antimicrobial activity than the parent sulfa drugs, and among the metals, gold derivatives are seen to be the most effective.We wish to thank for the material supplied by the Central Research Laboratories, Meiji Seika Kaisha, Ltd, for antimicrobial assay.     

Antihypertensive and cardiac effects of two novel beta-adrenoceptor blocking drugs.

Two new beta-adrenoceptor blocking drugs with acute antihypertensive and positive inotropic effects are described: Compound A (2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole) and MK-761 (2-(3-tert.butylamine-2-hydroxypropoxy)-3-cyanopyridine hydrochloride). In SH rats both compounds, given orally, lowered arterial pressure and were more potent than hydralazine. The antihypertensive effect of compound A but not of MK-761 was antagonized by timolol. Both compounds had positive inotropic activity on cat heart papillary muscles; these effects were antagonized by timolol. The pretreatment of animals with reserpine greatly reduced the positive inotropic effect of MK-761 but not of compound A. The acute antihypertensive and positive inotropic effects of compound A are like to be at least partially due to stimulation of beta-adrenoceptors, e.g. intrinsic sympathomimetic activity. The effects of MK-761 on the same parameters appear to be mediated by different mechanisms.     

S-adenosyl-L-homocysteine: A non-cytotoxic hypomethylating agent

The cytotoxic effect caused by the hypomethylating agent S-adenosyl-L-homocysteine (SAH) was compared with that of two drugs commonly used to induce DNA hypomethylation, 5-azacytidine and 5-aza-2-deocycytidine. Two in vitro cytotoxicity tests, the tetrazolium MTT assay and the intracellular lactate dehydrogenase (LDH) activity test, suggest that SAH induces hypomethylation without causing any cytotoxic effect. We propose the use of SAH as a non-cytotoxic agent which may be more suitable for inducing experimental DNA hypomethylation.     

Platelet monoamine oxidase B: use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Platelet monoamine oxidase B: Use and misuse

The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.     

Small molecule inhibitors of DNA repair nuclease activities of APE1

APE1 is a multifunctional protein that possesses several nuclease activities, including the ability to incise at apurinic/apyrimidinic (AP) sites in DNA or RNA, to excise 3′-blocking termini from DNA ends, and to cleave at certain oxidized base lesions in DNA. Pre-clinical and clinical data indicate a role for APE1 in the pathogenesis of cancer and in resistance to DNA-interactive drugs, particularly monofunctional alkylators and antimetabolites. In an effort to improve the efficacy of therapeutic compounds, such as temozolomide, groups have begun to develop high-throughput screening assays and to identify small molecule inhibitors against APE1 repair nuclease activities. It is envisioned that such inhibitors will be used in combinatorial treatment paradigms to enhance the efficacy of DNA-interactive drugs that introduce relevant cytotoxic DNA lesions. In this review, we summarize the current state of the efforts to design potent and selective inhibitors against APE1 AP site incision activity.