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PubMed1978

A morphological assessment of the stimulatory effect of coumarin on macrophages.

In examining the migration of macrophages on to subcutaneously implanted coverslips in rats, it was found that coumarin (5-6 benzo-alpha-pyrone) and a preparation (Venalot) containing the former, very significantly increased the total macrophage number as well as the percentage of stimulation on the skin side of the coverslip. For the muscle side, Venalot increased the total numbers and the percentage stimulated while coumarin alone had no effect compared with the control. It remains to be seen whether these stimulated macrophages are also activated.

Animals↗
PubMed1983

Electron microscopy of the effects of Unguentum lymphaticum on acute experimental lymphedema and various high-protein edemas.

Rats' legs and feet were studied by qualitative and quantitative electron microscopy, including mass densitometry of protein in the tissues and in the initial lymphatics. The tissues were either normal, or had been made edematous by lymphostasis, moderate burns, or dextran. It was found that Unguentum lymphaticum very greatly reduced the amount of edema in the legs with lymphostasis. Since the concentrations of plasma protein in the tissues and initial lymphatics, and its total amounts in the tissues were all greatly reduced, it appears that the cream's anti-lymphedematous activity is via a removal of the excess protein. Since the macrophages were greatly increased in number by the cream (and previous work shows that selectively poisoning these cells prevents much of the cream's effectiveness in lymphedema), very probably it is this increase in their numbers (and possibly their individual proteolytic activities) which is how the cream causes the removal of the excess protein--via an increased proteolysis. The cream also causes an increase in the amount of edema in the rat-foot (after all the injuries, including lymphedema); however the concentration and amount of protein in the tissues is reduced. This is consistent with an inflow of low protein fluid, caused by a vaso-dilatation of the blood microcirculation of this rather specialized tissue. All of these characteristics are very similar to those of many of the benzo-pyrone group of drugs.

Animals↗
PubMed1981

[Efficacy of benzopyrones in posttraumatic inflammations/Clinical double blind study in the postoperative treatment of episiotomy (author's transl)].

A clinical double-blind study of the effectiveness of the benzopyrone product 5.6-benzo-alpha-pyron + 3',4',7-tris-(hydroxy-ethyl)-rutin (coumarin + troxerutin, Venalot) was investigated in 560 patients following medio-lateral episiotomy. The compound was investigated at various dose levels, and its active components coumarin and troxerutin separately. It was shown that the symptoms of posttraumatic inflammation like edema, rubor around the incision wound, and posttraumatic pain as well as consumption of analgesics and the postoperative scar formation were beneficially influenced by the drug. As a guideline for dosing, 1 mg/kg/d related to the coumarin content, was calculated. The efficacy of the combination of the active compounds was superior to that found with the components applied separately. The significance of episiotomy as clinical model for posttraumatic inflammation in general is discussed and application of the benzopyrone product above all in plastic surgery is suggested.

Adolescent↗
PubMed1981

[The chemistry of antimicrobially active 1-hydroxy-2-pyridones (author's transl)].

The unsaturated delta-keto esters (3) obtained by condensation of acid chlorides with esters of di- or trialkyl-acrylic acids can be cyclized with hydroxylamine to yield 1-hydroxy-2-pyridones (4). However, in many cases a two-steps synthesis may be of advantage in preparative respect, the ketoesters being cyclized to 2-pyrones (7), which then are reacted with hydroxylamine in the presence of certain bases to give 4. The hydroxy-pyridones show pronounced antifungal activity in vitro as well as in experimental guinea pig dermatophytosis.

Animals↗
PubMed1995

Synthesis and antiproliferative activity of furocoumarin isosters.

Furocoumarins are a group of natural and synthetic compounds, some of which are used for the photochemotherapeutic treatment of certain skin diseases. With the aim of decreasing the side-effects of furocoumarin photochemotherapy and possibly increasing the therapeutic effects of these drugs, some new furocoumarin isosters were synthesized. The chemical synthesis of furocoumarin isosters at the furan ring, such as pyrrolo-, thieno-, oxazolo- and triazolocoumarins are reported. For all these compounds the key intermediate is a properly functionalized coumarin, to which the third heterocyclic ring is condensed by successive steps. Linear and angular pyrrolo-, tetrahydrobenzo- and benzopyrrolocoumarins show reduced photobiological activity, but have a strong antiproliferative effect in the dark, probably through an interaction with topoisomerases. Oxazolocoumarins are too unstable to be studied; triazolocoumarins show very poor activity. Tienocoumarins have not yet been studied. Furocoumarin isosters at the benzene ring are represented by 8-azapsoralens. Chemical synthesis involves the key 8-azacoumarin in the place of coumarin. These compounds have photochemical and photobiological properties which are very similar to those of psoralens. In particular, 4,4',5'- is effective in the photochemotherapeutic treatment of psoriasis. Furoquinolinones and 4-azapsoralens are reported among the isosters at the pyrone ring. While the synthesis of pyrroloquinolinones involves properly functionalized 7-aminoquinolinones as key intermediate, that of 4-azapsoralen requires a quite different synthetic pathway, involving a properly functionalized benzofuran derivative as key intermediate. Furoquinolinones have dramatically high activity both in the dark and under light activation; 4-azapsoralens have not yet been investigated.

Animals↗
PubMed1993

Azapsoralens-DNA interactions: crystal structure characterization of furan-side monoadduct and computer-aided studies.

In this paper a theoretical study, concerning molecular mechanics optimised structures, obtained by quantum mechanics as well as molecular mechanics calculations was carried out with the aim of correlating the theoretical model of the interactions between azapsoralens and DNA with the data experimentally obtained. The theoretical model suggests that both furan-side and pyrone-side double bonds may be involved in the cycloaddition with pyrimidines (although the cycloaddition at the level of furan is preferred), and is in line with the capacity of these compounds to form inter-strand cross-links. Moreover, concerning the theoretical intercalation model calculations on 3,4,4',5'-tetramethylazapsoralen intercalated inside a polynucleotide, they suggest a cis-syn arrangement between furan-side of the intercalated ligand and the above situated thymine, with which, under light activation, a cycloadduct may take place, having a cis-syn steric arrangement. Also this datum is in agreement with the cis-syn regio and stereochemistry of the isolated 4,4',5'-trimethylazapsoralen-thymine cycloadduct. Finally, from theoretical data, the role of nitrogen seems not important: in fact only small differences were found with the corresponding methylpsoralens so that the small differences observed may be mainly attributed to steric rather than to electronic effects. In general a good correlation between the theoretical model and the experimental data was observed.

Chromatography, High Pressure Liquid↗
PubMed1977

Tissue levels of (3(-14)C) coumarin in the rat: distribution and excretion.

The benzo-pyrones (including coumarin) are a very effective therapy for mild thermal oedema and cases of acute and chronic lymphoedema. In this preliminary report the distribution of a single injected dose of coumarin was followed in normal tissues of rats for 100 hours. Comparisons are to be made later with drug levels in thermally injured and lymphoedematous tissues. The resluts show 7-4% of the injected dose to remain in the tissues after 100 h. During this time 30-9% was excreted in the faeces and approximately 47% excreted in the urine. At any given time most of the dose was present in the gut, muscular tissues, skin and liver. For the gut tissues this was 33%, for the muscular tissues 28%, for the skin 18% and for the liver 16%. The highest concentrations per gram of tissue were however in the kidney and liver, representing the two organs of metabolism and excretion of the coumarin.

Animals↗
PubMedDate not supplied

A model of the factors affecting interstitial volume in oedema. Part II: Their effects at various abnormal steady-states.

A mathematical model has been used to investigate the alterations, in amount and importance, of the Factors controlling interstitial fluid volume in a number of steady-state oedemas. Steady-states were used because it is much easier to evaluate the effect of a specific Factor on oedema if all the others are constant. They are best compared if expressed in the same units: ml/min/100 g of tissue. The effects of lymphatic drainage on trauma are very important, as is the effect of tissue proteolysis on lymphoedema. Tissue proteolysis has minimal effects on the normal state and trauma; yet modelling its increase with benzo-pyrones markedly reduces oedema in both trauma and lymphoedema. Excess fibrosis greatly reduces lymphoedema. The effects of the individual Factors vary considerably between the different steady-states.

Edema↗
PubMedDate not supplied

Bioactivity of flavonoids.

Flavonoids are benzo-gamma-pyrone derivatives of plant origin. They possess wide spectrum of biological activity. From the therapeutical point of view the most important are their antioxidant properties. These are the result of high propensity to electron transfer, ferrous ions chelating activity and direct scavenging of reactive oxygen species. Flavonoids inhibit enormous number of enzymes. From the pharmacological point of view inhibition of cyclooxygenase and lipoxygenases as well as scavenging of superoxide anions seem to be essential. Flavonoids are antiinflammatory agents as the result of diminished formation of proinflammatory mediators (prostaglandins, leukotrienes, reactive oxygen species, nitric oxide). They are also antithrombotic owing to their ability to scavenge superoxide anions. These anions are strong inhibitors of prostacyclin production. Removal of superoxide anions by flavonoids facilitates antiaggregatory PGI2 formation. Superoxide anions generate proagregatory isoprostanes. The antiaggregatory effect of flavonoids may be due to the limitation of formation of isoprostanes. Empirical use of flavonoids as drugs acquired recently scientific confirmation.

Animals↗
PubMed1998

Piper methysticum (kava kava).

Piper methysticum (kava kava) is a plant native to the Pacific Island region, and has been used ceremonial for thousands of years. The active ingredients are a group of substances know as kava lactones (AKA kava pyrones). Four lactones in kava have been found to have significant analgesic and anesthetic effects via non-opiate pathways. Kava's most popular application is as a natural anxiolytic, comparing favorably in several studies to a number prescription medications, including benzodiazepines. CNS effects seem to be mediated by several mechanisms. Studies have been conflicting regarding its GABA-receptor-binding capacity, although this has been found to occur in some studies. In vitro kava has been found to block norepinephrine uptake. It also has some anti-convulsant capabilities, which appear to be mediated by Na+ channel receptor sites. The therapeutic dosage is in the range of 50-70 mg kava lactones three times daily. The most common side effect, usually seen only with long-term, heavy usage of the herb, is a scaly skin rash called "kava dermopathy." It has also been know to potentiate other medications such as barbiturates and Xanax.

Anti-Anxiety Agents↗
PubMed2003

Pathophysiology of the optic neuropathy associated with Friedreich ataxia.

OBJECTIVES: To describe the optic neuropathy associated with the genetic defect in Friedreich ataxia and suggest a pathophysiologic mechanism. METHODS: An experimental model of retinal ganglion cell death in the presence of metal chelation was used to test a hypothetical mechanism for the optic neuropathy of Friedreich ataxia. RESULTS: Study of cultured rat retinal ganglion cells suggests that abnormal regulation of intracellular iron levels could increase sensitivity to reactive oxygen species and lead to cell death in these metabolically active tissues. CONCLUSION: We hypothesize that decreased expression of frataxin, the mutated gene in Friedreich ataxia, could cause an optic neuropathy by increasing the sensitivity of retinal ganglion cells to oxidative stress.

Animals↗
PubMed1999

Structure-based discovery of Tipranavir disodium (PNU-140690E): a potent, orally bioavailable, nonpeptidic HIV protease inhibitor.

Efforts to develop therapeutically relevant HIV protease inhibitors as medicinal agents in confronting the AIDS crisis have been aided by the wealth of fundamental information acquired during related drug discovery campaigns against other aspartyl proteases. This knowledge base was brought to full force with the broad screening identification of small, nonpeptidic, inhibitory molecules as templates for chemical elaboration. Significantly, the ability to collect crystallographic data on the inhibitor-enzyme complexes in a rapid fashion afforded the opportunity for a structure-based approach to drug discovery. Iterative cycles of synthesis, biological testing, and structural information gathering followed by prudent design modifications afforded compounds suitable for clinical evaluation. Displaying high enzymatic inhibition (Ki = 8 pM), potent in vitro antiviral cell culture activity (IC90 = 100 nM), and a useful pharmacokinetic profile, PNU-140690E (Tipranavir disodium) has entered into clinical studies. Promising results from these early trials supported further evaluation of this compound in HIV-infected individuals. PNU-140690E is currently under extensive clinical study.

Administration, Oral↗
PubMed1997

Fluorescent brighteners: novel stains for the flow cytometric analysis of microorganisms.

Flow cytometry is a rapid method for measuring the optical properties of individual cells. The technique has found great utility in the study of mammalian cells, but microbiological applications have been more limited. We here show that UV-excited fluorescent whitening agents, in particular Tinopal CBS-X, are effective stains for both vegetative microbial cells and for spores of Gram-positive bacteria. Pretreatment of samples with ethanol speeds the staining process. Under favourable conditions, Tinopal CBS-X may be used to discriminate among organisms, a fact that may be useful when screening for a target microorganism against a high biological background.

Bacillus subtilis↗
PubMedDate not supplied

Inhibitors of HIV protease: unique non-peptide active site templates.

New templates were designed and prepared which straddle the active site of HIV-1 protease. These templates were designed to be "flexible scaffolds' upon which substituents could be appended to fill the pockets of HIV protease. The new templates prepared and analysed were 4-hydroxy-5H-furan-2-ones, 4-hydroxy-5,6-dihydropyrones, 3-hydroxy-cyclohex-2-enones, and 4-hydroxy-2(1H)-pyridinones, of which the 4-hydroxy-5,6-dihydropyrones were found to be the most potent inhibitors of HIV-1 protease.

Binding Sites↗
PubMed2001

Neuroprotective effects of (+/-)-kavain in the MPTP mouse model of Parkinson's disease.

This is the first study to investigate the potential protective effects of the lipophilic kavapyrone (+/-)-kavain in the experimental MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD). Male C57BL/6 mice were treated with (+/-)-kavain (50, 100, or 200 mg/kg i.p.) or vehicle 60 min before and 60 min after a single administration of MPTP (30 mg/kg s.c.) or saline, respectively. Mice were sacrificed after 7 days and the neostriatum was analyzed for dopamine and its metabolites using HPLC with electrochemical detection. Furthermore, nigral sections were processed for tyrosine hydroxylase (TH) immunocytochemistry. To determine the effects of (+/-)-kavain (200 mg/kg) on MPTP metabolism, HPLC analysis of striatal MPP(+) (1-methyl-4-phenylpyridinium) levels was performed. MPTP treatment alone led to a significant depletion of striatal dopamine levels to 12.61% of saline controls. The lower dosages of (+/-)-kavain (50 and 100 mg/kg) showed only a nonsignificant attenuation of MPTP-induced dopamine depletion, but a high dosage of (+/-)-kavain (200 mg/kg) significantly antagonized the dopamine depletion to 58.93% of saline control values. Remarkably, the MPTP-induced decrease of TH-immunoreactivity as well as the loss of nigral neurons was completely prevented by (+/-)-kavain (200 mg/kg). Striatal MPP(+) levels were not altered by (+/-)-kavain treatment. In conclusion, we found that MPTP metabolism was not influenced by (+/-)-kavain and postulate the antiglutamatergic effects of (+/-)-kavain for its protective effects against MPTP toxicity. (+/-)-Kavain may be a novel candidate for further preclinical studies in animal models of PD and other disorders with glutamatergic overactivity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗