Antibiotics from algae. XX. Low molecular phlorotannins from Cystoseirs baccata

Antibiotics from Algae, XX: Low-Molecular Phlorotannins from Cystoseira Baccata. The phlorotannins of Cystoseira baccata (Gmelin) Silva, a brown alga belonging to the fucales, have been isolated by means of their acetyl derivatives. The following compounds were identified: Phloroglucinol triacetate ( 1 ), bifuhalol hexaacetate ( 3 ), difucol hexaacetate ( 4 ), fucophlorethol-B octaacetate ( 6 ) and fucodiphlorethol-B decaacetate ( 8 ). The presence of trifuhalol octaacetate ( 5 ) and of a tetraphlorethol nonaacetate ( 7 ) seems probable.     

Antibiotics from Algae. XXXV. Phlorotannins from Ecklonia maxima1

New phloroglucinol derivatives were isolated from the ethanolic extract of ECKLONIA MAXIMA, a brown alga found off the west coast of South Africa. Most of these compounds contain dibenzo[1,4]dioxin elements. The common basic unit of all the compounds found is eckol, a hexahydroxyphenoxydibenzo[1,4]dioxin composed of 3 phloroglucinol units. Phloroeckol A and B represent four-ringed phloroglucinol derivatives, whereas the only five-ringed substance (furodehydroeckol) displays a furan structure in addition. Six-ringed phloroglucinol derivatives composed of two eckol units joined either symmetrically (such as 7,7'-bieckol, 9,9'-bieckol) or asymmetrically (7,9'-bieckol, dieckol) are found frequently. Apart from these, tetraphlorethol C, a four-ringed tetraphloroglucinol triether which lacks both dioxin and furan structures, also occurs.     

Preventing deaths from malaria.

To reduce the number of avoidable deaths from malaria in Britain the following five points are recommended. Parliament should pass a Malaria Prevention Act that compels travel agents and airlines to give written and verbal advice on prevention and diagnosis of malaria to people travelling to countries where the disease occurs. To improve diagnostic and therapeutic efficiency for all diseases the Department of Health and Social Security should prepare a procedure manual for the NHS that gives guidance for doctors and other medical staff. Avoidable deaths from all diseases should be the subject of open inquiries at district medical committees, with recorded evidence. Failure to perform diagnostic tests such as blood films for malaria in cases of sickness in people returning from the tropics should automatically be considered negligent. Compensation should be offered by the State to the next of kin of people who have died because of medical negligence from malaria or other diseases.     

Alkaloids from Strychnos floribunda.

From STRYCHNOS FLORIBUNDA stem bark. extracts, the alkaloids bisnordihydrotoxiferine, akagerine, decussine, rouhamine, Strychnocarpine, desacetylisoretuline and isorosibiline were isolated as well as a mixture of the sterols beta-sitosterol, stigmasterol and campesterol. Isorosibiline is a new indole alkaloid derived form desacetylisoretuline, having C-16 configuration inverted to that of rosibiline.     

Pneumocandins from Zalerion arboricola. I. Discovery and isolation.

HPLC bioautography of the directed biosynthesis of Zalerion arboricola led to the discovery of pneumocandin B0 (L-688,786), a new antifungal and anti-Pneumocystis carinii lipopeptide. Isolation techniques were developed to separate this component from pneumocandin A0 (L-671,329) in fermentations of a mutant of Zalerion arboricola. A number of related compounds were also isolated, which differ from pneumocandins A0 and B0 in the hydroxylation patterns on the ornithine, homotyrosine, and proline.     

Endogenous neurotoxins from tryptophan.

In most tissues, including brain, a major proportion of the tryptophan which is not used for protein synthesis is metabolised along the kynurenine pathway. Long regarded as the route by which many mammals generate adequate amounts of the essential co-factor nicotinamide adenine dinucleotide, two components of the pathway are now known to have marked effects on neurones. Quinolinic acid is an agonist at the N-methyl-D-aspartate sensitive subtype of glutamate receptors in the brain, while kynurenic acid is an antagonist and, thus, a potential neuroprotectant. A third kynurenine, 3-hydroxykynurenine, is involved in the generation of free radicals which can also damage neurones. Quinolinic acid is increasingly implicated in neurodegenerative disorders, most especially the AIDS-dementia complex and Huntington's disease, while kynurenic acid has become a standard for the identification of glutamate-releasing synapses, and has been used as the parent for several groups of compounds now being developed as drugs for the treatment of epilepsy and stroke.     

Antimalarial agents from plants. III. Trichothecenes from Ficus fistulosa and Rhaphidophora decursiva

Bioassay-directed fractionation of an extract prepared from the dried leaves and stem barks of Ficus fistulosa Reinw. ex Blume (Moraceae) led to the isolation of verrucarin L acetate (1), together with 3alpha-hydroxyisohop-22(29)-en-24-oic acid, 3beta-gluco-sitosterol, 3,4-dihydro-6,7-dimethoxyisocarbostyril, 3,4,5-trimethoxybenzyl alcohol, alpha-methyl-3,4,5-trimethoxybenzyl alcohol, indole-3-carboxaldehyde, palmanine, and aurantiamide acetate. Roridin E (2) was identified in a subfraction from the dried leaves and stems of Rhaphidophora decursiva Schott (Araceae). Verrucarin L acetate and roridin E were characterized as macrocyclic trichothecene sesquiterpenoids and found to inhibit the growth of Plasmodium falciparum with IC 50 values below 1 ng/ml.     

Alkaloids from annonaceae.

From diverse parts of POLYALTHIA NITIDISSIMA, thirteen isoquinoline alkaloids have been isolated and identified. They belong to the structural types of benzylisoquinolines, aporphinoids, protoberberines and mainly bisbenzylisoquinolines. Four of these dimers, namely N,N'-dimethyllindoldhamine, isodaurisoline, 7-O-methyllindoldhamine and 7'-O-methyllindoldhamine, are new natural products.     

Coumarins from Polygala paniculata.

From the petrol ether and chloroform extracts of POLYGALA PANICULATA L. (Polygalaceae), possessing both molluscicidal and antifungal properties, four coumarins were isolated by flash chromatography and centrifugal thin-layer chromatography. They were identified as aurapten, phebalosin, murrangatin and 7-methoxy-8-(l,4-dihydroxy-3-methyl-2-butenyl)coumarin, a new natural product. Among these compounds phebalosin showed biological activity, but proved to be very unstable in aqueous solution.     

Protracted withdrawal syndromes from benzodiazepines.

The benzodiazepine withdrawal syndrome is a complex phenomenon which presents serious difficulties in definition and measurement. It is particularly difficult to set out precise limits on its duration. Many withdrawal symptoms are a result of pharmacodynamic tolerance to benzodiazepines, some mechanisms for which are discussed. Such tolerance develops unevenly in different brain systems and may be slow to reverse. Withdrawal symptoms occurring in the first week after cessation of drug use tend to merge with more persistent symptoms that may last for many months. These prolonged symptoms do not necessarily constitute "true" pharmacological withdrawal symptoms, but are nevertheless related to long-term benzodiazepine use. Such symptoms can include anxiety, which may partly result from a learning deficit imposed by the drugs, and a variety of sensory and motor neurological symptoms. The protracted nature of some of these symptoms raises the possibility that benzodiazepines can give rise not only to slowly reversible functional changes in the central nervous system, but may also occasionally cause structural neuronal damage.     

New Guaianolides from Centaurea aegyptica.

CENTAUREA AEGYPTICA gave in addition to known guaianolides two new ones, closely related to chlorojanerin, a new C (17)-carbinol and several widespread compounds. The structures were elucidated by spectroscopic methods.     

Non-conventional toxins from Elapid venoms.

Non-conventional toxins constitute a poorly characterized class of three-finger toxins isolated exclusively from Elapidae venoms. These toxins are monomers of 62-68 amino acid residues and contain five disulfide bridges. However, unlike alpha/kappa-neurotoxins and kappa-neurotoxins which have the fifth disulfide bridge in their middle loop (loop II), the fifth disulfide bridge in non-conventional toxins is located in loop I (N-terminus loop). Overall, non-conventional toxins share approximately 28-42% identity with other three-finger toxins including alpha-neurotoxins, alpha/kappa-neurotoxins and kappa-neurotoxins. Recent structural studies have revealed that non-conventional toxins also display the typical three-finger motif. Non-conventional toxins are typically characterized by a lower order of toxicity (LD(50) approximately 5-80 mg/kg) in contrast to prototype alpha-neurotoxins (LD(50) approximately 0.04-0.3 mg/kg) and hence they are also referred to as 'weak toxins'. Further, it is generally assumed that non-conventional toxins target muscle (alpha(2)beta gamma delta) receptors with low affinities several orders of magnitude lower than alpha-neurotoxins and alpha/kappa-neurotoxins. However, it is now known that some non-conventional toxins also antagonize neuronal alpha 7 nicotinic acetylcholine receptors. Hence, non-conventional toxins are not a functionally homogeneous group and other, yet unknown, molecular targets for this class of snake venom toxins may exist. Non-conventional toxins may therefore be a useful source of ligands with novel biological activity targeting the plethora of neuronal nicotinic receptors as well as other physiological processes.     

Baclofen-assisted detoxification from opiates. A pilot study.

In an open label pilot study, five opiate-dependent patients underwent baclofen-assisted opiate detoxification after abrupt discontinuation of methadone. Patients received baclofen in oral doses up to 80 mg/day, and all patients subjectively reported some reduction in discomfort. However, 3 of 5 (60%) patients could not complete detoxification with baclofen, primarily because of insufficient suppression of vomiting, myalgias, and headache. These patients successfully completed their detoxification with clonidine. These findings suggest that, in the dose range studied, baclofen is of limited use as a primary treatment for opiate dependence, although adjunctive roles for this medication in detoxification should be explored.     

Cellobiohydrolase from Trichoderma reesei.

The secondary structure pattern of a cellobiohydrolase from Trichoderma reesei was predicted using three different algorithms. The relative amounts of the different secondary structure classes derived by this procedure were in good agreement with the values determined by circular dichroism measurements. A twofold internal sequence homology with a repeat distance of approximately 200 residues is observed and possibly also a third, partial, repetition in the C-terminal region. The predicted secondary structure and hydrophobicity pattern show a similar repeat.     

Alicyclic Diterpenes from Cronquistianthus bishopii.

The aerial parts of CRONQUISTIANTHUS BISHOPII gave in addition to known compounds a new toxol derivative and two alicyclic diterpenes.     

Pneumocandins from Zalerion arboricola. III. Structure elucidation.

Pneumocandin B0 (6) and six related lipopeptides are antifungal and anti-Pneumocystis carinii agents from mutants of Zalerion arboricola, whose structures were determined mainly on the basis of spectroscopic analysis. They belong, along with pneumocandin A0 (L-671,329) previously isolated from these laboratories, to the echinocandin class of antifungal agents. The product from base-catalyzed ring opening involving the hemiaminal position of the dihydroxyornithine residue of B0, has been clearly defined as 6b. Modifications were limited to the 3-hydroxy-4-methylproline, 3,4-dihydroxyhomotyrosine and 4,5-dihydroxyornithine residues of pneumocandin A0.     

Availability of propylphenazone from suppositories. 2. Bioavailability

The examination of the bioavailability from 4 different preparations of propyphenazone suppositories on a fatty base, studied in 10 healthy volunteers, showed bioequivalence as was judged by means of the AUC-values. Aminophenazone suppositories of an equivalent dosage led to significant higher values of plasma concentrations if compared with propyphenazone. The in vivo findings correlate with in vitro results of availability.     

Assessment of intake from the diet.

Exposure assessment is one of the key parts of the risk assessment process. Only intake of toxicologically significant amounts can lead to adverse health effects even for a relatively toxic substance. In the case of chemicals in foods this is based on three major aspects: (i) how to determine quantitatively the presence of a chemical in individual foods and diets, including its fate during the processes within the food production chain; (ii) how to determine the consumption patterns of the individual foods containing the relevant chemicals; (iii) how to integrate both the likelihood of consumers eating large amounts of the given foods and of the relevant chemical being present in these foods at high levels. The techniques used for the evaluation of these three aspects have been critically reviewed in this paper to determine those areas where the current approaches provide a solid basis for assessments and those areas where improvements are needed or desirable. For those latter areas, options for improvements are being suggested, including, for example, the development of a pan-European food composition database, activities to understand better effects of processing on individual food chemicals, harmonisation of food consumption survey methods with the option of a regular pan-European survey, evaluation of probabilistic models and the development of models to assess exposure to food allergens. In all three areas, the limitations of the approaches currently used lead to uncertainties which can either cause an over- or underestimation of real intakes and thus risks. Given these imprecisions, risk assessors tend to build in additional uncertainty factors to avoid health-relevant underestimates. This is partly done by using screening methods designed to look for "worst case" situations. Such worse case assumptions lead to intake estimates that are higher than reality. These screening methods are used to screen all those chemicals with a safe intake distribution. For chemicals with a potential risk, more information is needed to allow more refined screening or even the most accurate estimation. More information and more refined methods however, require more resources. The ultimate aims are: (1) to obtain appropriate estimations for the presence and quantity of a given chemical in a food and in the diet in general; (2) to assess the consumption patterns for the foods containing these substances, including especially those parts of the population with high consumption and thus potentially high intakes; and (3) to develop and apply tools to predict reliably the likelihood of high end consumption with the presence of high levels of the relevant substances. It has thus been demonstrated that a tiered approach at all three steps can be helpful to optimise the use of the available resources: if relatively crude tools - designed to provide a "worst case" estimate - do not suggest a toxicologically significant exposure (or a relevant deficit of a particular nutrient) it may not be necessary to use more sophisticated tools. These will be needed if initially high intakes are indicated for at least parts of the population. Existing pragmatic approaches are a first crude step to model food chemical intake. It is recommended to extend, refine and validate this approach in the near future. This has to result in a cost-effective exposure assessment system to be used for existing and potential categories of chemicals. This system of knowledge (with information on sensitivities, accuracy, etc.) will guide future data collection.     

Cardiotonic agents. 5. Fragments from the heterocycle-phenyl-imidazole pharmacophore

To examine the role of each component in the heterocycle-phenyl-imidazole inotropic pharmacophore, several imidazolone derivatives, an arylimidazole, a substituted 3,4-dihydro-4-oxopyrimidine, and a quinolin-2(1H)-one derivative were prepared as structural fragments or representatives from this relationship. Tests for cardiac inotropic activity in ferret papillary muscle strips (FPM) and for inhibition of crude cAMP phosphodiesterase obtained from canine cardiac tissue suggest that, while all three components contribute significantly toward potent activity (active at less than 1 microM concentrations in FPM), any combination of two components, in approximately a preferred geometry, represents the minimal requirements for weak activity (active at less than 25 microM concentrations). No single component appears to be requisite in an absolute sense.     

Improving safety reporting from randomised trials.

Randomised clinical trials offer a unique opportunity for capturing safety information under a controlled setting that minimises biases in the comparison of different therapeutic options. Nevertheless, empirical evidence across diverse medical fields suggests that the reporting of safety information in clinical trials is largely neglected and receives less attention compared with efficacy outcomes. An analysis of 192 randomised trials has shown that reasons for withdrawals due to toxicity were specified per study arm in only 46% of the trial reports. Adequate reporting of clinical adverse effects and laboratory-determined toxicity occurred in only 39 and 29% of the trials, respectively, even with lenient definitions of what constitutes adequate reporting. The use of standardised scales for adverse effects is a prerequisite for improved reporting on safety in randomised trials. Safety data need to be collected and analysed in a systematic fashion and active surveillance for toxicity during the conduct of a randomised trial is preferable to passive surveillance. Standardised reporting of safety data does not necessarily require extensive space to accomplish. It is essential to provide numerical data per study arm on each type of adverse effect along with a categorisation of the severity of the adverse effects with an emphasis on severe and life-threatening reactions. The severity grading must be referred to well-known standardised scales and new scales need to be carefully defined. Information on withdrawals due to toxicity is also important to report, along with the specific reasons leading to discontinuation. Tabulation of information may be helpful and rare or not previously reported adverse effects should be described in detail. The availability of newer options such as electronic publication, publication of raw databases, large database research, meta-analytic approaches, and prospective registration of clinical trials and of their databases may further improve the safety insights we can gain from randomised clinical trials.