Safety Assessment of Polyene Group as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of polyenes, which are reported to function in cosmetics primarily as film formers and viscosity increasing agents. The Panel reviewed relevant data related to these ingredients, not inggaps in the available safety data for some of the polyenes in this safety assessment. The data available for many of the ingredients are sufficient and can be extrapolated to support the safety of the entire group because of the similarities in the chemical structures, chemical properties, use concentrations, and reported functions across the group. The Panel concluded that polyenes were safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Molecular Umbrellas Modulate the Selective Toxicity of Polyene Macrolide Antifungals.

Antifungal polyene macrolide antibiotics Amphotericin B (AmB) and Nystatin (NYS) were conjugated through the ω-amino acid linkers with diwalled "molecular umbrellas" composed of spermidine-linked deoxycholic or cholic acids. The presence of "umbrella" substituents modulated biological properties of the antibiotics, especially their selective toxicity. Some of the AmB-umbrella conjugates demonstrated antifungal in vitro activity comparable to that of the mother antibiotic but diminished mammalian toxicity, especially the hemolytic activity. In contrast, antifungal in vitro activity of NYS-umbrella conjugates was strongly reduced and all these conjugates demonstrated poorer than NYS selective toxicity. No correlation between the aggregation state and hemolytic activity of the novel conjugates was found.

Storage of red blood cells in a novel polyolefin blood container: a pilot in vitro study.

BACKGROUND AND OBJECTIVES: The present general plasticizer di-2-ethylhexyl-phthalate in polyvinylchloride (PVC) blood bags is only physically dispersed in PVC and will therefore leach into blood components. The objective of this study was to perform a first preliminary red blood cell (RBC) storage evaluation in a new blood bag manufactured of polyolefin without any inclusion of potentially migrating substances. STUDY DESIGN AND METHODS: This is a RBC storage study for 42 days. Blood collection was performed in a polyolefin-based PVC-free blood bag. RBCs were prepared within 8 h. Two different RBC additive solutions were used, either PAGGS-M or PAGGG-M. We weekly measured pH, K+ , glucose, lactate, haemolysis, red cell ATP and 2,3-DPG. RESULTS: RBC storage in PAGGS-M resulted in high haemolysis levels already after 21 days, exceeding the European maximum limit of 0·8%, and low ATP levels by the end of the storage period. With PAGGG-M, haemolysis exceeded 0·8% after 28 days of storage. For additional parameters, the results were comparable to those of previous studies in conventional blood bags. CONCLUSION: This is a first preliminary study of RBC storage in a new type of blood bags. PAGGG-M gave encouraging results except for its inability to prevent increased haemolysis. There will be room for further development of RBC additive solutions to address the haemolysis problems. Plasma should also be tested regarding the stability of coagulation and activation pathway variables. There may also be a potential for future use of the bag for preparation of pooled buffy-coat-derived platelets.

Global and targeted metabolomics reveal that Bupleurotoxin, a toxic type of polyacetylene, induces cerebral lesion by inhibiting GABA receptor in mice.

Polyacetylenes are widely distributed in food plants and medicinal herbs, which have been shown to have highly neurotoxic effects. However, there were insufficient studies on the toxicity of these compounds. Thus, a series of experiments was designed to elucidate the toxicity mechanism of bupleurotoxin (BETX) as a representative polyacetylene. First, male BALB/c mice were intragastrically administered 2.5 mg/kg of bodyweight BETX once a day for seven consecutive days. The histopathological results showed that BETX could induce severe morphological damages in the brain hippocampus. We then used metabolomics approaches to screen serum samples from the control and BETX-treated groups. The global metabolomics results revealed 17 metabolites that were perturbed after BETX treatment. Four of these metabolites were then verified by targeted metabolomics. Bioinformatics analysis with the Ingenuity Pathway Analysis (IPA) software found a strong correlation between the GABA receptor signaling pathway and these metabolites. On the basis of these results, a validation test using a rat hippocampal neuron cell line was performed, and the results confirmed that BETX inhibited GABA-induced currents (IGABA) in a competitive manner. In summary, our study illustrated the molecular mechanism of the toxicity of polyacetylenes. In addition, our study was instructive for the study of other toxic medical herbs.

Roots of the invasive species Carduus nutans L. and C. acanthoides L. produce large amounts of aplotaxene, a possible allelochemical.

The invasive thistle Carduus nutans has been reported to be allelopathic, yet no allelochemicals have been identified from the species. In a search for allelochemicals from C. nutans and the closely related invasive species C. acanthoides, bioassay-guided fractionation of roots and leaves of each species were conducted. Only dichloromethane extracts of the roots of both species contained a phytotoxin (aplotaxene, (Z,Z,Z)-heptadeca-1,8,11,14-tetraene) with sufficient total activity to potentially act as an allelochemical. Aplotaxene made up 0.44 % of the weight of greenhouse-grown C. acanthoides roots (ca. 20 mM in the plant) and was not found in leaves of either species. It inhibited growth of lettuce 50 % (I 50) in soil at a concentration of ca. 0.5 mg g(-1) of dry soil (ca. 6.5 mM in soil moisture). These values gave a total activity in soil value (molar concentration in the plant divided by the molarity required for 50 % growth inhibition in soil = 3.08) similar to those of some established allelochemicals. The aplotaxene I 50 for duckweed (Lemna paucicostata) in nutrient solution was less than 0.333 mM, and the compound caused cellular leakage of cucumber cotyledon discs in darkness and light at similar concentrations. Soil in which C. acanthoides had grown contained aplotaxene at a lower concentration than necessary for biological activity in our short-term soil bioassays, but these levels might have activity over longer periods of time and might be an underestimate of concentrations in undisturbed and/or rhizosphere soil.

Observational cross-sectional case study of toxicities of antifungal drugs.

OBJECTIVES: In this study, we examined the toxicities, including poisoning and overdoses, with polyene, azole, flucytosine and echinocandin antifungals reported to the Swiss National Poison Centre. METHODS: An observational cross-sectional study on antifungals was performed based on reports between 1995 and 2016 to Tox Info Suisse. Patient demographic and clinical characteristics were summarised among all reported calls, stratified by age group. In secondary analyses, we evaluated cases with clinical follow-up information. RESULTS: In total, 149 cases were reported to the National Poison Centre during the study period, of which 49 (32.9%) were male and 91 (61.1%) were female, and 95 (63.8%) were adults and 54 (36.2%) were children (age ≤16 years). The most frequently reported drug class was azoles (136; 91.3%). In 31 cases (20.8%) reported by treating physicians, further clinical follow-up information was available. Nearly one-half of these patients were asymptomatic (15/31; 48.4%). In 11 patients (35.5%) among those with symptoms, the symptoms of toxicity were categorised with a strong causality to the respective antifungal. Clinical findings caused by triazoles were effects in the gastrointestinal tract, hallucinations and predelirium state. Clinical findings caused by polyenes were mostly minor symptoms with infusion-related effects or hypokalaemia. The severity was categorised as minor in 6 (54.5%) of 11 cases and as moderate in 5 cases (45.5%). CONCLUSION: Despite high administered doses, no severe or fatal cases occurred within the study period. Although various toxicities can occur with antifungal administration and overdoses, they showed a favourable safety profile.

New nystatin-related antifungal polyene macrolides with altered polyol region generated via biosynthetic engineering of Streptomyces noursei.

Polyene macrolide antibiotics, including nystatin and amphotericin B, possess fungicidal activity and are being used as antifungal agents to treat both superficial and invasive fungal infections. Due to their toxicity, however, their clinical applications are relatively limited, and new-generation polyene macrolides with an improved therapeutic index are highly desirable. We subjected the polyol region of the heptaene nystatin analogue S44HP to biosynthetic engineering designed to remove and introduce hydroxyl groups in the C-9-C-10 region. This modification strategy involved inactivation of the P450 monooxygenase NysL and the dehydratase domain in module 15 (DH15) of the nystatin polyketide synthase. Subsequently, these modifications were combined with replacement of the exocyclic C-16 carboxyl with the methyl group through inactivation of the P450 monooxygenase NysN. Four new polyene macrolides with up to three chemical modifications were generated, produced at relatively high yields (up to 0.51 g/liter), purified, structurally characterized, and subjected to in vitro assays for antifungal and hemolytic activities. Introduction of a C-9 hydroxyl by DH15 inactivation also blocked NysL-catalyzed C-10 hydroxylation, and these modifications caused a drastic decrease in both antifungal and hemolytic activities of the resulting analogues. In contrast, single removal of the C-10 hydroxyl group by NysL inactivation had only a marginal effect on these activities. Results from the extended antifungal assays strongly suggested that the 9-hydroxy-10-deoxy S44HP analogues became fungistatic rather than fungicidal antibiotics.

A model study of fecapentaenes: mutagens of bacterial origin with alkylating properties.

Fecapentaene-14 and -12 are directly acting mutagens that do not require metabolic activation. Their unusual structure suggests a possible mechanism of action. A carbocation that is formed by the addition of an electrophilic species (such as a proton) to the enol ether is most probably the reactive species. A series of model enol ethers with conjugated systems of various lengths was prepared, and a correlation between mutagenicity and increasing reactivity of derived carbocations was found. The glycerol moiety does not play a crucial role in the overall reactivity of the fecapentaenes.

Final report of the cosmetic ingredient review expert panel on the safety assessment of Polyisobutene and Hydrogenated Polyisobutene as used in cosmetics.

Polyisobutene and Hydrogenated Polyisobutene are homopolymers of isobutene. These ingredients are produced in a wide range of molecular weights. Polybutene is a chemically related cosmetic ingredient previously determined to be safe as used in cosmetic products. Polyisobutene is used in cosmetic products as a binder, film former, and nonaqueous viscosity-increasing agent. Hydrogenated Polyisobutene functions as a skin-conditioning agent-emollient and nonaqueous viscosity-increasing agent with a wide range of uses in cosmetic formulations. The estimated octanol water partition coefficient for Hydrogenated Polyisobutene and Polybutene is log K(ow) of 13.27 and the estimated water solubility was 5.6 x 10(-3) ng/L for Hydrogenated Polyisobutene and Polybutene. Acute oral toxicity testing demonstrated no effects other than lethargy in one rat study. The oral LD(50) was > 5.0 g/kg in rats. No short-term or subchronic animal toxicity data were available. A 2-year chronic oral toxicity study of Polybutene revealed no gross or microscopic pathological changes, and no changes in body weights or food consumption, hematological results, urology, or tumor formation that could be correlated with Polybutene ingestion, except that in the 20,000 ppm group, three out of six males that died between weeks 17 and 24 exhibited hematuria. In a 2-year chronic oral toxicity study of Polybutene in Beagle dogs, no abnormalities in body weight, food consumption, survival, behavioral patterns, hematology, blood chemistry, urinalysis, liver function, gross and histopathologic examinations, or organ weights and ratios were reported. In a three-generation reproductive study in Charles River albino rats that ingested Polybutene, none of the animals in successive generations differed from controls with regard to weight gain, litter size, the number of stillborn, and the number of viable pups during lactation. The survival, body weights, and reactions of test animals were comparable to those of controls. Neither Polyisobutene nor Hydrogenated Polyisobutene were ocular irritants, nor were they dermal irritants or sensitizers. Polyisobutene was not comedogenic in a rabbit ear study. Polyisobutene did not induce transformation in the Syrian hamster embryo (SHE) cell transformation assay, but did enhance 3-methylcholanthrene-induced transformation of C3H/10T1/2 cells. In a carcinogenicity study in mice, Polyisobutene was not carcinogenic, nor did it promote the carcinogenicity of 7,12-dimethylbenz(alpha)anthracene. Clinical patch tests uncovered no evidence of dermal irritation and repeat-insult patch tests with a product containing 4% Hydrogenated Polyisobutene or 1.44% Hydrogenated Polyisobutene found no reactions greater than slight erythema. These products also were not phototoxic or photoallergenic. The product containing 4% Hydrogenated Polyisobutene was not an ocular irritant in a clinical test. The Cosmetic Ingredient Review (CIR) Expert Panel recognized that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used and at what concentrations indicate a pattern of use, which was considered by the Expert Panel in assessing safety. Although there is an absence of dermal absorption data for Polyisobutene and Hydrogenated Polyisobutene, the available octanol water partition coefficient data and the low solubility in water suggest very slow absorption, so additional data are not needed. Gastrointestinal absorption is also not a major concern due to the low solubility of these chemicals. Although one in vitro study did report that Polyisobutene did promote cellular transformation, a mouse study did not find evidence of tumor promotion. Because lifetime exposure studies using rats and dogs exposed to Polybutene failed to demonstrate any carcinogenic or tumor promotion effect, and a three-generation reproductive/developmental toxicity study produced no adverse effects, the CIR Expert Panel does not believe these large, mostly insoluble polymers present any risks in the practices of use and concentration as described in this safety assessment.

Modulation of polyene antibiotics self-association by ions from the Hofmeister series.

The toxicity of the antifungal polyene antibiotic amphotericin B (AMB) has been related to its low solubility, more specifically to a self-associated form termed toxic aggregate. In addition, AMB in aqueous medium gives rise to concentration, ionic strength, and time-dependent polydisperse systems. For this reason different approaches, including the use of several lipid aggregates, have been used in attempts to improve the drug's solubility and increase its therapeutic index. In this context, understanding AMB's self-association properties should help in the preparation of less toxic formulations. Ions from the Hofmeister series alter water properties: while kosmotropes (water structure makers-sulfate, citrate, phosphate) decrease solute solubility, chaotropes (water structure breakers-perchlorate, thiocyanate, trichloroacetate, and the neutral molecule urea) have opposite effects. This work reports a study of the effect of Hofmeister ions and urea on the self-aggregation of AMB and some of its derivatives. Optical absorption and circular dichroism spectra were used to monitor monomeric and aggregated antibiotic. While kosmotropes increased aggregation in a concentration-dependent manner, the opposite was observed for chaotropes. It is shown, for the first time, that thiocyanate and trichloroacetate can induce complete AMB monomerization. The understanding of these processes at the physicochemical and molecular levels and the possibility of modulating the aggregation state of AMB and its derivatives should contribute to elucidate the mechanisms of action and toxicity of this widely used antibiotic and to develop more efficient and less toxic preparations.

Pharmacologic control of a humanized gene therapy system implanted into nude mice.

Systemic delivery of specific therapeutic proteins by a parenteral route of administration is a recognized practice in the management of several gene defects and acquired diseases. As an alternative to repetitive parenteral administration, gene therapy may provide a novel means for systemic delivery of therapeutic proteins while improving patient compliance and therapeutic efficacy. However, for gene therapy to be an efficacious and safe approach to the clinical management of such diseases, gene expression must be tightly regulated. These investigations demonstrate precise in vivo control of protein expression from cells that are engineered to secrete human growth hormone (hGH) in response to stimulation by rapamycin. The cells were implanted intramuscularly into nu/nu mice and stimulated by intravenous or oral administration of rapamycin. In vivo experiments demonstrate that the activity and pharmacokinetics of rapamycin determine the level of serum hGH that result from the engineered cells. In addition, responsiveness of the cells to rapamycin, number of cells implanted, hGH expression kinetics, and the pharmacokinetics of hGH itself, also influence the circulating levels of hGH after rapamycin stimulation. Controlled manipulation of several of these parameters, either independently or in combination, allows for precise regulation of circulating hGH concentration in vivo.

Amylosin from Bacillus amyloliquefaciens, a K+ and Na+ channel-forming toxic peptide containing a polyene structure.

Bacillus amyloliquefaciens strains isolated from the indoor environment of moisture-damaged buildings produce a 1197 Da toxin, named amylosin. Nuclear magnetic resonance (NMR) data showed that amylosin contains a chromophoric polyene structure and the amino acids leucine/isoleucine, proline, aspartic acid/asparagine, glutamic acid/glutamine and tyrosine. A quantitation method for amylosin was developed using commercially available amphotericin B as a reference compound and a known concentration of amylosin determined by NMR with the electronic reference to access in vivo concentration (ERETIC) method. Purified amylosin inhibited motility of boar sperm cells at an exposure concentration of 135 nM and hyperpolarized their cell membrane and depolarized their mitochondria at exposure to concentration of 33-67 nM for 10 min. In a 3-d exposure time only 27 nM of amylosin was needed to provoke the same toxicity functions. Amylosin was cytotoxic to feline lung cells at concentrations of <170 nM. Purified amylosin provoked adenosine 5'-triphosphate (ATP)-independent cation influx into isolated rat liver mitochondria (RLM), inducing swelling of the mitochondria at concentrations of 200 nM K(+) or >250 nM Na(+) medium. In the K(+)- or Na(+)-containing medium, amylosin uncoupled RLM, causing oxidation of pyridine nucleotides (PN), loss of the mitochondrial membrane potential, and suppressed ATP synthesis. Purified amylosin produced cation channels in black-lipid membranes (BLMs) with a selectivity K(+)>Na(+) at a concentration of 26 nM, i.e. the same concentration at which amylosin was toxic to boar sperm cells. The amylosin cation channels were cholesterol- and ATP-independent and more effective with K(+) than with Na(+). We propose that the toxicity of amylosin may be due its ionophoric properties, representing the first K(+)/Na(+) channel-forming substance reported from B. amyloliquefaciens.

Selective activity of polyene macrolides produced by genetically modified Streptomyces on Trypanosoma cruzi.

The growth inhibitory effects on Trypanosoma cruzi of several natural tetraene macrolides and their derivatives were studied and compared with that of amphotericin B. All tetraenes strongly inhibited in vitro multiplication. Proliferation of epimastigotes was arrested by all these drugs at < or =3.6 microM, which were also active on amastigotes proliferating in fibroblasts. Compared with amphotericin B, the compounds were less effective but also less toxic, showing no effect on the proliferation of J774 and NCTC 929 mammalian cells at concentrations active against the parasites. CE-108B (a polyene amide) appeared to be an especially potent trypanocidal compound, with strong in vivo trypanocidal activity and very low or no toxic side effects, and thus should be considered for further studies.

Isolation and structure elucidation of cytotoxic polyacetylenes and polyenes from Echinacea pallida.

Bioassay-guided fractionation of n-hexane extracts of Echinacea pallida (Asteraceae) roots led to the isolation and structure elucidation of two polyacetylenes (1, 3) and three polyenes (2, 4, 5). Two are known hydroxylated compounds, namely 8-hydroxy-pentadeca-(9E)-ene-11,13-diyn-2-one (1) and 8-hydroxy-pentadeca-(9E,13Z)-dien-11-yn-2-one (2). Two dicarbonylic constituents, namely pentadeca-(9E)-ene-11,13-diyne-2,8-dione (3) and pentadeca-(9E,13Z)-dien-11-yne-2,8-dione (4), were isolated and characterized for the first time. Furthermore, the structure elucidation of pentadeca-(8Z,13Z)-dien-11-yn-2-one (5) is described. The structure of the compounds isolated was determined on the basis of UV, IR, NMR (including 1D and 2D NMR experiments, such as 1H-1H gCOSY, gHSQC-DEPT, gHMBC, gNOESY) and MS spectroscopic data. The cytotoxic activity of the isolated constituents against MIA PaCa-2 human pancreatic adenocarcinoma cells was evaluated in the concentration range 1-100 microg/ml. Results show that the hydroxylated compounds (1, 2) have low cytotoxicity, while the more hydrophobic polyacetylenes (3) and polyenes (4, 5) displayed moderate activity.

Bcl-2-associated X protein is the main mediator of manumycin a-induced apoptosis in anaplastic thyroid cancer cells.

We previously demonstrated that the combination of paclitaxel and manumycin A, a farnesyltransferase inhibitor, enhanced apoptosis of anaplastic thyroid cancer (ATC) cells. However, the mechanism of the manumycin-induced apoptosis is not fully understood. In this study, we discovered that mitochondrial ultrastructure condensation occurred after treatment with manumycin or manumycin plus paclitaxel. Bongkrekic acid and cyclosporin A, which are known inhibitors of the voltage-dependent anion channel, failed to inhibit cytochrome c release induced by manumycin or manumycin plus paclitaxel, suggesting that mitochondrial permeability transition pores were not involved. We also found that manumycin induced translocation of Bcl-2-associated X protein (Bax), another possible mediator of cytochrome c release, from the cytosol to the mitochondria. Silencing Bax with a specific small interfering RNA blocked manumycin-induced mitochondrial condensation and cytochrome c release, arguing the dependence of manumycin-induced apoptosis on Bax. Using a binary adenoviral vector system, we found that overexpression of Bax enhanced manumycin-induced apoptosis of ATC cells, and the combination of manumycin and overexpression of Bax increased inhibition of ATC xenograft growth in nude mice. Thus, we concluded that manumycin-induced apoptosis in ATC cells was primarily mediated by Bax and that increasing Bax expression may sensitize ATC cells to manumycin.

SPK-843 (Aparts/Kaken).

SPK-843 is a water-soluble antibiotic under co-development by Aparts and Kaken for the potential treatment of systemic fungal infections. By November 2004, SPK-843 was in phase II trials for systemic mycosis.

A non-polyene antifungal antibiotic from Streptomyces albidoflavus PU 23.

In all 312 actinomycete strains were isolated from water and soil samples from different regions. All these isolates were purified and screened for their antifungal activity against pathogenic fungi. Out of these, 22% of the isolates exhibited activity against fungi. One promising strain, Streptomyces albidoflavus PU 23 with strong antifungal activity against pathogenic fungi was selected for further studies. Antibiotic was extracted and purified from the isolate. Aspergillus spp. was most sensitive to the antibiotic followed by other molds and yeasts. The antibiotic was stable at different temperatures and pH tested and there was no significant loss of the antifungal activity after treatment with various detergents and enzymes. Synergistic effect was observed when the antibiotic was used in combination with hamycin. The antibiotic was fairly stable for a period of 12 months at 4 degree C. The mode of action of the antibiotic seems to be by binding to the ergosterol present in the fungal cell membrane resulting in the leakage of intracellular material and eventually death of the cell. The structure of the antibiotic was determined by elemental analysis and by ultraviolet (UV), Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) and liquid chromatography mass spectra (LCMS). The antibiotic was found to be a straight chain polyhydroxy, polyether, non-proteinic compound with a single double bond, indicating a nonpolyene antifungal antibiotic.

Biocompatibility and characterization of polylactic acid/styrene-ethylene-butylene-styrene composites.

Polylactic acid (PLA)/styrene-ethylene-butylene-styrene (SEBS) composites were prepared by melt blending. Differential scanning calorimetry (DSC) and wide angle X-ray diffraction (WXRD) were used to characterize PLA and PLA/SEBS composites in terms of their melting behavior and crystallization. Curves from thermal gravimetric analysis (TGA) illustrated that thermostability increased with SEBS content. Further morphological analysis of PLA/SEBS composites revealed that SEBS molecules were not miscible with PLA molecules in PLA/SEBS composites. The tensile testing for PLA and PLA/SEBS composites showed that the elongation at the break was enhanced, but tensile strength decreased with increasing SEBS content. L929 fibroblast cells were chosen to assess the cytocompatibility; the cell growth of PLA was found to decrease with increasing SEBS content. This study proposes possible reasons for these properties of PLA/SEBS composites.

Rapamycin: a bone sparing immunosuppressant?

Immunosuppressant therpay is associated with osteoporosis both clinically, post-transplantation, and experimentally. In rats, cyclosporin A (CsA) and FK506 induce a state of high turnover rapid bone loss. After 14 days of administration in immunosuppressive doses, the more recently discovered immunosuppressant, rapamycin, resulted in no change of cancellous bone volume. A longer study over 28 days has now been carried out; contrasting the new drug with CsA and FK506. Sixty, 10-week-old Sprague-Dawley rats were randomly divided into five groups of 12 rats each. The first group served as an aging control. The remaining four groups received, by daily gavage, a combined vehicle placebo, CsA 15 mg/kg, FK506 5 mg/kg, and rapamycin 2.5 mg/kg, respectively. CsA- and FK506-treated rats, but not those treated with rapamycin, demonstrated high turnover osteoporosis with raised serum 1,25(OH)2D (p < 0.05) and elevated serum osteocalcin (p < 0.05). The trabecular bone area was decreased by 66% (p < 0.01) in the CsA group and 56% (p < 0.05) in the FK506-treated group compared with the control animals. The CsA- and the rapamycin-treated groups failed to gain weight and developed severe hyperglycemia (> 20 mmol/l, p < 0.001) by day 14 but which largely resolved by day 28. Unlike the groups treated with CsA and FK506, rapamycin-treated rats had no loss of trabecular bone volume but there was increased modeling and remodeling and a decreased longitudinal growth rate. Rapamycin may thus confer a distinct advantage over the established immunosuppressants in not reducing bone volume in the short term.(ABSTRACT TRUNCATED AT 250 WORDS)

Polyene--sterol interaction and selective toxicity.

From permeability experiments carried out with series of amphotericin B derivatives in both biological and model membranes, it was concluded that derivatives, whose carboxyl group at the C18 position is blocked by substitution, are much more efficient at inducing permeability in ergosterol-containing than in cholesterol-containing membranes, whereas derivatives whose carboxyl group is free and ionizable are equally efficient in both membranes types. Binding measurements on erythrocyte membranes showed that all amphotericin B derivatives simply partition between membrane lipids and aqueous medium, according to their lipid solubility. There is no relationship between binding and efficiency in inducing permeability. Permeability studies carried out on lipidic vesicles containing various sterols showed that: 1) derivatives having their carboxyl free induced permeability of the 'channel' type, regardless of the sterol present, and no detectable permeability in sterol-free membranes; 2) derivatives whose carboxyl group is blocked induce channels only in membranes containing ergosterol or sterols having an alkyl side chain identical to that of ergosterol. In the presence of other sterols or in sterol-free membranes, their ionophoric activity is poor and always of the 'mobile-carrier' type. A model of polyene-sterol interaction is proposed, accounting for the data obtained with both biological and model membranes.