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PubMed1995

Induction of aneuploidy in Chinese hamster oocytes following in vivo treatments with trimethoxybenzoic compounds and their analogues.

Many inhibitors of tubulin polymerization have a trimethoxybenzene ring in their molecules. Such trimethoxybenzoic compounds and their analogues may therefore have a potency to induce meiotic nondisjunction of oocytes. In this study, a single dose of reserpine (0.5 microgram/g body weight), podophyllotoxin (20.0 micrograms/g b.w.), trimethoxybenzoic acid (500.0 micrograms/g b.w.) or vinblastine sulfate (3.0 micrograms/g b.w.) was injected intraperitoneally to mature female Chinese hamsters at the onset of the first meiotic spindle formation of oocytes. Within 6 h after spontaneous ovulation, MII oocytes were collected from the oviducts for morphological examination and cytogenetic analysis. The incidence of morphologically abnormal oocytes with unusually large first polar body or bodies increased significantly after the treatment with reserpine (18/202; 8.9%), podophyllotoxin (28/172; 16.3%) and vinblastine sulfate (63/197; 32.0%), as compared with the control (3/214; 1.4%). Chromosome analysis of oocytes revealed that podophyllotoxin and vinblastine sulfate were effective in inducing aneuploidy (62/154; 40.3% and 128/156; 82.1% vs. 3/198; 1.5% of the control) by inhibiting the formation of spindle microtubules at the first meiosis. Aneuploids were found more frequently in morphologically abnormal oocytes than in normal oocytes. No aneugenic activity of reserpine and trimethoxybenzoic acid was observed. These results indicate that trimethoxybenzoic compounds do not necessarily exhibit aneugenic activity.

Aneuploidy↗
PubMed1985

Comparative neurotoxicity of tubulin-binding drugs: inhibition of goldfish optic nerve regeneration.

Intraperitoneal or intraocular (io) injection of tubulin-binding drugs in goldfish, Carassius auratus L., inhibited axonal regeneration or restoration of functional synapses in optic axons following optic nerve crush. One eye was used to detect effects on regeneration and the other was kept intact to detect effects on maintenance of established optic circuits. Regeneration was assessed by measuring the time to reappearance of a visually evoked branchial suppression response. Three drugs, vincristine, vinblastine, and podophyllotoxin, administered semiweekly by ip injection, each inhibited regeneration at doses that did not impair maintenance of response. Similar results were previously reported for ip colchicine. Vincristine was several times more potent than podophyllotoxin or colchicine and 25 times more potent than vinblastine. Picropodophyllotoxin, an isomer of podophyllotoxin which has low affinity for tubulin, did not inhibit regeneration. The io experiments showed that maintenance of vision was reversibly inhibited by a single injection of 0.05 micrograms/g of colchicine but unaffected by 0.01 microgram/g, and that administration of the lower dose immediately following optic nerve crush inhibited regeneration. Intraocular lumicolchicine, a colchicine photoisomer which has low affinity for tubulin, did not inhibit maintenance or regeneration. In contrast, an io dose of vincristine sufficient to inhibit visual recovery also blocked maintenance of vision. Thus regeneration and maintenance effects could not be dissociated for io vincristine suggesting its mechanism of action on retinal cells is different. A conditioning lesion was shown to decrease the time to reappearance of the visually evoked branchial response following optic nerve crush, which indicates that it is a sensitive index of the rate of axonal outgrowth to the optic tectum.

Analysis of Variance↗
PubMed1997

Comparative induction of micronuclei in repair-deficient and -proficient Chinese hamster cell lines following clastogen or aneugen exposures.

The Chinese hamster cell line V79-4 and two ionising radiation-sensitive mutants irs1 and irs3, were used to assess the genotoxic effects of a clastogen (X-rays), an aneugen (podophyllotoxin) and an agent having both activities (etoposide), using the cytokinesis-block micronucleus assay combined with kinetochore labelling. All three agents induced micronuclei in a dose-dependent manner. Between 70 and 90% of the micronuclei induced by X-rays were kinetochore-negative and indicative of clastogenic activity, the relative frequencies of which were increased in the repair-deficient cell lines. In contrast, podophyllotoxin induced mainly kinetochore-positive micronuclei (up to 97%) and could be classified as an inducer of chromosome lagging and was essentially aneugenic in its activity. Micronuclei induced by etoposide were 61-84% kinetochore-negative and 26-39% kinetochore-positive, indicating both clastogenic and aneugenic activity. In the case of both etoposide and podophyllotoxin, there were no observed differences in the induction of micronuclei between the wild-type and repair-deficient cell lines. The data demonstrate the effectiveness of the cytokinesis-block micronucleus/kinetochore assay in determining the mechanisms of action of both chemicals and radiations upon chromosome structure and number and the potential influences of repair upon micronuclei induction.

Aneuploidy↗
PubMed1981

Taxol binds to polymerized tubulin in vitro.

Taxol, a natural plant product that enhances the rate and extent of microtubule assembly in vitro and stabilizes microtubules in vitro and in cells, was labeled with tritium by catalytic exchange with (3)H(2)O. The binding of [(3)H]taxol to microtubule protein was studied by a sedimentation assay. Microtubules assembled in the presence of [(3)H]taxol bind drug specifically with an apparent binding constant, K(app), of 8.7 x 19(-7) M and binding saturates with a calculated maximal binding ration, B(max), of 0.6 mol taxol bound/mol tubulin dimer. [(3)H]Taxol also binds and assembles phosphocellulose-purified tubulin, and we suggest that taxol stabilizes interactions between dimers that lead to microtubule polymer formation. With both microtubule protein and phosphocellulose- purified tubulin, binding saturation occurs at approximate stoichiometry with the tubulin dimmer concentration. Under assembly conditions, podophyllotoxin and vinblastine inhibit the binding of [(3)H]taxol to microtubule protein in a complex manner which we believe reflects a competition between these drugs, not for a single binding site, but for different forms (dimer and polymer) of tubulin. Steady-state microtubules assembled with GTP or with 5'-guanylyl-alpha,beta-methylene diphosphonate (GPCPP), a GTP analog reported to inhibit microtubule treadmilling (I.V. Sandoval and K. Weber. 1980. J. Biol. Chem. 255:6966-6974), bind [(3)H]taxol with approximately the same stoichiometry as microtubules assembled in the presence of [(3)H]taxol. Such data indicate that a taxol binding site exists on the intact microtubule. Unlabeled taxol competitively displaces [(3)H]taxol from microtubules, while podophyllotoxin, vinblastine, and CaCl(2) do not. Podophyllotoxin and vinblastine, however, reduce the mass of sedimented taxol-stabilized microtubules, but the specific activity of bound [(3)H]taxol in the pellet remains constant. We conclude that taxol binds specifically and reversibly to a polymerized form of tubulin with a stoichiometry approaching unity.

Actins↗
PubMed1975

A correlation between the effects of anti-mitotic drugs on microtubule assembly in vitro and the inhibition of axonal transport in noradrenergic neurones.

1. Podophyllotoxin, colchicine and griseofulvin inhibit the intra-axonal movement of noradrenaline storage vesicles in cat hypogastric nerve/inferior mesenteric ganglion preparations maintained in vitro, cause the disappearance of axonal microtubules and inhibit the assembly of microtubules from tubulin in vitro. The order of potency of the three effects is podophyllotoxin greater than colchicine greater than griseofulvin. 2. Lumicolchicine is without effect on the three parameters and does not interfere with the binding of tritiated colchicine to tubulin. 3. Podophyllotoxin causes a more rapid loss of microtubules from axons than the same concentration of colchicine. 4. The experiments provide strong evidence that microtubules are components of the system responsible for the intra-axonal migration of noradrenaline storage vesicles.

Animals↗
PubMed1974

Microtubule assembly and function in Chlamydomonas: inhibition of growth and flagellar regeneration by antitubulins and other drugs and isolation of resistant mutants.

The distribution of microtubules in Chlamydomonas reinhardtii suggests that they are involved in mitosis, cell and nuclear cleavage, and generation of flagella. Vinblastine, colchicine, and podophyllotoxin bind to the protein building block of microtubules (tubulin) and prevent normal assembly. Mutants resistant to these "antitubulin" drugs are candidates to have alterations in tubulin primary structure. We report the ability to inhibit growth, and flagellar regeneration after amputation, of: vinblastine, several colchicine derivatives, two water-soluble derivatives of podophyllotoxin (succinylpodophyllotoxin and epipodophyllotoxin thiuronium bromide), and other substances which may interfere with flagellar assembly or motility (isopropyl N-phenyl carbamate, 2-methoxy-5-nitrotropone, chloral hydrate, caffeine, and nickel acetate). The ability of each drug to inhibit binding of labeled colchicine or podophyllotoxin to mammalian brain tubulin was also determined. The results suggest that only in the cases of colchicine, colcemide, and epipodophyllotoxin thiruonium bromide was the toxicity to Chlamydomonas mediated by inhibition of tubulin assembly. The requirement for high concentrations of colchicine may be due to permeability barriers, since colchicine toxicity was potentiated by deoxycholate. Mutants resistant to antitubulins were isolated after treatment with methyl methanesulfonate. The results with vinblastine were equivocal. Of three mutants resistant to inhibition of growth and flagellar regeneration by colchicine, one was also cross-resistant to epipodophyllotoxin thiuronium bromide.

Alkanesulfonates↗
PubMed1985

[Kinetics of etoposide cytotoxicity against mouse P388 leukemia].

The in vitro cytotoxicity of etoposide against mouse P388 leukemia cells was kinetically studied and compared with those of podophyllotoxin, the parent compound, and other antitumor agents. When P388 cells were exposed to etoposide, surviving-cell fraction decreased with etoposide concentration and exposure time. Similar results were obtained with doxorubicin, peplomycin and cisplatin. The cytotoxicity of melphalan was dependent on concentration but scarcely on exposure time. From these data, n in Cn X T = K where T, C and K are exposure time, concentration required for killing 90% of P388 cells and a constant, respectively, was calculated. Etoposide gave an n value of 1.16. n values for doxorubicin, peplomycin and cisplatin, all belonging to the Shimoyama type Ib group where the cytotoxicity of the agent depends on both concentration and exposure time, were 1.29, 1.28 and 3.03, respectively. The n value for melphalan, belonging to the type Ia group where cytotoxicity depends only on concentration, was 54.0. From these results, it was concluded that etoposide is of type Ib. The cytotoxicities of podophyllotoxin, 5-fluorouracil, cytarabine and vinblastine were greatly dependent on exposure time. Podophyllotoxin may be an agent of type II whose cytotoxicity depends only on exposure time.

Animals↗
PubMed1985

The effects of colchicine analogues on the reaction of tubulin with iodo[14C]acetamide and N,N'-ethylenebis(iodoacetamide).

We have previously found (Ludueña, R. F., and Roach, M. C. (1981b) Biochemistry 20, 4444-4450) that colchicine and podophyllotoxin inhibit the alkylation of tubulin by iodo[14C]acetamide and the formation of an intrachain cross-link in the beta-tubulin subunit by N,N'-ethylenebis(iodoacetamide) (EBI). It was not clear whether these effects were due to conformational changes in tubulin induced by drugs or to direct steric blockage of the sulfhydryl groups involved. In an effort to characterize further these phenomena, we have examined the effects of single-ring and bicyclic analogues of colchicine on the reaction of tubulin with iodo[14C]acetamide and EBI. We have found that neither the A-ring analogues, 3,4,5-trimethoxybenzyl alcohol, 3,4,5-trimethoxybenzaldehyde, 2,3,4-trimethoxybenzaldehyde, and benzaldehyde, nor the C-ring analogues, tropolone and tropolone methyl ether, inhibited alkylation. In contrast, colchicine, podophyllotoxin, and nocodazole and the bicyclic analogues, 5-(2',3',4'-trimethoxyphenyl)-2-methoxytropone and combretastatin, inhibited tubulin alkylation. Since the presence of a bond joining the A and C rings seems to be the determining factor in the suppression of alkylation, it is likely that inhibition by colchicine of the reaction with iodo[14C] acetamide is due largely to a conformational change induced by colchicine. A different pattern was obtained when the effects on cross-link formation by EBI were examined. Here, all the A-ring analogues, the bicyclic analogues, and colchicine, podophyllotoxin, and nocodazole all inhibited formation of the cross-link, whereas the C-ring analogue tropolone methyl ether did not inhibit cross-link formation. Since compounds whose effect on alkylation is markedly different have the same effect on cross-link formation, it is possible that this effect is a steric one and that perhaps the A-ring of colchicine binds to tubulin very close to one of the sulfhydryls involved in the intrachain cross-link formed by EBI in beta-tubulin.

Alkylation↗
PubMed1981

Effects of inhibitors of tubulin polymerization on GTP hydrolysis.

The effects of a number of antimitotic drugs on the GTPase activity of tubulin were examined. The previously reported stimulation with colchicine and inhibition with podophyllotoxin and vinblastine wee confirmed. Maytansine, which competes with vinblastine in binding to tubulin, was comparable to the latter in inhibiting GTP hydrolysis. Nocodazole, which competes with colchicine in binding to tubulin, was significantly superior to colchicine in enhancing GTP hydrolysis. This superiority arose from the more rapid bindng of nocodazole to tubulin, as the two drugs had comparable activity when drug and tubulin were preincubated prior to the addition of GTP. Both colchicine and podophyllotoxin contain a trimethoxybenzene ring, while the closest structural analogy of nocodazole to colchicine includes the trimethoxybenzene ring. To explore this apparent paradox, we examined a number of simpler colchicine analogs for their effects on tubulin-dependent GTP hydrolysis. While tropolone was without effect, 3,4,5-trimethoxybenzaldehyde and 2,3,4-trimethoxybenzaldehyde stimulated the reaction. We therefore conclude that the trimethoxybenzene ring of colchicine is primarily responsible for the drug's stimulation of the GTPase activity of tubulin and that the inhibitory effect of podophyllotoxin must derive from the latter's tetrahydronaphthol moiety.

Animals↗
PubMed1981

Taxol-induced polymerization of purified tubulin. Mechanism of action.

Incubation of tubulin with taxol resulted in the assembly of tubulin in the absence of microtubule associated proteins. Optimum assembly occurred at approximately equal concentrations of tubulin and taxol. Both podophyllotoxin and colchicine inhibited the taxol-induced tubulin polymerization. Microtubules formed with taxol were also resistant to podophyllotoxin-induced depolymerization. The rate of tubulin subunit exchange into taxol-induced microtubules at steady state was 5-fold lower than into microtubule-associated protein (MAP2)-stimulated microtubules. There was a marked difference in the kinetics of tubulin polymerized in the presence of both taxol and MAP2 as compared to that obtained with either of them alone. In binding experiments, no competition was observed between taxol and MAP2 or the anti-tubulin drugs, e.g. colchicine, podophyllotoxin, and vinblastine.

Alkaloids↗
PubMed1983

Comparative cytotoxic and cytokinetic effects of the epipodophyllotoxins 4'-demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-beta-D-glucopyranoside) and 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-beta-D-glucopyranoside) and their metabolites on human leukemic lymphoblasts.

We compared the effects of the epipodophyllotoxins 4'-demethylepipodophyllotoxin-9-(4,6-O-2-ethylidene-beta-D-glucopyranoside) (VP-16-213) and 4'-demethylepipodophyllotoxin-9-(4,6-O-2-thenylidene-beta-D-glucopyranoside) (VM-26) and several of their derivatives on cell cycle progression and viability of human leukemic lymphoblasts (CCRF-CEM). The cis-(picro)-lactone derivatives, like both VP-16-213 and VM-26, produced G2-phase arrest and cytotoxicity, but only at concentrations 100 times greater than required with the parent compounds. The epiaglycone derivative showed potent cytotoxicity: at 100 to 250 nM, it reduced cloning efficiency by 50%, an effect requiring 25 to 40 nM VM-26 and 340 to 425 nM VP-16-213. In contrast to VM-26 and VP-16-213, the epiaglycone arrested cells in M, consistent with evidence that it, like podophyllotoxin, is an inhibitor of microtubule assembly. At concentrations resulting in 50% cell kill and an increase of cells in M, however, the epiaglycone produced little change in the proportion of cells in G1 or early S phase, while podophyllotoxin produced a shift of cells to mid- and late S. The hydroxy acid derivatives, although found in detectable quantities in patients' urine and serum, were inactive in vitro. Structural differences among the compounds account for their different biochemical and cell kinetic effects and, hence, different cytotoxic activities. Because the epiaglycone is a potent compound and combines activities of both the podophyllotoxins and 4'-demethyl derivatives, further studies of its cytotoxicity are indicated.

Cell Cycle↗
PubMed1978

Evidence for involvement of microtubules in the action of vasopressin in toad urinary bladder. II. Colchicine binding properties of toad bladder epithelial cell tubulin.

Colchicine, podophyllotoxin and vinblastine have been found to inhibit the action of vasopressin on water movement in the toad urinary bladder. Tubulin is the major colchicine binding component of toad bladder epithelial cells, accounting for approximately 3.3% of the total cell protein. More than 99% of the tubulin is found in the soluble fraction after sonication, the remainder is in the particulate fraction. Similar to the characteristics of the binding of colchicine to tubulins from other sources, the binding of colchicine to toad bladder tubulin is temperature- and time-dependent, is inhibited competitively by podophyllotoxin (Ki= 5.5 x 10(-7)m), and has a binding constant of 1 X 10(6) liters/mole at 37 degrees. Binding activity decays according to first-order kinetics and is stabilized by vinblastine. The characteristics of the interactions of colchicine and podophyllotoxin with epithelial cell tubulin in vitro closely parallel the ability of these drugs to inhibit the response to vasopressin in vivo. These results, coupled with those of functional and morphological studies, support the view that the ability of these drugs to affect vasopressin-induced water movement across toad bladder epithelial cells is related to the depolymerization of cytoplasmic microtubules.

Animals↗
PubMed1990

The effect of antimitotic agents on the intraneuronal distribution of lysosomes.

We previously showed that a single injection of colchicine into the lateral cerebral ventricle of the rat causes a redistribution of lysosomes from their normal localization in neuronal cell bodies into dendrites. In the present report we have examined the time course and specificity of this effect using a variety of microtubule poisons. Dipeptidylaminopeptidase II (Dpp II), a lysosomal marker enzyme, histochemistry was used to visualize lysosomes at the light microscopic level. Acid phosphatase, another lysosomal enzyme, histochemistry was used to confirm the Dpp II localization of lysosomes. Two h after an intracerebroventricular (i.c.v.) injection of colchicine, the distribution of neuronal lysosomes was drastically altered. Lysosomes in a number of neuronal populations were observed to move from the soma to the dendrites. This effect was maximal between 12 and 24 h and was partially reversed by 96 h. Injections of colcemid or podophyllotoxin, drugs that bind to tubulin rapidly, and much less tightly than colchicine, produced a much less pronounced alteration in the intraneuronal distribution of lysosomes. Injections of vinblastine or vincristine, whose binding kinetics range between that of colchicine and that of colcemid and podophyllotoxin, resulted in a redistribution of lysosomes which was less pronounced than the effects of colchicine but more pronounced than that caused by colcemid and podophyllotoxin. Likewise, treatment with other related compounds, 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone (A-C compound) and lumicolchicine, whose binding to tubulin is extremely rapid and reversible or non-existent, produced little or no alteration in the intraneuronal distribution of lysosomes. The results suggest that lysosome redistribution may be dependent upon a relatively slow dissociation rate constant of these drugs from tubulin, and this transport may occur when normal microtubule function is compromised.

Acid Phosphatase↗
PubMed2003

Cytotoxic and cytostatic activity of erlangerins from Commiphora erlangeriana.

The resin of Commiphora erlangeriana is known to be poisonous to humans and animals and has traditionally been used as an arrow poison. Since recent phytochemical studies on this plant material has identified four major lignans (named, Erlangerins A to D) that closely relate to the structure of podophyllotoxin, it was hypothesised that the well known poisoning effect of the resin could in part be due to direct toxicity to mammalian cells. Hence, the toxicity of Erlangerins was studied by measuring the viability of two human (HeLa and EAhy926) and two murine (L929 and RAW 264.7) cell lines. As assessed by the MTT assay, the effect of Erlangerin C and D closely follow the activity profile of podophyllotoxin: they induced a concentration-dependent cytotoxicity in the murine macrophage cells (RAW 264.7) and a cytostatic effect in HeLa, EAhy926 and L929 cells. In contrast, Erlangerins A and B suppressed cell viability at relatively higher concentrations (EC(50) values higher than 3 micro M as compared with nM concentration range for Erlangerins C and D and podophyllotoxin) and their activity appears to be consistent with a cytotoxic mode of action in all cell lines studied. The structure-activity-relationship established from the study is discussed.

Animals↗
PubMed1992

Mechanism of binding of the new antimitotic drug MDL 27048 to the colchicine site of tubulin: equilibrium studies.

MDL 27048 [trans-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2- methyl-2-propen-1-one] fluoresces when bound to tubulin but not in solution. This effect has been investigated and found to be mimicked by viscous solvents. Therefore, MDL 27048 appears to be a fluorescent compound whose intramolecular rotational relaxation varies as a function of microenvironment viscosity. The binding parameters of MDL 27048 to tubulin have been firmly established by fluorescence of the ligand, quenching of the protein fluorescence, and gel equilibrium chromatography. The apparent binding equilibrium constant was (2.75 +/- 0.45) x 10(6)M-1, and the binding site number was 0.81 +/- 0.12 (10 mM sodium phosphate-0.1 mM GTP, pH 7.0, at 25 degrees C). The binding is exothermic. The binding of MDL 27048 overlaps the colchicine and podophyllotoxin binding sites. Binding of MDL 27048 to the colchicine site was also measured by competition with MTC [2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one] , a well-characterized reversibly binding probe of the colchicine site [Andreu et al. (1984) Biochemistry 23, 1742-1752; Bane et al., (1984) J. Biol. Chem. 259, 7391-7398]. In contrast with close analogues of colchicine, MDL 27048 and podophyllotoxin neither affected the far-ultraviolet circular dichroism spectrum of tubulin, within experimental error, nor induced tubulin GTPase activity. Like podophyllotoxin, an excess of MDL 27048 over tubulin induced no abnormal cooperative polymerization of tubulin, which is characteristic of colchicine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Effect of colchicine binding on the reversible dissociation of the tubulin dimer.

The reversible subunit-dissociation equilibria of the tubulin alpha beta dimer and of the colchicine-tubulin dimer complex have been examined by equilibrium ultracentrifugation at 4.6 degrees C. The dissociation constants (KD) of tubulin from bovine brain and from flagellar outer-doublet microtubules of the sea urchin Strongylocentrotus purpuratus were 7.4 x 10(-7) M and 15.2 x 10(-7) M, respectively. In contrast, both brain and outer-doublet colchicine-tubulin complexes dissociated less readily into their alpha- and beta-tubulin monomers; KD = 2.7 x 10(-7) M for the brain complex and KD = 5.0 x 10(-7) M for the outer-doublet colchicine-tubulin species. Podophyllotoxin (2 x 10(-4) M), tropolone (10(-4) M), or both podophyllotoxin and tropolone (2 x 10(-4) and 5 x 10(-4) M, respectively) had no effect on the dissociation constant of brain tubulin. Under these experimental conditions, the initial colchicine-binding capacities of brain and flagellar tubulins were 0.87 +/- 0.05 and 0.70 +/- 0.07 mol/mol, respectively. The colchicine-binding activities of free tubulins decayed at 4 degrees C according to first-order kinetics with half-times of 37 h for brain tubulin and 26 h for flagellar tubulin. However, colchicine-tubulin complexes (brain or flagellar) showed no decay of binding activity when stored at 4 degrees C for periods up to 4 days. These results strongly support the following conclusions: (1) colchicine binding induces or stabilizes a conformational isomer of tubulin that dissociates into its alpha and beta monomers less readily than free tubulin; (2) the conformational change in tubulin is specific for binding of the intact colchicine molecule and does not occur when ligands specific for the trimethoxyphenyl subdomain (i.e., podophyllotoxin) or tropolone subdomain of the colchicine-binding site bind singly or simultaneously to tubulin; and (3) bound colchicine stabilizes tubulin against loss of colchicine-binding activity at 4 degrees C. This altered conformation of tubulin may be involved in the substoichiometric poisoning of microtubule assembly produced by the addition of colchicine-tubulin complexes to the ends of microtubules.

Animals↗
PubMed1982

Treatment of podophyllin poisoning with resin hemoperfusion.

1 A 43-year-old man was admitted in a coma after oral ingestion of a suspected lethal dose of podophyllin solution in alcohol. 2 Hemoperfusion with a resin filter was started 7 h after ingestion. Hemoperfusion rapidly decreased plasma concentrations of podophyllotoxin with an extraction ratio of 0.76 over the filter. The relatively low plasma concentrations of podophyllotoxin and consequently small amount removed might be explained by the rapid metabolism of the drug to an unknown derivate. 3 This metabolite was completely cleared during passage over the filter, suggesting the removal of significant amounts of podophyllotoxin metabolites. 4 No neurological deficit was observed before or after hemoperfusion. At a two-month follow-up the patient remained healthy. Hemoperfusion may possibly prevent the development of coma and neurologic deficit with loss of deep tendon reflexes.

Adult↗
PubMedDate not supplied

Patients with genital warts: how are they managed by general practitioners?

This study was carried out to assess the management by general practitioners of patients with genital warts. An anonymized postal questionnaire was sent to 2060 general practitioners in the north west of England; 1260 (61.2%) completed questionnaires were returned. A total of 76.69% of GPs saw one or more cases per quarter. Of 468 (37.1%) GPs who managed patients in-house, 393 (83.9%) used podophyllin of concentration between 0.5 and 50%; 169 (43%) did not specify the podophyllin concentration and 112(23.9%) used podophyllotoxin. Of 395 GPs (31.3%) prescribing patient self-treatment, 259 (65.6%) prescribed podophyllin, but 60.23% did not specify the concentration; 134(33.9%) prescribed podophyllotoxin. Screening for selected sexually transmitted infections (STIs) was performed by 258/618 (41.7%) GPs. Only 74 (11.97%) screened for Chlamydia trachomatis and Neisseria gonorrhoeae and Trichomonas vaginalis. Partner notification was advised by 1138 (90.3%) and condom use by 1027 (81.5%). Only 333 (26.4%) referred all patients to GUM departments. Many GPs manage patients in-house, most using podophyllin solutions which vary in concentration, are non-standardized and potentially hazardous. Most GPs who instigate patient self-treatment prescribe podophyllin which is not licensed for this usage. Podophyllotoxin 0.5% is a safe, effective alternative. Few non-referring GPs screened for the 3 common STIs, thus putting patients at risk of complications such as pelvic inflammatory disease. Non-referral of patients with genital warts to GUM departments may have costly medical and financial consequences.

Condylomata Acuminata↗