Biomedical subjects

J Wiegand

Publications and source records attributed to J Wiegand.

At least 19 recordsLinked to original sources

PubMed2001

Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives.

A new means of accessing N(1)-cyclopropylmethyl-N(11)-ethylnorspermine (CPMENSPM) and the first synthesis of (2R,10S)-N(1)-cyclopropylmethyl-2,10-dihydroxy-N(11)-ethylnorspermine [(2R,10S)-(HO)(2)CPMENSPM] are described. Both of these polyamine analogues are shown to be more active against L1210 murine leukemia cell growth than either N(1),N(11)-diethylnorspermine (DENSPM) or (2R,10R)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2R,10R)-(HO)(2)DENSPM] after 96 h of treatment; the activity was comparable to that of (2S,10S)-N(1),N(11)-diethyl-2,10-dihydroxynorspermine [(2S,10S)-(HO)(2)DENSPM] at 96 h. Both cyclopropyl compounds reduced putrescine and spermidine pools, but less effectively than did DENSPM and its derivatives. Only CPMENSPM, and not (2R,10S)-(HO)(2)CPMENSPM, lowered spermine pools. As with DENSPM and (2R,10R)-(HO)(2)DENSPM, both cyclopropyl analogues diminished ornithine decarboxylase and S-adenosylmethionine decarboxylase activity. Unlike the hydroxylated DENSPM compounds, both cyclopropyl norspermines substantially upregulated spermidine/spermine N(1)-acetyltransferase. The most interesting effect of hydroxylating CPMENSPM is the profound reduction in toxicity compared with that of the parent drug. The same phenomenon had been observed for the DENSPM/(2R,10R)-(HO)(2)DENSPM pair. Thus, hydroxylation of norspermine analogues appears to be a way to maintain the compounds' antiproliferative activity while reducing their toxicity.

Acetyltransferases↗

PubMed2001

Significance of asymmetric sites in choosing siderophores as deferration agents.

The syntheses of the microbial iron chelators L-fluviabactin, its unnatural enantiomer, D-fluviabactin, L-homofluviabactin, and L-agrobactin, are described. The key steps involve the selective bis-acylation of the terminal nitrogens of norspermidine, spermidine, or homospermidine with 2,3-bis(benzyloxy)benzoic acid in the presence of 1,1-carbonyldiimidazole, followed by coupling of the N-hydroxysuccinimide ester of CBZ-protected L- or D-threonine with the central nitrogen. The effectiveness of each of these ligands in supporting the growth of Paracoccus denitrificans in a low-iron environment and the ability of these compounds to promote iron uptake are evaluated. The stereochemical configuration of the oxazoline ring is shown to be the major structural factor controlling both microbial growth stimulation and iron uptake. L-Fluviabactin, L-homofluviabactin, and L-agrobactin all promoted growth and iron uptake; D-fluviabactin was only marginally active. As with the microorganism's native siderophore, L-parabactin, all three ligands in the L-configuration investigated exhibited biphasic, i.e., both high-affinity and low-affinity, kinetics. The high-affinity system (iron concentration < 1 microM) yielded K(m) values between 0.11 and 0.23 microM and V(max) values from 157 to 129 pg-atoms Fe min(-1) (mg of protein)(-1), whereas the low-affinity scheme (iron concentration > 1 microM) gave K(m) values from 0.53 to 3.5 microM and V(max) values between 96 and 413 pg-atoms Fe min(-1) (mg of protein)(-1). Both L- and D-fluviabactin are very effective at clearing iron from the bile duct-cannulated rodent; when given subcutaneously at a dose of 150 micromol/kg, both ligands had iron clearing efficiencies of >13%, which is much greater than that of desferrioxamine in this model. Thus, by altering the stereochemistry of certain microbial siderophores, it is possible to generate deferration agents that are still effective at clearing iron from animals, yet do not promote microbial growth.

Animals↗

PubMed2001

Polyamine analogue antidiarrheals: a structure-activity study.

The syntheses of a group of spermine polyamine analogues and their evaluation as antidiarrheals are described. Each compound was assessed in a rodent castor oil-induced diarrhea model for its ability to reduce stool output and weight loss in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct antidiarrheals. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. The toxicity profile is also quite dependent on these same structural features. On the basis of subcutaneous dose-response data and toxicity profiles, two compounds, N(1),N(12)-diisopropylspermine and N(1),N(12)-diethylspermine, were taken forward into more complete evaluation. These measurements included formal acute and chronic toxicity trials, drug and metabolic tissue distribution studies, and assessment of the impact of these analogues on tissue polyamine pools. Finally, the remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to further explore this framework as a pharmacophore for the construction of other antidiarrheal agents.

Administration, Oral↗

PubMed2001

Control of irritable bowel syndrome with polyamine analogs: a structure-activity study.

The evaluation of a group of polyamine analogs as agents to ameliorate diarrhea-predominant irritable bowel syndrome is described. Each compound was assessed when administered subcutaneously in a psychological stress-induced model of irritable bowel syndrome in rodents for its ability to reduce stool output in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct compounds to treat irritable bowel syndrome. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. In addition to the subcutaneous studies, several compounds, N1,N11-diethylnorspermine, N1,N12-diethylspermine, N1,N12-diisopropylspermine, N1,N14-diethylhomospermine, N,N'-bis[5-(ethylamino)pentyl]-1,4-butanediamine, N,N'-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane, and N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine, were subsequently evaluated for oral efficacy. The remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to explore this framework further as a pharmacophore for the construction of other analogues to relieve the symptoms of diarrhea-predominant IBS.

Animals↗

PubMed2000

Metabolism and pharmacokinetics of N1,N11-diethylnorspermine in a Cebus apella primate model.

The tissue distribution, metabolic profile, and pharmacokinetic parameters of i.v.-administered N1,N11-diethylnorspermine (DENSPM) are evaluated in Cebus apella primates, and the results are compared with data gathered from canine and human studies. Although the metabolic processing of DENSPM (i.e., deethylation and deaminopropylation) in dogs and primates is very similar, there are some significant differences in tissue distribution of the parent drug. In dogs, the organ concentration of DENSPM follows the order kidney >> liver approximately = lung > spleen. In the primate, the order is liver >> kidney approximately = spleen > lung. The difference in pharmacokinetic parameters between the species is profound with (area under the time-concentration curve)primate << (area under the time-concentration curve)dog; (terminal elimination half-life)primate << (terminal elimination half-life)dog; and (mean residence time)primate << (mean residence time)dog. The most notable difference between dogs and primates is seen in the fraction of parent drug excreted unchanged in the urine, 50% in the dog and < 1% in the primate. However, the pharmacokinetic parameters and urinary drug clearance in C. apella primates are remarkably similar to those in humans. Thus, C. apella is established as an excellent model for assessing the metabolism, tissue distribution, and pharmacokinetic properties of polyamine analogues.

Animals↗

PubMed2000

Radon and thoron in cave dwellings (Yan'an, China).

222Rn and 220Rn concentrations were measured in cave dwellings and brick houses in the region of Yan'an (China) during summer 1997. The underground dwellings are built into Quaternary loess, and all investigated houses are founded on it. The median values of indoor 222Rn and 220Rn concentrations are 42 (n = 18) and 77 Bq m(-3) (n = 15) for brick houses and 92 (n = 23) and 215 (n = 17) Bq m(-3) for cave dwellings. To classify the dwellings in respect to their "cave-character," the fraction of walls having a direct contact to the loses is calculated for each dwelling. While the 222Rn concentrations are increasing with higher fractions, the 220Rn concentrations are not correlated with this fraction. On the other hand, due to the short half-life of 220Rn the distance from the measuring point to the walls is negatively correlated with the 220Rn concentration, while there is no correlation with the 222Rn concentration. Therefore, concentric isolines of 220Rn concentrations showing a strong gradient were detected in cave dwellings. An influence of the ventilation rate is distinct for 222Rn but weak for 220Rn. The effective dose rates for 222Rn and 220Rn and their progenies are calculated for brick houses (2.7 mSv y(-1)), cave dwellings (7.1 mSv y(-1)), and for traditional cave dwellings with a bed foundation built with loess (16.7 mSv y(-1)). These calculations are based on summer measurements only. It is expected that the true effective dose rates will be significantly higher.

China↗

PubMed1999

Evaluation of the desferrithiocin pharmacophore as a vector for hydroxamates.

A series of (S)-desmethyldesferrithiocin (DMDFT, 1) hydroxamates and a bis-salicyl polyether hydroxamate are evaluated for their iron-clearing properties in rodents; some of these are further assessed in primates. These hydroxamates include (S)-desmethyldesferrithiocin, N-methylhydroxamate (2); (S)-desmethyldesferrithiocin, N-[5-(acetylhydroxyamino)pentyl]hydroxamate (3); desmethyldesferrithiocin, N-benzylhydroxamate (4); (S,S)-N(1), N(8)-bis[4,5-dihydro-2-(3-hydroxy-2-pyridinyl)-4-thiazoyl]-N(1), N(8)-dihydroxy-3,6-dioxa-1,8-octanediamine (5); and N(1), N(8)-bis(2-hydroxybenzoyl)-N(1),N(8)-dihydroxy-3,6-dioxa-1, 8-octanediamine (6). The ligands are evaluated when given both orally (po) and subcutaneously (sc) in the bile-duct-cannulated rodent model. In iron-overloaded primates, ligands 1-4 are assessed when administered po and sc. The efficiencies of the hydroxamates are shown to vary considerably; giving the compounds sc consistently resulted in greater chelating efficiency in vivo. After oral administration in the primate, compound 3, a pentacoordinate unsymmetrical dihydroxamate, produces iron excretion sufficient to warrant further preclinical evaluation both as a potential orally active iron-chelating agent and as a parenteral iron chelator. The increased iron clearance of several of these ligands when administered sc versus po also underscores the idea that parenteral administration is a reasonable alternative to a less efficient, orally active device which would require large and frequent doses.

Administration, Oral↗

PubMed1999

Effects of C-4 stereochemistry and C-4' hydroxylation on the iron clearing efficiency and toxicity of desferrithiocin analogues.

Additional structure-activity studies of desferrithiocin analogues are carried out. The effects of stereochemistry at C-4 on the ligands' iron clearing efficiency are reviewed and assessed using the enantiomers 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(R)-carboxylic acid and 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid. The utility of 4'-hydroxylation as a method of reducing the toxicity of desazadesferrithiocin analogues is also examined further with the synthesis and in vivo comparison of 4, 5-dihydro-2-(2-hydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid, which is the natural product 4-methylaeruginoic acid, and 4, 5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid. The stereochemistry at C-4 is shown to have a substantial effect on the iron clearing efficiency of desferrithiocin analogues, as does C-4'-hydroxylation on the toxicity profile. All of the compounds are evaluated in a bile-duct-cannulated rodent model to determine iron clearance efficiency and are carried forward to the iron-overloaded primate for iron clearing measurements. On the basis of the results of the present work, although 4,5-dihydro-2-(2, 4-dihydroxyphenyl)thiazole-4(S)-carboxylic acid is still the most promising candidate for clinical evaluation, 4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid (4'-hydroxydesazadesferrithiocin) also merits further preclinical assessment.

Animals↗

PubMed1999

Desazadesmethyldesferrithiocin analogues as orally effective iron chelators.

Further structure-activity studies of desferrithiocin analogues are carried out. (S)-Desazadesmethyldesferrithiocin, 2-(2-hydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid, serves as the principal framework in the current paper. Desazadesmethyldesferrithiocin can be structurally altered with facility, and data are already available on its iron-clearing properties and toxicity parameters. Four different kinds of structural modifications of this framework are undertaken: introduction of hydroxy, carboxy, or methoxy groups on the aromatic ring; alteration of the thiazoline ring; increasing the distance between the ligand donor atoms; and benz-fusion of the aromatic rings. The structural modifications described are shown to have a tremendous impact on both the iron clearance and toxicity profiles of the desazadesmethyldesferrithiocin molecule. All of the compounds are assessed in a bile-duct-cannulated rodent model to determine iron clearance efficiency. Ligands which demonstrate an efficiency of greater than 2% are carried forward to the iron-overloaded primate for iron-clearing measurements. Ligands with efficiencies greater than 3% in the primate are then evaluated in a formal toxicity study in rodents. On the basis of the results of the present work, 2-(2, 4-dihydroxyphenyl)-Delta2-thiazoline-4(S)-carboxylic acid is a promising candidate for clinical evaluation.

Administration, Oral↗

PubMed1999

HBED: the continuing development of a potential alternative to deferoxamine for iron-chelating therapy.

To further examine the potential clinical usefulness of the hexadentate phenolic aminocarboxylate iron chelator N, N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) for the chronic treatment of transfusional iron overload, we performed a subchronic toxicity study of the HBED monosodium salt in rodents and have evaluated the iron excretion in primates induced by HBED. The HBED-induced iron excretion was determined for the monohydrochloride dihydrate that was first dissolved in a 0.1-mmol/L sodium phosphate buffer at pH 7.6 and administered to the primates either orally (PO) at a dose of 324 micromol/kg (149.3 mg/kg, n = 5), subcutaneously (sc) at a dose of 81 micromol/kg (37.3 mg/kg, n = 5), sc at 324 micromol/kg (n = 5), and sc at 162 micromol/kg (74.7 mg/kg) for 2 consecutive days for a total dose of 324 micromol/kg (n = 3). In addition, the monosodium salt of HBED in saline was administered to the monkeys sc at a single dose of 150 micromol/kg (64.9 mg/kg, n = 5) or at a dose of 75 micromol/kg every other day for three doses, for a total dose of 225 micromol/kg (n = 4). For comparative purposes, we have also administered deferoxamine (DFO) PO and sc in aqueous solution at a dose of 300 micromol/kg (200 mg/kg). In the iron-loaded Cebus apella monkey, whereas the PO administration of DFO or HBED even at a dose of 300 to 324 micromol/kg was ineffective, the sc injection of HBED in buffer or its monosodium salt, 75 to 324 micromol/kg, produced a net iron excretion that was nearly three times that observed after similar doses of sc DFO. In patients with transfusional iron overload, sc injections of HBED may provide a much needed alternative to the use of prolonged parenteral infusions of DFO. Note: After the publication of our previous paper (Blood, 91:1446, 1998) and the completion of the studies described here, it was discovered that the HBED obtained from Strem Chemical Co (Newburyport, MA) that was labeled and sold as a dihydrochloride dihydrate was in fact the monohydrochloride dihydrate. Therefore, the actual administered doses were 81, 162, or 324 micromol/kg; not 75, 150, or 300 micromol/kg as was previously reported. The new data have been recalculated accordingly, and the data from our earlier study, corrected where applicable, are shown in parentheses.

Administration, Oral↗

PubMed1999

Pharmacokinetics of orally administered desferrithiocin analogs in cebus apella primates.

The pharmacokinetic behavior of three iron chelators based on the desferrithiocin (DFT) pharmacophore, (S)-4, 5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (desmethyldesferrithiocin, DMDFT, 2); (S)-4,5-dihydro-2-(2, 4-dihydroxyphenyl)-4-thiazolecarboxylic acid [4-(S)-hydroxydesazaDMDFT, 3); and (R)-2-(2-hydroxyphenyl)-4-oxazolinecarboxylic acid, the oxazoline analog of desazaDMDFT, 4, is described. Although 2 and 3 are comparably effective in inducing iron excretion upon oral administration, they exhibit markedly different plasma pharmacokinetics. Ligand 2 achieves a substantially higher plasma concentration than does 3, yet the renal clearance of these compounds is similar. The oxazoline analog 4 shows poor iron clearance when administered orally, although it remains in the plasma for extended periods. Chelator 4 demonstrates a marked capacity to bind to human serum albumin compared with the thiazoline derivatives. The possible implications for designing ligands for the treatment of transfusional iron overload are discussed.

Administration, Oral↗

PubMed1998

The origin of the differences in (R)- and (S)-desmethyldesferrithiocin. Iron-clearing properties.

The iron clearance properties, toxicity, and pharmacokinetics of (R)- and (S)-desmethyldesferrithiocin (DMDFT) are described. The studies were performed in rodent and primate models. While both enantiomers were found to be effective iron chelators with minimal toxicity in the rodents, only (S)-DMDFT was able to induce the clearance of any iron in the primates. In addition, two out of nine of the monkeys given (R)-DMDFT died within 24 h of drug administration. The reason for the differences in iron clearance properties and the apparent toxicity of the (R)-enantiomer in the primates is likely related to the disparities in the pharmacokinetics of the two analogues. The pharmacokinetic data suggest enantioselectivity in renal clearance of the desferrithiocins and their iron complexes with (S)-DMDFT clearance 3.5 times greater than that of (R)-DMDFT, and FeIII [(S)-DMDFT]2 clearance 6.8 times greater than that of FeIII [R-DMDFT]2. In all primates studied FeIII [(R)-DMDFT]2 in the plasma exceeded 25 mg/L (50 microM) for several hours and remained above 10 mg/L (20 microM) at 8 h while levels of FeIII [(S)-DMDFT]2 never exceeded 50 microM and were at or below the limits of detection 8 h post-injection.

Animals↗

PubMed1998

HBED: A potential alternative to deferoxamine for iron-chelating therapy.

To examine the potential clinical usefulness of the hexadentate phenolic aminocarboxylate iron chelator N, N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid (HBED) for the chronic treatment of transfusional iron overload, we compared the iron excretion induced by subcutaneous (SC) injection of HBED and deferoxamine (DFO), the reference chelator, in rodents and primates. In the non-iron-overloaded, bile-duct-cannulated rat, a single SC injection of HBED, 150 micromol/kg, resulted in a net iron excretion that was more than threefold greater than that after the same dose of DFO. In the iron-loaded Cebus apella monkey, a single SC injection of HBED, 150 micromol/kg, produced a net iron excretion that was more than twice that observed after the same dose of SC DFO. In patients with transfusional iron overload, SC injections of HBED may provide a much needed alternative to the use of prolonged parenteral infusions of DFO.

Animals↗

PubMed1998

Polyamine analogue antiarrhythmics.

A group of polyamine analogues was assessed for their ability to prevent isoproterenol-induced ventricular fibrillation and death in a desoxycorticosterone acetate (DOCA)/saline rodent model. The compounds tested included polyamine antimetabolites and putrescine mimics. A structure-activity analysis revealed that tetraamines that are dicationic at physiological pH with their terminal nitrogens incorporated into pyridine rings are the most active analogues. It is clear from this study that there was no correlation between the compounds' ability to diminish polyamine metabolism and their effects on the electrical properties of the heart. In fact, the most potent polyamine antimetabolites were among the least effective antiarrhythmics. The most active of the compounds investigated, N1, N3-bis(4-pyridyl)-1,3-diaminopropane, PYR(3,3,3), was shown to both prevent isoproterenol-induced arrhythmias in DOCA/saline-treated rodents and reverse the progression of arrhythmic events that would otherwise culminate in ventricular fibrillation and death. Electrocardiographic tracings demonstrated that PYR(3,3,3) and propranolol both protect from and reverse the progression of arrhythmic events to ventricular fibrillation. In addition, cardiac pathologies from rats treated with both drugs are similar, but are substantially different from the control (isoproterenol)-treated animals. (c) 1998 The Italian Pharmacological Society.

Animals↗

PubMed1998

The influence of traffic vibrations on the radon potential.

The influence of traffic vibrations on the radon potential is analyzed in this study. Generally, the radon concentration in soil-gas increases through traffic vibrations. The influence of the vibrations is determined near railway tracks and heavy-traffic roads. Soils above natural, in-place, bedrock (solid and unconsolidated rocks) and backfills were studied. The type of vibrations, as well the soil material, have a pronounced influence on the amount of increase of the radon concentration. The spatial radius of influence is wider with railway traffic (>30 m) than with motor vehicle traffic (<25 m). Close to the traffic lanes the increase of the radon concentration by motor vehicle traffic is significantly higher (37%) than that by railway traffic (11.5%). There are no differences between locations, which lay above unconsolidated rock (11.1%), and locations above solid rock (11.8%). In addition to the increased radon concentrations, the averaged radon concentration decreases with increasing distance to the vibration source, but only at locations that lay above solid rock. Both phenomena can be explained by a "pump effect": the mechanical vibration of soil and mineral particles leads to an upward motion of the whole volume of soil-gas. During the vibrations the topmost soil layers lose radon to the atmosphere and as a result the upward transport is increased.

Automobiles↗

PubMed1997

[Not Available].

Explore the source record for details and available documents.

Bicycling↗

PubMed1996

Synthesis and biological evaluation of naphthyldesferrithiocin iron chelators.

The synthesis and iron-clearing properties of the naphthyldesferrithiocins 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4R)-carboxylic acid, 2-(2'-hydroxynaphth-1'-yl)-delta2-thiazoline-(4S)-carboxylic acid, 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4R)-carboxylic acid, and 2-(3'-hydroxynaphth-2'-yl)-delta2-thiazoline-(4S)-carboxylic acid are described. While the bile duct-cannulated rat model clearly demonstrates that the 3'-hydroxynaphthyl-2'-yl compounds are orally active iron-clearing agents and the corresponding 2'-hydroxynaphthyl-1'-yl compounds are not, in the primate model none of the benz-fused desazadesferrithiocin analogues are active. Oral versus subcutaneous administration of these ligands strongly suggests that metabolism is a key issue in their iron-clearing properties and that these benz-fused desferrithiocins are not good candidates for orally active iron-clearing drugs.

Animals↗

PubMed1996

Metabolism and pharmacokinetics of N1,N14-diethylhomospermine.

The pharmacokinetics and metabolism of N1,N14-diethylhomospermine (DEHSPM) is described. Analysis of 15 min constant rate intravenous infusion data in dogs gave mean values of: plasma t1/2 = 1.04 hr; Vd = 0.514 liter/kg; CL = 0.343 liter/hr/kg; and AUC0-infinity = 43.2 mg/hr/liter. The renal t1/2 = 0.99 hr, with 36% of the drug recovered in the urine between 0-4 hr unchanged. In other experiments, the drug was administered to dogs by subcutaneous injection. Noncompartmental analysis of plasma concentration-time data showed a mean residence time (MRT) of 4.67 hr (subcutaneous) vs. 1.93 hr (intravenous). Mice and dogs received DEHSPM chronically to evaluate tissue distribution of DEHSPM and its metabolites. All tissues examined contained DEHSPM and its N-deethylated metabolites, N1-ethylhomospermine (MEHSPM) and homospermine (HSPM). On day 1 posttreatment, 35% of the total dose administered to mice was present in the liver (25%) and kidney (10%). The DEHSPM present declines rapidly (liver t1/2 = 1.6 days). The majority of the original dose was present as HSPM, which persisted in tissues for weeks (liver t1/2 = 15.4 days). These data suggest that DEHSPM and MEHSPM are metabolized by N-deethylation, but that HSPM is not susceptible to further degradation by polyamine catabolic enzymes that involves stepwise removal of aminopropyl equivalents by spermine/spermidine N1-acetyltransferase/polyamine oxidase. Thus, chronic DEHSPM dosing regimens in both dogs and mice may result in the accumulation of HSPM, which is retained by tissues for an extended period of time resulting in disruption of normal polyamine homeostasis in these tissues. These findings correlate with clinical and histopathological signs of toxicity in dogs and in mice.

Animals↗