2007 Week 36: Erythritol toxicity

ENTIRE CATALOG OF FERRET PROTEINS TO DATE


Sugar diseases are a problem for ferrets - particularly insulinoma - and we are always looking for safe sweeteners to help the medicine go down easier. (Frankly, I got tired of pink Pepto Bismol baths pretty quickly.)

Erythritol is under consideration as it is widely available in Japan. But as it is a sugar alcohol like xylitol, it raises some questions of toxicity.

Here are some papers from PubMed regarding its effects after testing on dogs, rats, mice, and rabbits.

"Chronic (1-year) oral toxicity study of erythritol in dogs."
Highlights from the abstract:
-> There were no clinically relevant changes in hematological or clinicochemical parameters attributable to treatment.
-> ...however, the available data did not indicate treatment-related effects on the urinary excretion of electrolytes (K+, Na+, Mg2+, and Pi) or enzymes (gamma-glutamyltranspeptidase, N-acetyl glucosaminidase, and lactate dehydrogenase
-> Quantitation of erythritol in the urine demonstrated that 50 to 80% of the ingested dose was absorbed and excreted in the urine.
-> It was concluded that daily erythritol consumption of up to 3.5 g/kg body wt was well tolerated by dogs.

"Four-week oral toxicity study with erythritol in rats."
Highlights from the abstract:
->Soft stools and diarrhea were observed in male and female animals of the 10% group and in female animals of the 5% group. These symptoms disappeared during the course of the study.
->Small statistically significant changes in certain hematological, clinical chemistry, and urine parameters were noted in the high-dose group but were judged not to be biologically important.
->Based on these results, it was concluded that the feeding of erythritol at a dietary level of 10% did not result in toxicologically significant effects.

"Subchronic oral toxicity studies with erythritol in mice and rats."
Highlights from the abstract:
->There were no treatment-related mortalities in either mice or rats.
->Hematological and clinicochemical examinations of blood and plasma did not reveal any treatment-related effects.
->Urine output increased with increasing erythritol dose.
->Increased relative and absolute kidney weights were observed in both sexes of mice in the 20% erythritol group, in male mice of the 5 and 10% groups, and in rats of the 10 and 20% erythritol groups.
->In rats, the creatinine-normalized urinary excretion of GGT, NAG, and some electrolytes (Na+, K+, and Ca2+) was increased in some erythritol groups but a clear dose-response relationship was evident only for calcium.
->In particular, the morphological integrity of the kidneys was not adversely affected by the treatment in either species. The increases in urinary excretion of protein, GGT, NAG, and electrolytes were considered to result from extensive osmotic diuresis and a potential overload of the renal excretory system at the high dose levels employed.

"Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data."
Highlights from the abstract:
->The majority of the safety studies conducted were feeding studies in which erythritol was mixed into the diet at concentrations as high as 20%
->The metabolic studies in animals have shown that erythritol is almost completely absorbed, not metabolized systemically and is excreted unchanged in the urine.
->The safety studies have demonstrated that erythritol is well tolerated and elicits no toxicological effects.
->Erythritol administered orally to humans was rapidly absorbed from the gastrointestinal tract and quantitatively excreted in the urine without undergoing metabolic change.

"Chronic toxicity and carcinogenicity study of erythritol in rats."
Highlights from the abstract:
->All treatments were well tolerated without diarrhea or other side effects.
->Hematological and clinicochemical examinations did not reveal noticeable changes which could be attributed to treatment.
->urine samples collected during five 48-hr periods ... showed that about 60% of ingested erythritol was excreted unchanged. The urine volumes increased with increasing dietary erythritol levels.
->Except for more frequent pelvic nephrocalcinosis (precipitation of calcium phosphate in the renal tubules, with resultant renal insufficiency.)in female rats of all erythritol dose groups, the histopathological examinations did not reveal any nonneoplastic, preneoplastic, or neoplastic changes that could be attributed
->In the absence of morphological alterations in the kidneys or other signs of nephrotoxicity, the increased excretions of NAG, GGT, LMP, and TP are regarded as innocuous, functional sequelae of the renal elimination of erythritol.
->Except for nephrocalcinosis, which is commonly seen in polyol-fed rats, no other treatment-related, morphological changes were observed in the kidneys. Evidence for a tumor-inducing or tumor-promoting effect of erythritol was not seen.

"Embryotoxicity and teratogenicity study with erythritol in rats."
Highlights from the abstract:
->The treatment was generally well tolerated and no mortality occurred in any group.
->Examination of the fetuses for external, visceral, and skeletal alterations did not reveal any fetotoxic, embryotoxic, or teratogenic effects.
->In conclusion, no adverse effects were observed at erythritol doses of up to about 6.6 g/kg body wt/day, i.e., the highest dose tested.

"Teratology study of erythritol in rabbits."
Highlights from the abstract:
->Maternal effects (auricular edema, and bradypragia) were observed in the high-dose group.
->No deaths or significant abnormalities occurred in animals given 1.0 or 2.24 g/kg
->No effect was observed in the reproductive performance of the dams or in fetal development from ingestion at any of the treatment levels.

"Erythritol: a review of biological and toxicological studies."
Highlights from the abstract:
->NONE AVAILABLE

One thing often mentioned in the studies is that there were noticable changes (enlargements, weight increases) to the 'cecum'. As ferrets do not have one, I did not list it with the other highlights.

If you read the abstracts with dosing details you will also notice that testing was done a rather high levels. I would think from these that it is _possible_ to safely use erythritol in healthy ferrets especially in the under 1gm/kg range that I am considering. However, there are certain drugs that cause increases or decreases in K or other electrolyte uptake. That is something to consider before using erythritol as a sweetener for medicine .

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2007 Week 34: Herbal Studies - Drug Interactions

ENTIRE CATALOG OF FERRET PROTEINS TO DATE



Identification of drugs that interact with herbs in drug development
School of Life Sciences, Queensland University of Technology, Brisbane, Australia.

To date, several clinically important drugs have been identified that interact with commonly used herbs. These drugs include (among others) warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Because drug-herb interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of drugs that interact with commonly used herbal medicines has important implications in drug development. In silico, in vitro, animal and human studies are often used to identify drug interactions with herbs. We propose that drug-herb and herb-CYP interaction studies should be incorporated into drug development.
PMID: 17706549

Herb-drug interactions: a literature review
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.
PMID: 15916450

Interactions between herbal medicines and prescribed drugs: a systematic review
Department of Experimental Pharmacology, University of Naples 'Federico II', Naples, Italy.

Despite the widespread use of herbal medicines, documented herb-drug interactions are sparse. We have reviewed the literature to determine the possible interactions between the seven top-selling herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and prescribed drugs. Literature searches were performed using the following databases: Medline (via Pubmed), Cochrane Library, Embase and phytobase (all from their inception to July 2000). All data relating to herb-drug interactions were included regardless of whether they were based on case reports, case series, clinical trials or other types of investigation in humans. In vitro experiments were excluded. Data were extracted by the first author and validated by the second author. 41 case reports or case series and 17 clinical trials were identified. The results indicate that St John's wort (Hypericum perforatum) lowers blood concentrations of cyclosporin, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline; furthermore it causes intermenstrual bleeding, delirium or mild serotonin syndrome, respectively, when used concomitantly with oral contraceptives (ethinylestradiol/desogestrel), loperamide or selective serotonin-reuptake inhibitors (sertaline, paroxetine, nefazodone). Ginkgo (Ginkgo biloba) interactions include bleeding when combined with warfarin, raised blood pressure when combined with a thiazide diuretic and coma when combined with trazodone. Ginseng (Panax ginseng) lowers blood concentrations of alcohol and warfarin, and induces mania if used concomitantly with phenelzine. Garlic (Allium sativum) changes pharmacokinetic variables of paracetamol, decreases blood concentrations of warfarin and produces hypoglycaemia when taken with chlorpropamide. Kava (Piper methysticum) increases 'off' periods in Parkinson patients taking levodopa and can cause a semicomatose state when given concomitantly with alprazolam. No interactions were found for echinacea (Echinacea angustifolia, E. purpurea, E. pallida) and saw palmetto (Serenoa repens). In conclusion, interactions between herbal medicines and synthetic drugs exist and can have serious clinical consequences. Healthcare professionals should ask their patients about the use of herbal products and consider the possibility of herb-drug interactions.
PMID: 11772128



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