Association of diet with clinical outcomes in dogs with dilated cardiomyopathy and congestive heart failure.

INTRODUCTION: Dilated cardiomyopathy (DCM) in dogs has been associated with feeding of grain-free (GF), legume-rich diets. Some dogs with presumed diet-associated DCM have shown improved myocardial function and clinical outcomes following a change in diet and standard medical therapy. HYPOTHESIS: Prior GF (pGF) diet influences reverse cardiac remodeling and clinical outcomes in dogs with DCM and congestive heart failure (CHF). ANIMALS AND METHODS: A retrospective study was performed with 67 dogs with DCM and CHF for which diet history was known. Dogs were grouped by diet into pGF and grain-inclusive (GI) groups. Dogs in the pGF group were included if diet change was a component of therapy. Survival was analyzed using Kaplan-Meier curves and the Cox proportional-hazards model. RESULTS: The median survival time was 344 days for pGF dogs vs. 253 days for GI dogs (P = 0.074). Statistically significant differences in median survival were identified when the analysis was limited to dogs surviving longer than one week (P = 0.033). Prior GF dogs had a significantly worse outcome the longer a GF diet was fed prior to diagnosis (P = 0.004) or if they were diagnosed at a younger age (P = 0.017). Prior GF dogs showed significantly greater improvement in normalized left ventricular internal diastolic diameter (P = 0.038) and E-point septal separation (P = 0.031) measurements and significant decreases in their furosemide (P = 0.009) and pimobendan (P < 0.005) dosages over time compared to GI dogs. CONCLUSIONS: Prior GF dogs that survived at least one week after diagnosis of DCM, treatment of CHF, and diet change had better clinical outcomes and showed reverse ventricular remodeling compared to GI dogs.

Prevalence of an angiotensin-converting enzyme gene variant in dogs.

BACKGROUND: Genetic heterogeneity of the canine angiotensin converting enzyme (ACE) gene is functionally important because the degree of aldosterone breakthrough with ACE-inhibitor therapy is greater in variant positive dogs compared to variant negative dogs, but the prevalence of the variant is not known. The purpose of this study was to determine ACE gene variant-positive prevalence in a population of 497 dogs of different breeds. RESULTS: Overall variant-positive prevalence was 31%, with 20% of dogs heterozygous and 11% of dogs homozygous. The variant was overrepresented in Irish Wolfhounds (prevalence 95%; P < .001), Dachshunds (prevalence 90%; P < .001), Cavalier King Charles Spaniels (prevalence 85%; P < .001), Great Danes (prevalence 84%; P < .001), and Bull Mastiffs (prevalence 58%; P = .02). Irish Wolfhounds were more likely to be homozygous than heterozygous (P < .001). CONCLUSIONS: Nearly one-third of dogs in this study were positive for a functionally important ACE gene variant, with wide prevalence variability between breeds. The clinical importance of high ACE gene variant-positive prevalence in some breeds requires further study because the highest prevalences were found in breeds that are predisposed to heart disease and therefore may be treated with ACE-inhibitors.

Absence of known feline MYH7 and MYBPC3 variants in a diverse cohort of cats with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common cause of heart disease in the domestic cat with a genetic predisposition in a few breeds. In the Maine Coon and Ragdoll breeds, two variants associated with the HCM phenotype have been identified in the cardiac myosin binding protein C gene (MYBPC3; p.Ala31Pro and p.Arg820Trp respectively), and a single variant has been identified in the myosin heavy chain gene (MYH7; p.Glu1883Lys) in one domestic cat with HCM. It is not known if these variants influence the development of HCM in other cohorts of the feline population. The objective of this study was to evaluate the presence of the known MYBPC3 and MYH7 variants in a population of cats with HCM. DNA was isolated from samples collected from non-Ragdoll and non-Maine Coon domestic cats diagnosed with HCM through the North Carolina State University College of Veterinary Medicine and genotyped for the three variants. One-hundred and three DNA samples from cats with HCM were evaluated from domestic shorthair, domestic longhair and purebred cats. All samples were wt for the MYBPC3 and MYH7 variants. Although this study was limited by its inclusion of cats from one tertiary hospital, the lack of these MYBPC3 and MYH7 variants in this feline HCM population indicates that the clinical utility of genetic testing for these variants may be isolated to the two cat breeds in which these variants have been identified. Further studies to identify the causative variants for the feline HCM population are warranted.

Cardiac Leiomyosarcoma in a Cat Presenting for Bilateral Renal Neoplasia.

A 10-year-old neutered female domestic longhair cat was presented to a tertiary care veterinary hospital for evaluation of a right renal mass that was identified incidentally on abdominal radiographs and classified further as a sarcoma based on fine needle aspiration cytology. Further diagnostic workup, including ultrasound and cytology, identified a sarcoma in the left kidney. After approximately 1 month of conservative medical management, the clinical condition deteriorated and the cat was humanely destroyed. Post-mortem examination confirmed bilateral renal masses with multifocal infarction and extensive necrosis, and further identified a large mass at the apex of the heart as well as multiple pulmonary nodules. Microscopical examination of the masses identified a population of poorly-differentiated neoplastic spindle cells, consistent with sarcoma. Immunohistochemically, the neoplastic cells expressed smooth muscle actin and muscle-specific actin, but were negative for myoglobin and factor VIII. Phosphotungstic acid-haematoxylin staining was unable to identify cross-striations in the neoplastic cells. Based on these results and the pattern of lesion distribution, the cat was diagnosed with cardiac leiomyosarcoma with pulmonary and bilateral renal metastasis.

Myxomatous mitral valve disease in the miniature poodle: A retrospective study.

Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disease in the dog. The natural history of the disease is wide ranging and includes patients without clinical signs as well as those with significant clinical consequences from cardiac arrhythmias, pulmonary hypertension and/or congestive heart failure. The factors that determine which dogs remain asymptomatic and which develop clinical disease are not known. Disease characteristics could be breed or family related; some breeds of dogs, particularly the Cavalier King Charles spaniels, develop MMVD at an early age. The purpose of this study was to retrospectively characterize MMVD in the miniature poodle, a commonly affected breed in which MMVD has not been well characterized. Thirty-two miniature poodles met the inclusion criteria. Mean age was 11±three years. Clinical signs included exercise intolerance, syncope and coughing. Eighteen dogs were classified as ACVIM Stage B1, 12 as stage B2, and two as stage C. Mean vertebral heart scale (VHS) was 10.2 (±standard deviation of 0.9); 15 of 28 dogs had a VHS <10.3. One dog had radiographic evidence of congestive heart failure. Mean diastolic left ventricle dimension normalized to body weight was 1.6 (±0.4) and mean systolic was 0.8 (±0.3). Mitral valve prolapse was subjectively classified as mild or moderate in 19 dogs and severe in two. In the miniature poodles reported here, MMVD appears to be a fairly late onset disease and often is a mild phenotype.

Evaluation of genes associated with human myxomatous mitral valve disease in dogs with familial myxomatous mitral valve degeneration.

Myxomatous mitral valve disease (MMVD) is the most common heart disease in the dog. It is believed to be heritable in Cavalier King Charles spaniels (CKCS) and Dachshunds. Myxomatous mitral valve disease is a familial disease in human beings as well and genetic mutations have been associated with its development. We hypothesized that a genetic mutation associated with the development of the human form of MMVD was associated with the development of canine MMVD. DNA was isolated from blood samples from 10 CKCS and 10 Dachshunds diagnosed with MMVD, and whole genome sequences from each animal were obtained. Variant calling from whole genome sequencing data was performed using a standardized bioinformatics pipeline for all samples. After filtering, the canine genes orthologous to the human genes known to be associated with MMVD were identified and variants were assessed for likely pathogenic implications. No variant was found in any of the genes evaluated that was present in least eight of 10 affected CKCS or Dachshunds. Although mitral valve disease in the CKCS and Dachshund is a familial disease, we did not identify genetic cause in the genes responsible for the human disease in the dogs studied here.

Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model.

INTRODUCTION: Diuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide. ANIMALS: Six healthy male dogs. METHODS: Raw data and stored samples from one arm of a previously published study were further analyzed to mechanistically investigate causes of diuretic braking in these dogs. Urine volume was recorded hourly during a 5-h furosemide CRI. Urine and blood samples were collected hourly to measure serum and urine electrolytes, urine aldosterone, and plasma and urine furosemide. Serum electrolyte fractional excretion was calculated. Urine sodium concentration was indexed to urine potassium (uNa:uK) and urine furosemide (uNa:uFur) concentrations, plasma furosemide concentration was indexed to urine furosemide concentration (pFur:uFur), and urine aldosterone was indexed to urine creatinine (UAldo:C). Temporal change and the relationship to urine volume were evaluated for these measured and calculated variables. RESULTS: Urine volume was significantly correlated with urine electrolyte amounts and with uNa:uK. The ratio of pFur:uFur decreased during the infusion, whereas furosemide excretion was unchanged. CONCLUSIONS: There was a strong relationship between urine volume and absolute urine electrolyte excretion. Urine volume was strongly correlated to uNa:uK, giving it potential as a spot indicator of urine production during diuresis. The decrease in uNa:uK over time during the infusion is consistent with mineralocorticoid modification of urinary electrolyte excretion, supporting renin-angiotensin-aldosterone activation as a cause of diuretic braking in this model.

Long-term Stability of a Compounded Suspension of Torsemide (5 mg/mL) for Oral Administration.

BACKGROUND: Torsemide use for congestive heart failure (CHF) has been reported, but prescription frequency is unknown. Commercially available tablet sizes in North America limit dosing precision, indicating a need to evaluate its strength and stability in suspension. OBJECTIVES: To determine the frequency of torsemide prescriptions and to determine a beyond use date (BUD) of a compounded suspension of torsemide for oral administration stored under 2 temperature conditions for 90 days. ANIMALS: No animals used. METHODS: Pharmacy records were retrospectively reviewed for torsemide and furosemide prescriptions from 2008 to 2015 at 2 veterinary referral centers. After preliminary strength testing, compounded torsemide suspension (5 mg/mL) for oral administration was prepared using torsemide tablets suspended in OraPlus:OraSweet 1:1, buffered to a pH of 8.3 and stored at refrigeration (2-8°C) and room temperature (20-25°C) in 2 oz amber plastic bottles. Samples were analyzed by reverse phase high-performance liquid chromatography (RP-HPLC) on days 0, 14, 30, 60, and 90. RESULTS: Prescriptions for torsemide increased from 2008 to 2015. Analysis of the torsemide 5 mg/mL suspension for oral administration at each time point met United States Pharmacopeia (USP) requirements for torsemide content of 90-110% of label claim. The average strength at 90 days decreased to 92 ± 3% at 2-8°C and 95 ± 2% at 20-25°C. Stability testing did not detect unknown impurities. CONCLUSIONS: Increasing torsemide use warrants availability of a validated and stable compounded formulation. Our results support the assignment of a 90-day BUD for torsemide 5 mg/mL suspension for oral administration compounded in OraPlus:Sweet 1:1 buffered to a pH of 8.3.

Furosemide continuous rate infusion diluted with 5% dextrose in water or hypertonic saline in normal adult dogs: a pilot study.

OBJECTIVE: The goal of this study was to investigate the short-term safety and diuretic efficacy of furosemide constant rate infusion (CRI) diluted with 5% dextrose in water (D5W) compared to dilution with 2.4% hypertonic saline in healthy dogs. ANIMALS: Six healthy dogs. METHODS: Dogs were studied in a randomized, blinded, crossover manner. Furosemide 3.3mg/kg was diluted to 2.2mg/mL with either 1.5mL/kg D5W for the DEX method or with 1.0mL/kg D5W and 0.5mL/kg of 7.2% hypertonic saline for the H-SAL method. After a 0.66mg/kg furosemide IV bolus, the infusion rate was 0.3 mL/kg/hr for 5 h such that both methods delivered 0.66 mg/kg/hr (total 3.3mg/kg) furosemide in equal volume for the study duration. Urine output, water intake, central venous pressure (CVP), physical parameters, furosemide concentrations, blood and urine electrolytes, and urine aldosterone to creatinine ratio (UAldo:C) were evaluated. RESULTS: Measured variables were not different between methods but showed changes over time consistent with diuresis. Mean CVP decreased over time similarly for both methods. Plasma furosemide and urine concentrations were stable and not different between methods. Both furosemide CRI methods showed an increase in the UAldo:C, however, the rise was greater for DEX than for H-SAL. CONCLUSIONS: Diuresis was similar for both furosemide CRI methods; however, the H-SAL method induced less renin-angiotensin-aldosterone system activation than the DEX method. The absence of intravascular volume expansion based on CVP suggests that dilution of a furosemide CRI with 2.4% hypertonic saline may be well tolerated in heart failure.

Relationship of plasma N-terminal pro-brain natriuretic peptide concentrations to heart failure classification and cause of respiratory distress in dogs using a 2nd generation ELISA assay.

BACKGROUND: Cardiac biomarkers provide objective data that augments clinical assessment of heart disease (HD). HYPOTHESIS/OBJECTIVES: Determine the utility of plasma N-terminal pro-brain natriuretic peptide concentration [NT-proBNP] measured by a 2nd generation canine ELISA assay to discriminate cardiac from noncardiac respiratory distress and evaluate HD severity. ANIMALS: Client-owned dogs (n = 291). METHODS: Multicenter, cross-sectional, prospective investigation. Medical history, physical examination, echocardiography, and thoracic radiography classified 113 asymptomatic dogs (group 1, n = 39 without HD; group 2, n = 74 with HD), and 178 with respiratory distress (group 3, n = 104 respiratory disease, either with or without concurrent HD; group 4, n = 74 with congestive heart failure [CHF]). HD severity was graded using International Small Animal Cardiac Health Council (ISACHC) and ACVIM Consensus (ACVIM-HD) schemes without knowledge of [NT-proBNP] results. Receiver-operating characteristic curve analysis assessed the capacity of [NT-proBNP] to discriminate between dogs with cardiac and noncardiac respiratory distress. Multivariate general linear models containing key clinical variables tested associations between [NT-proBNP] and HD severity. RESULTS: Plasma [NT-proBNP] (median; IQR) was higher in CHF dogs (5,110; 2,769-8,466 pmol/L) compared to those with noncardiac respiratory distress (1,287; 672-2,704 pmol/L; P < .0001). A cut-off >2,447 pmol/L discriminated CHF from noncardiac respiratory distress (81.1% sensitivity; 73.1% specificity; area under curve, 0.84). A multivariate model comprising left atrial to aortic ratio, heart rate, left ventricular diameter, end-systole, and ACVIM-HD scheme most accurately associated average plasma [NT-proBNP] with HD severity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma [NT-proBNP] was useful for discriminating CHF from noncardiac respiratory distress. Average plasma [NT-BNP] increased significantly as a function of HD severity using the ACVIM-HD classification scheme.

Prevalence of orthostatic hypotension and relationship with drug use amongst older patients.

INTRODUCTION: Orthostatic hypotension (OH) is said to be highly prevalent in older people. Drugs are often involved as causative factor. Nevertheless, few data are available about the prevalence of OH and its relationship with drugs in olders. OBJECTIVES: To review data about (i) the prevalence and characteristics of OH in older patients; and (ii) the relationship between OH and drugs. METHODS: Review of publications from Ovid (PubMed) from 1980 to May 2011 using the following key words: "orthostatic hypotension" combined with "elderly" or equivalent for the analysis of prevalence (first search) and "orthostatic hypotension" combined with "drugs" or equivalent to assess the relationship between OH and drugs (second search). RESULTS: Fifty-one publications (of which 14 with original data) were retrieved from the prevalence search, 31 for the second search (8 with original data: 7 retrospective studies and 1 prospective cohort study) and 12 reviews or experts opinions. Prevalence of OH varies according to the characteristics of the subjects, the settings of the studies, and the procedures of blood pressure measurement. In acute geriatrics units, two studies reported a prevalence of over 30% and one study mentioned that 68% of the patients presented with at least one episode during the day. OH was associated with several geriatric problems: gait disorders, balance disorders, falls, cerebral hypoperfusion, transient ischemic attacks, cognitive impairment, acute myocardial infarct and systolic hypertension. OH can also be asymptomatic or with atypical presentation: falls, gait disorders and confusion. Psychotropic agents (antipsychotics, sedatives, antidepressants), and cardiovascular drugs (antihypertensive agents, vasodilators, diuretics) were associated with OH. DISCUSSION: If the hypothesis of causality between drug treatment and OH is confirmed, the identification of the involved drugs could be of value for the prevention of OH and its complications. In this context, the Working Group Pharmacology Pharmacotherapy and Pharmaceutical Care of the Belgian Society of Gerontology and Geriatrics proposes to conduct a multicentre study to assess the prevalence of OH in Belgian acute geriatrics units and its relationship with drugs.

Perceptions of quality of life and priorities of owners of cats with heart disease.

BACKGROUND: Owners' perceptions and priorities regarding quality of life (QoL) are important considerations given the unknown efficacy of many commonly administered medications, stress of hospital visits, difficulties providing home care, and personal choices including euthanasia. OBJECTIVE: To describe the relative importance of quality versus quantity of life to owners of cats with heart disease. ANIMALS: Two hundred and thirty-nine cats with heart disease. METHODS: Prospective questionnaire-based clinical study. Cat owners completed a questionnaire to identify important parameters when assessing their cat's QoL, the relative importance of quality versus quantity of life, and willingness to trade survival time for QoL. Variables associated with these parameters were evaluated with multivariate analyses. RESULTS: Appetite, owner interaction, sleep patterns, and litterbox habits were deemed important to QoL. Concern over pet suffering was significantly greater than concern over life expectancy. Ninety-three percent of owners were willing to trade survival time for good QoL; 57% of these were willing to trade up to 6 months. On multivariate analysis, the only factor significantly (P=.002) associated with willingness to trade 6 months was study site. Owner concern regarding stress of administering medications at home increased with number and frequency of medications. CONCLUSIONS AND CLINICAL RELEVANCE: These results indicated that QoL is more important to owners of cats with heart disease than longevity. The various priorities and concerns of cat owners should be taken into account in order to provide optimal care.

[Generics: similarities, bioequivalence but no conformity]. / Les génériques: essentiellement similaires, bioéquivalents mais non identiques.

The using of generic forms (GF) is presented as a potential source of budgetary "saving of money" in the field of pharmaceutical expenses. Not frequently prescribed in Belgium, they win a new interest thanks to the recent making use of the "reference repayment". Sale's authorization of GF is controlled by european rules, but some questions about their identity to original medications remain. Do similarities based only upon qualitative and quantitative composition in active molecules, pharmaceutical forms and biodisponibility give us all requested guaranties? Several cases of discordances can appear; the major elements of non conformity are the nature of excipients, notice's contents and the value of biodisponibility studies. However, in term of economy, in the drug market, development of GF appears to constitute an unavoidable phenomenon.

Efficacy of a single oral dose of isorsorbide 5-mononitrate in normal dogs and in dogs with congestive heart failure.

Isosorbide 5-mononitrate (5-ISMN) was evaluated in normal dogs and dogs with congestive heart failure (CHF) in a randomized, blinded, and placebo-controlled study. Equilibrium blood pool imaging was used to detect changes in regional blood volume distribution. Six normal dogs were administered placebo, 2, 3, and 4 mg/kg 5-ISMN PO on separate days with a 1-week washout period between randomized dosings. Six dogs with CHF were administered placebo or 4 mg/kg 5-ISMN on separate days with a 1-week washout period between randomized dosings. Data were collected at baseline and at 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 minutes after dosing. Measured variables included indirect arterial blood pressure (BP), heart rate (HR), packed cell volume (PCV), scintigraphic count rates for normal dogs, and scintigraphic count rates for CHF dogs. Blood for plasma 5-ISMN concentration determination was collected at 60 minutes. Scintigraphic counts were corrected for decay and expressed as a percentage of the whole. No differences were detected in BP, HR, PCV, thoracic blood volume percentage (TBVP), or abdominal blood volume percentage (ABVP) between placebo and 5-ISMN in normal dogs at any dose. No differences were detected in TBVP or ABVP between placebo and 5-ISMN in dogs with CHF Plasma 5-ISMN concentration exceeded the minimum therapeutic concentration in all dogs and at all doses 60 minutes after drug administration. Equilibrium blood pool imaging failed to detect a shift in blood volume with oral 5-ISMN administration at any dose tested in normal dogs and dogs with CHF, despite adequate drug absorption. On the basis of the results of this study, 5-ISMN may not be beneficial in the treatment of dogs with CHF.

[Generics: essentially similar, bioequivalent but not identical]. / Les génériques: essentiellement similaires, bioéquivalents mais non identiques.

The using of generic forms (GF) is presented as a potential source of budgetary "saving of money" in the field of pharmaceutical expenses. Not frequently prescribed in Belgium, they win a new interest thanks to the recent making use of the "reference repayment". Sale's authorization of GF is controlled by european rules, but some questions about their identity to original medications remain. Do similarities based only upon qualitative and quantitative composition in active molecules, pharmaceutical forms and biodisponibility give us all requested guarantees? Several cases of discordances can appear: the major elements of non conformity are the nature of excipients, notice's contents and the value of biodisponibility studies. However, in term of economy, in the drug market, development of GF appears to constitute an unavoidable phenomenon.

Drug use in relation to clinical activities as an instrument for prospective drug budgeting. The Belgian experience.

In an effort to control escalating health expenditures, especially in hospitals, many countries are planning or experimenting with prospective budgeting systems. Belgium is no exception and has recently introduced, with some success, limited fixed charges per hospital admission and/or per hospitalisation day for laboratory tests and radiographic investigations. More recently, the focus has shifted to hospital drug expenditures, which have shown high growth rates over the past few years. Until now, such expenditures have been reimbursed on a fee-for-service system, often with limited out-of-pocket charges for hospitalised patients. In order to curb the growth of drug expenditures, it is appropriate to investigate whether the financing of hospital drugs through a prospective budgeting system could be a feasible solution. Therefore, we constructed a database of over 270 000 admissions from a sample of 23 Belgian general and teaching (university) hospitals for the year 1991. Data were obtained from the official Minimum Basic Data Set or Résumé Clinique Minimum, which contains summarised clinical and administrative information, plus detailed expenditures (including medications) for each hospital stay. This information allowed us to categorize each stay into an appropriate diagnosis-related group (DRG). Our first descriptive analysis identified a number of major variables that influenced patients' drug expenditures: all-patient DRG (APDRG), age, disease severity, length of stay in an intensive care unit, emergency admission, death during hospitalisation, and hospital type (teaching or general). A covariance analysis was then performed on all hospital stays combined, and separately on surgical and medical stays. The results indicated that these variables taken together account for between 56.5 and 76.3% of drug expenditures in medical and surgical stays, respectively, with the major variance explained by differences in APDRG category. However, when the data were disaggregated according to major diagnosis category, a large degree of heterogeneity in the explained variance was observed. In patients with drug use- and alcohol-related disorders, 5.2% of drug billings/expenditures were attributable to the APDRG, and the corresponding figure in patients undergoing circulatory system surgery was 84%. This means that, if DRGs are used to define a global prospective drug budget for a hospital, using the hospital's historical case mix as a weighting factor, we should pay particular attention to the hospital profile because the predictive power of such a system could be relatively low in some hospitals. Consequently, we need to construct larger confidence intervals for hospitals in which historical drug expenditures have low predictive power, or search for additional explanatory variables for expenditures in these hospitals.

[Is economic rational opposed to medical rational?]. / La rationalité économique s'oppose-t-elle à la rationalité médicale?

Economic and medical rationalities could be conciliated. In a view of relative convergence various administrative decisions and new medicosurgical strategies are highlighted. The role of centres promoting continuous medical formation is stressed. They should also organize repetitive information campaigns.

[Drug antagonism]. / A propos des antagonismes médicamenteux.

The mechanisms responsible of either a loss of therapeutic efficiency or a beneficial cancellation of toxic phenomena are reviewed. References are specifically made to antagonists of anti-vitamin K, oral contraceptives, antihypertensive drugs and statin. Concerning the antidotes, the importance of anti-digoxin antibodies, naloxone and flumazenil is emphasised.

Current status of antidotal therapies in acute human intoxications.

The purpose of this work is a review of usefulness, indications and handling of some antidotes which are at our disposal for therapeutic use since several years, especially naloxone, flumazenil, Fab fragments of digoxin specific antibodies, hydroxocobalamine, 4-methyl-pyrazole, N-acetylcystein or the new metal chelators. Older clinically relevant substances are also reviewed.