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Adverse effects of ketoconazole in dogs ? A retrospective study
Veterinary Dermatology
Abstract
Although ketoconazole has been used extensively in dogs for the treatment of various fungal infections, information about adverse effects is mainly anecdotal. Common adverse effects in humans include dose-dependant anorexia, nausea and vomiting, allergic rashes and pruritus. Drug-induced hepatitis is very rare, but potentially fatal. The aim of this study was to evaluate the type and frequency of adverse effects associated with ketoconazole therapy in dogs treated for skin diseases and any possible influence of dosage, duration of therapy, signalment or concurrent medication. The medical records of 632 dogs treated with ketoconazole (2.6-33.4 mg/kg) were reviewed. Adverse effects occurred in 14.6% (92 dogs) and included vomiting (7.1%), anorexia (4.9%), lethargy (1.9%), diarrhea (1.1%), pruritus (0.6%), erythema (0.3%) and other adverse effects (2.5%). Of the dogs with other adverse effects, four of 16 (25%) were ataxic and three of these received concurrent ivermectin. Adverse effects were significantly more often recorded in dogs concurrently treated with ciclosporin (P = 0.034) or ivermectin (P = 0.007). Increased liver enzyme levels were reported rarely, and icterus was not seen in any of the dogs. However, monitoring liver enzymes during therapy is recommended, although this might not necessarily prevent severe idiosyncratic hepatotoxicity.
... In dogs, Malassezia overgrowth is recognised as a complication in hypersensitivity disorders, keratinisation defects, endocrine dermatoses, immunologic dysfunction, staphylococcal pyoderma, and long-term glucocorticoid therapy. Genetic predisposition is suspected in certain breeds and West Highland white terrier, basset hound, Shih Tzu, American cocker spaniel, and Cavalier King Charles spaniel are at significantly increased risk for Malassezia dermatitis [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. A recent evidencebased review recommended with fair evidence systemic drugs as ketoconazole or itraconazole and with good evidence topical therapy with 2% miconazole nitrate and 2% chlorhexidine gluconate shampoo for Malassezia dermatitis treatment [21]. ...
... However, only few studies have evaluated the effectiveness of shampoos against Malassezia yeasts in dogs. The efficacy of shampoos containing from 2% to 4% chlorhexidine was demonstrated in vitro [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] as well as in vivo in association with miconazole [5][6][7][8][9][10][11][12][13][14][15][16][17] or alone [11][12][13][14][15][16][17]. Climbazole is a member of the azole chemical group and is incorporated in some veterinary products (shampoos or wipes). ...
... However, only few studies have evaluated the effectiveness of shampoos against Malassezia yeasts in dogs. The efficacy of shampoos containing from 2% to 4% chlorhexidine was demonstrated in vitro [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] as well as in vivo in association with miconazole [5][6][7][8][9][10][11][12][13][14][15][16][17] or alone [11][12][13][14][15][16][17]. Climbazole is a member of the azole chemical group and is incorporated in some veterinary products (shampoos or wipes). ...
Objective of the study:
Shampoo therapy is often recommended for the control of Malassezia overgrowth in dogs. The aim of this study was to evaluate the in vivo activity of a 2% climbazole shampoo against Malassezia pachydermatis yeasts in naturally infected dogs.
Animals:
Eleven research colony Beagles were used.
Materials and methods:
The dogs were distributed randomly into two groups: group A (n=6) and group B (n=5). Group A dogs were washed with a 2% climbazole shampoo, while group B dogs were treated with a physiological shampoo base. The shampoos were applied once weekly for two weeks. The population size of Malassezia yeasts on skin was determined by fungal culture through modified Dixon's medium contact plates pressed on left concave pinna, axillae, groins, perianal area before and after shampoo application. Samples collected were compared by Wilcoxon rank sum test.
Results:
Samples collected after 2% climbazole shampoo application showed a significant and rapid reduction of Malassezia population sizes. One hour after the first climbazole shampoo application, Malassezia reduction was already statistically significant and 15days after the second climbazole shampoo, Malassezia population sizes were still significantly decreased. No significant reduction of Malassezia population sizes was observed in group B dogs.
Conclusion:
The application of a 2% climbazole shampoo significantly reduced Malassezia population sizes on the skin of naturally infected dogs. Application of 2% climbazole shampoo may be useful for the control of Malassezia overgrowth and it may be also proposed as prevention when recurrences are frequent.
... This reduced CSA [32,34]. A retrospective analysis of dogs administered KTZ showed vomiting, anorexia, lethargy, and diarrhea to be the most common adverse effects with drug induced hepatopathy being extremely rare but potentially fatal [171]. Adverse events, particularly those of gastrointestinal upset were reported more commonly with co-administration of CSA and KTZ [171]. ...
... A retrospective analysis of dogs administered KTZ showed vomiting, anorexia, lethargy, and diarrhea to be the most common adverse effects with drug induced hepatopathy being extremely rare but potentially fatal [171]. Adverse events, particularly those of gastrointestinal upset were reported more commonly with co-administration of CSA and KTZ [171]. ...
... However, side effects from CSA have been generally observed to be dose-dependent, supporting the importance of using the lowest effective dose. Though a recent retrospective analysis of the side effects of KTZ in dogs did not indicate that dose was a factor in the number or severity of side effects for KTZ, it has been shown that vomiting occurred more often with co-administration of CSA and KTZ [169,171]. ...
... In most cases the length of treatment for Malassezia dermatitis varies between three and four weeks [18]. However, in some cases the duration of treatment is up to 300 days [19]. In accordance with the recommendations of the ketoconazole manufacturer, therapy of Malassezia dermatitis should be continued for an adequate period of time to ensure mycological cure. ...
... If lesions persist after 8 weeks of treatment, medication should be re-evaluated. Ketoconazole can cause adverse effects in 15% of dogs, most commonly gastrointestinal conditions, but without correlation between adverse effects and duration of therapy [19]. In our case, no gastrointestinal adverse effects such as diarrhoea, vomiting, reduced appetite, were observed. ...
Background
Ketoconazole, an antifungal agent, adversely affects spermatogenesis in rodents, but knowledge on adverse effects of prolonged administration of ketoconazole on the fertility of male dogs is lacking. A case of reversible infertility with azoospermia in a male American Staffordshire terrier treated with ketoconazole is reported here.
Case presentation
A seven-year old male American Staffordshire terrier treated for 3 months with ketoconazole for a persistent Malassezia dermatitis displayed reduced libido and mating of 3 bitches had been unsuccessful. The dog was presented at the clinic 40 days after the treatment had been stopped . At first presentation, low libido and complete absence of sperm in the ejaculate (azoospermia) associated with low testosterone level were found. Repeated examinations revealed that sperm quality and testosterone level had restored 100 days after ketoconazole had been withdrawn. Thereafter, the dog successfully mated 2 bitches .
Conclusion
The treatment with ketoconazole for 3 months may have led to reversible infertility characterized by azoospermia. Therefore, owners of stud dogs should be informed of this risk prior to initiating such treatment and in case of infertility, previous treatment with ketoconazole should be considered as a possible cause.
... Adverse reactions are regularly reported with the use of ketoconazole in dogs; a retrospective study of 632 dogs that received a median daily dose of 10 mg/kg reported adverse effects in 14.6%, including primarily vomiting (7.1%), anorexia (4.9%), lethargy (1.9%) and diarrhoea (1.1%). 429 Adverse effects were significantly more frequent in dogs receiving concurrent ivermectin or ciclosporin. 429 Itraconazole: Itraconazole appears to be effective based on the few clinical trials that have evaluated its efficacy for the treatment of canine Malassezia dermatitis 427,430 (Table 4; SoR B-moderate). ...
... 429 Adverse effects were significantly more frequent in dogs receiving concurrent ivermectin or ciclosporin. 429 Itraconazole: Itraconazole appears to be effective based on the few clinical trials that have evaluated its efficacy for the treatment of canine Malassezia dermatitis 427,430 (Table 4; SoR B-moderate). Two were comparative versus ketoconazole. ...
Background – The genus Malassezia is comprised of a group of lipophilic yeasts that have evolved as skin commensals and opportunistic cutaneous pathogens of a variety of mammals and birds.
Objectives – The objective of this document is to provide the veterinary community and other interested parties with current information on the ecology, pathophysiology, diagnosis, treatment and prevention of skin diseases associated with Malassezia yeasts in dogs and cats.
Methods – The authors served as a Guideline Panel (GP) and reviewed the literature available prior to October 2018. The GP prepared a detailed literature review and made recommendations on selected topics. The World Association of Veterinary Dermatology (WAVD) Clinical Consensus Guideline committee provided guidance and oversight for this process. The document was presented at two international meetings of veterinary dermatology societies, and one international mycology workshop; it was also made available for comment on the WAVD website for a period of six months. Comments were shared with the GP electronically, and responses incorporated into the final document.
Conclusions and clinical importance – There has been a remarkable expansion of knowledge on Malassezia yeasts and their role in animal disease, particularly since the early 1990’s. Malassezia dermatitis in dogs and cats has evolved from a disease of obscurity and controversy on its existence, to now being a routine diagnosis in general veterinary practice. Clinical signs are well-recognised, and diagnostic approaches are well-developed. A range of topical and systemic therapies is known to be effective, especially when predisposing factors are identified and corrected.
... Adverse reactions are regularly reported with the use of ketoconazole in dogs; a retrospective study of 632 dogs that received a median daily dose of 10 mg/kg reported adverse effects in 14.6%, including primarily vomiting (7.1%), anorexia (4.9%), lethargy (1.9%) and diarrhoea (1.1%). 429 Adverse effects were significantly more frequent in dogs receiving concurrent ivermectin or ciclosporin. 429 Itraconazole: Itraconazole appears to be effective based on the few clinical trials that have evaluated its efficacy for the treatment of canine Malassezia dermatitis 427,430 (Table 4; SoR B-moderate). ...
... 429 Adverse effects were significantly more frequent in dogs receiving concurrent ivermectin or ciclosporin. 429 Itraconazole: Itraconazole appears to be effective based on the few clinical trials that have evaluated its efficacy for the treatment of canine Malassezia dermatitis 427,430 (Table 4; SoR B-moderate). Two were comparative versus ketoconazole. ...
Background
The genus Malassezia is comprised of a group of lipophilic yeasts that have evolved as skin commensals and opportunistic cutaneous pathogens of a variety of mammals and birds.
Objectives
The objective of this document is to provide the veterinary community and other interested parties with current information on the ecology, pathophysiology, diagnosis, treatment and prevention of skin diseases associated with Malassezia yeasts in dogs and cats.
Methods and material
The authors served as a Guideline Panel (GP) and reviewed the literature available prior to October 2018. The GP prepared a detailed literature review and made recommendations on selected topics. The World Association of Veterinary Dermatology (WAVD) Clinical Consensus Guideline committee provided guidance and oversight for this process. The document was presented at two international meetings of veterinary dermatology societies and one international mycology workshop; it was made available for comment on the WAVD website for a period of six months. Comments were shared with the GP electronically and responses incorporated into the final document.
Conclusions and clinical importance
There has been a remarkable expansion of knowledge on Malassezia yeasts and their role in animal disease, particularly since the early 1990's. Malassezia dermatitis in dogs and cats has evolved from a disease of obscurity and controversy on its existence, to now being a routine diagnosis in general veterinary practice. Clinical signs are well recognised and diagnostic approaches are well developed. A range of topical and systemic therapies is known to be effective, especially when predisposing factors are identified and corrected.
... In addition, a large retrospective study indicated that adverse effects were relatively uncommon (14.6%) in dogs treated with ketoconazole for skin disorders, and the most common adverse effect was GI disturbance. 25 Increased liver enzyme activities were reported rarely and the adverse effects were considered idiosyncratic and not dose-dependent. 25 In this case, the dog did not have abnormal liver enzyme activities despite receiving a high dose of ketoconazole, which supports that alterations in liver enzyme activity after receiving this drug may be idiosyncratic in nature. ...
... 25 Increased liver enzyme activities were reported rarely and the adverse effects were considered idiosyncratic and not dose-dependent. 25 In this case, the dog did not have abnormal liver enzyme activities despite receiving a high dose of ketoconazole, which supports that alterations in liver enzyme activity after receiving this drug may be idiosyncratic in nature. ...
A 11‐year‐old male neutered Shih Tzu was referred to a tertiary facility with a history of weight loss, decreased appetite, polydipsia, and lethargy. The dog had a 10‐year history of nonspecific allergic dermatitis and was being treated with 16 mg/kg of ketoconazole q12h for Malassezia dermatitis. Vague gastrointestinal signs, hypocholesterolemia, and lack of a stress leukogram increased suspicion for hypoadrenocorticism (HA). An adrenocorticotropic hormone (ACTH) stimulation test identified hypocortisolemia on pre‐ and post‐ACTH samples and ketoconazole was discontinued. After a short course of corticosteroid treatment, an ACTH stimulation test was repeated and pre‐ACTH cortisol concentration was within the reference range, and the post‐ACTH cortisol concentration was mildly increased. The temporal association between return of adequate adrenocortical cortisol production and discontinuation of ketoconazole led to the conclusion that the dog had developed iatrogenic HA secondary to ketoconazole treatment.
... 3 In a retrospective study of 632 dogs treated with systemic ketoconazole for skin disorders, the frequency of adverse effects of ketoconazole therapy was close to 15%. 4 Topical treatment can reduce the cost and adverse effects associated with systemic antifungal treatment. Furthermore, antifungal resistance may arise and topical treatment may be a good alternative for the treatment of M. pachydermatis dermatitis. ...
Background
Treatment of Malassezia pachydermatis dermatitis can be performed by systemic or topical route. As M. pachydermatis is located on the stratum corneum, topical therapy alone may be sufficient to resolve the infection. Owing to systemic antifungal resistance and adverse effects, topical treatment alone may improve treatment outcome.
Hypothesis/Objectives
To evaluate the efficacy of a topical spray composed of sodium benzoate, alcohol and botanical oils, compared to a shampoo containing 2% chlorhexidine gluconate and 2% miconazole nitrate for the treatment of Malassezia pachydermaitis dermatitis in dogs.
Animals
Sixteen client owned dogs diagnosed with symmetrical interdigital lesions as a result of secondary Malassezia dermatitis.
Methods
The study design was prospective, randomised and single‐blinded, using a split body protocol. Malassezia yeasts were determined by cytology at the inclusion day (day0) and after treatment (day14). All dogs were treated during 14 days with both shampoo at one paw and spray on the other paw.
Results
At day 14 a reduction of Malassezia dermatitis was shown at both paws. No statistical difference was demonstrated between treatment with shampoo or spray.
Conclusions and clinical importance
We could not show a difference in efficacy between application of the test spray once daily and the topical use of 2%miconazole/2%chlorhexidine shampoo every other day. No adverse effects were reported.
... Posee diversos mecanismos de acción como la inhibición de las enzimas P450 y 11β hidroxilasa (Loose et al, 1983;Loli et al, 1986). Los resultados en felinos con el uso de ketoconazol han sido aleatorios (Dantín et al, 2016) y las respuestas al tratamiento (5-10 mg/Kg dos veces/día) han sido parciales, observándose con frecuencia efectos secundarios (Caney, 2007) como molestias gastrointestinales y en menor medida, toxicidad hepática (Lien et al, 2008;Mayer et al, 2008). ...
El hiperadrenocorticismo felino es una endocrinopatía poco frecuente, caracterizada por niveles elevados de cortisol en sangre. Puede ser causado por afecciones primarias de la hipófisis o de las glándulas adrenales. Los signos clínicos de esta patología incluyen poliuria, polidipsia, polifagia y dermatopatías. La edad promedio de presentación es de 10 años y suele asociarse a otros desórdenes endocrinos, principalmente la diabetes mellitus. El diagnóstico se basa en pruebas de función adrenal y diagnóstico por imagen. La terapia instaurada puede ser médica, quirúrgica o una combinación de las dos.
... However, its efficacy is underwhelming, especially in light of better medical options being available, despite some reports suggesting it to be relatively effective, with improvement of HAC-associated clinical signs in 43 of 48 dogs and survival times comparable to mitotane and trilostane (median survival 810 vs 622 to 852 days, respectively) (Barker et al, 2005;Lien and Huang, 2008;Fracassi et al, 2014). Idiosyncratic ketoconazole-induced hepato-and other toxicity appear to be rare, but therapy is commonly associated with gastrointestinal upset (Lien and Huang, 2008;Mayer et al, 2008). ...
The common causes of hyperadrenocorticism (HAC) are pituitary ACTH-secreting corticotroph tumours, known as pituitary-dependent hyperadrenocorticism, and cortisol-secreting adrenal tumours. The only licensed medical treatment in the UK is trilostane. This treatment improves the clinical signs of HAC in the majority of cats and dogs. There are a number of alternative treatment options that are available for use in non-responders or as first-line treatment instead of trilostane. After a diagnosis of HAC is made, each option should be discussed with clients. This article discusses medical, surgical and radiotherapy options that should be considered to create an individualised treatment plan for each patient and owner.
... Recurrences are in fact one of the most troublesome aspects of CMD. If recurrences are frequent, shampoos and/or topical rinses on a once-or twice-weekly basis or oral ketoconazole every 3 days could be employed [11], but this treatment requires a good pet owner's compliance and the use of ketoconazole for long term therapy can provoke adverse effects [9]. The herbal remedium was well-accepted from both pets and owners, who moreover appreciated good smell of Malacalm 1 , efficiently fighting the strong rancid odor characteristic of CMD. ...
Malassezia pachydermatis is a common cause of more widespread dermatitis in dogs (CMD). Recurrences are common, and this disorder can be very troubling for both dogs and for the pet owner.
The treatment of 20 dogs affected by dermatitis due to M. pachydermatis, with Malacalm(®), a commercially available mixture consisting of essential oils (Citrus aurantium 1%, Lavandula officinalis 1%, Origanum vulgare 0.5%, Origanum majorana 0.5%, Mentha piperita 0.5% and Helichrysum italicum var. italicum 0.5%, in sweet almond oil and coconut oil) is reported. The effectiveness of the whole mixture, of component essential oils and of their more represented compounds against clinical isolates was evaluated by a microdilution test. Twenty animals were topically administered the mixture twice daily for 1 month. Ten animals were treated with a conventional therapy based on ketoconazole 10mg/kg/day and chlorhexidine 2% twice a week for 3 weeks. At the end of both treatments animals significantly improved their clinical status. Adverse effects were never noticed. Follow-up visit performed on day 180th allowed to observe a recurrence of clinical signs in all the subjects treated conventionally, while not significant clinical changes were referred in dogs treated with Malacalm(®). The overall MIC value of Malacalm(®) was 0.3%. O. vulgare showed the lowest minimum inhibitory concentrations (MIC), being active at 0.8%, followed by M. piperita (1%), O. majorana (1.3%), C. aurantium (2%) and L. officinalis (4%) while H. italicum did not yield any antimycotic effect up to 10%. Active major compounds were thymol, carvacrol, p-cymene, 1,8-cineol, limonene and menthol.
The phytotherapic treatment achieved a good clinical outcome, and no recurrence of skin disorders on day 180th was recorded. This herbal remedium appeared to be a safe tool for limiting recurrences of CMD.
... Recurrences are in fact one of the most troublesome aspects of CMD. If recurrences are frequent, shampoos and/or topical rinses on a once-or twice-weekly basis or oral ketoconazole every 3 days could be employed [11], but this treatment requires a good pet owner's compliance and the use of ketoconazole for long term therapy can provoke adverse effects [9]. The herbal remedium was well-accepted from both pets and owners, who moreover appreciated good smell of Malacalm 1 , efficiently fighting the strong rancid odor characteristic of CMD. ...
Objectif
Hôte habituel de la flore cutanée chez le chien, Malassezia pachydermatis est une levure qui est capable dans certains cas, de se multiplier de manière anarchique et de provoquer ainsi une dermatite. Beaucoup d’options thérapeutiques sont envisageables dans le traitement de cette infection mais cela nécessite temps et argent. Et de plus, les récidives sont fréquentes.
Matériels et méthodes
L’objectif de l’étude est d’évaluer l’efficacité clinique de cette mycose vis-à-vis d’un mélange d’huiles essentielles composé de Citrus aurantium 1 %, Lavandula officinalis 1 %, Origanum vulgare 0,5 %, Origanum majorana 0,5 %, Mentha piperita 0,5 % et d’Helichrysum italicum var. italicum 0,5 %, en huiles d’amande douce et de noix de coco comme adjuvant. Le produit est disponible dans le commerce sous le nom de Malacalm® et il s’applique en topique deux fois par jour durant 1 mois lorsqu’une dermatite à Malassezia est diagnostiquée chez un chien. La sensibilité in vitro de 5 souches de M. pachydermatis a été évaluée vis-à-vis de la mixture des composants et des substances les plus représentées. En parallèle, 10 chiens ont été traités par le kétoconazole (10 mg/kg, une fois par jour durant 21 jours) en association avec une solution de chlorexidine à 2 % (deux fois par semaine pendant 21 jours).
Résultats
Au terme des deux protocoles, les animaux traités présentent une amélioration clinique de leur état et aucun effet secondaire n’est constaté. Après six mois, le groupe d’animaux traités avec l’application de kétoconazole et de chlorexidine présente une rechute. La CMI du Malacalm® est de 0,3 %. L’huile essentielle d’O. vulgare se révèle la plus active (CMI 0,8 %), suivie par M. piperita (1 %), O. majorana (1,3 %), C. aurantium (2 %) et L. officinalis (4 %). L’activité antifongique d’H. italicum n’est efficace qu’à partir d’une concentration à 10 %. Les composants les plus actifs sont le thymol, le carvacrole, le p-cymene, le limonène et le menthol.
Conclusion
Le traitement de la dermatite à Malassezia chez le chien à l’aide d’huiles essentielles procure une amélioration clinique et il ne présente aucun effet secondaire après six mois d’application. L’application de ce mélange peut être employée afin de limiter les rechutes de cette infection mycosique.
... Other P-glycoprotein inhibitors, such as ketoconazole or ciclosporin, if given concurrently, increase the likelihood of adverse effects (COE III). 55,56 More recently, an ABCB1-D1 (MDR-1) mutation considered responsible for the acute toxicity in collie dogs and several other herding breeds has been identified. [57][58][59] Testing for this defect is possible. ...
Canine demodicosis, a disease caused by a proliferation of Demodex mites, typically leads to alopecia, comedones, follicular papules and pustules, scaling, and crusting. It may be treated with either amitraz rinses or macrocyclic lactones. Amitraz rinse is approved for application every 2 weeks at a concentration of 0.025%. Higher concentrations and more frequent applications increase the success rate but also increase the risk for adverse effects. Ivermectin is used at 0.3 to 0.6 mg/kg/d PO and moxidectin at 0.2 to 0.5 mg/kg/d PO. Both drugs may cause adverse neurologic effects in sensitive dogs. Milbemycin oxime at 1 to 2 mg/kg/d PO is a safer treatment option. A weekly spot-on combination of 2.5% moxidectin and 10% imidacloprid is recommended for milder forms of the disease.
... Other P-glycoprotein inhibitors, such as ketoconazole or ciclosporin, if given concurrently, increase the likelihood of adverse effects (COE III). 55,56 More recently, an ABCB1-D1 (MDR-1) mutation considered responsible for the acute toxicity in collie dogs and several other herding breeds has been identified. [57][58][59] Testing for this defect is possible. ...
These guidelines were written by an international group of specialists with the aim to provide veterinarians with current recommendations for the diagnosis and treatment of canine demodicosis.
Published studies of the various treatment options were reviewed and summarized. Where evidence in form of published studies was not available, expert consensus formed the base of the recommendations.
Demodicosis can usually be diagnosed by deep skin scrapings or trichograms; in rare cases a skin biopsy may be needed for diagnosis. Immune suppression due to endoparasitism or malnutrition in young dogs and endocrine diseases, neoplasia and chemotherapy in older dogs are considered predisposing factors and should be diagnosed and treated to optimize the therapeutic outcome. Dogs with disease severity requiring parasiticidal therapy should not be bred. Secondary bacterial skin infections frequently complicate the disease and require topical and/or systemic antimicrobial therapy. There is good evidence for the efficacy of weekly amitraz rinses and daily oral macrocyclic lactones such as milbemycin oxime, ivermectin and moxidectin for the treatment of canine demodicosis. Weekly application of topical moxidectin can be useful in dogs with milder forms of the disease. There is some evidence for the efficacy of weekly or twice weekly subcutaneous or oral doramectin. Systemic macrocyclic lactones may cause neurological adverse effects in sensitive dogs, thus a gradual increase to the final therapeutic dose may be prudent (particularly in herding breeds). Treatment should be monitored with monthly skin scrapings and extended beyond clinical and microscopic cure to minimize recurrences.
... Die Nebenwirkungen sollten dann nach 24-48 Stunden abgeklungen sein (19). Manche Medikamente, die ebenfalls in der Leber metabolisiert werden (wie Cyclosporin oder Ketoconazol), erhöhen die Wahrscheinlichkeit von Nebenwirkungen der Ivermectintherapie (17). Bei Hunden mit einer MDR-1-Mutation kann es bei Dosierungen über 100 μg/kg KM zu akutem Koma mit letalem Ausgang kommen. ...
This article briefly reviews pathogenesis, clinics and diagnosis of canine demodicosis and summarizes treatment options for this disease based on published evidence. The disease is caused by excessive proliferation of Demodex mites in the hair follicles that may be due to genetic factors or immunosuppressive diseases or treatments. The disease is characterized by alopecia, papules, pustules and crusts. Diagnosis is confirmed by detection of several mites in deep skin scrapings or trichograms. Based on published studies, licensed successful treatments for many patients are weekly amitraz rinses in a concentration of 0.05% and (in dogs with mild to moderate clinical signs) weekly spot-ons containing moxidectin. In severe, treatment-resistant cases, daily oral macrocyclic lactones such as milbemycin oxim (1-2 mg/kg), ivermectin or moxidectin (0.3 mg/kg after daily gradual dose increases from 0.05mg/kg) may be used. Doramectin orally or subcutaneously at 0.6 mg/kg has also been reported as successful therapy. Secondary bacterial skin infections are common and should be treated with antimicrobial shampoos and possibly oral antibiotics.
... However, coadministration of cyclosporine with either ketoconazole or diltiazem exposes the animal to the inherent risks associated with the boosting agent. In fact, a recent report found a 15% frequency for adverse effects during ketoconazole therapy, with vomiting, anorexia, lethargy and diarrhoea being the most common (Mayer et al., 2008). ...
Hanley, M. J., Cerundolo, R., Radwanski, N., Court, M. H. Grapefruit juice, lyophilized grapefruit juice, and powdered whole grapefruit inhibit cytochrome P450-mediated triazolam hydroxylation by beagle dog liver microsomes. J. vet. Pharmacol. Therap. 33, 189–195.
Coadministration of grapefruit juice (GFJ) has been proposed to enhance the systemic availability and decrease the required dose of drugs such as cyclosporine that are extensively metabolized in the intestine and liver. Although GFJ inhibits human cytochrome P450 (CYP) 3A, effects on dog CYP have not yet been reported. Consequently, we determined whether GFJ inhibits triazolam hydroxylation by Beagle dog liver microsomes (DLM) using human liver microsomes (HLM) as positive control. Results were compared with the effects of lyophilized GFJ and commercially-available powdered grapefruit capsules, which may be more convenient dosage forms. GFJ inhibited α-hydroxytriazolam formation in both DLM and HLM with similar IC50 (inhibitor concentration producing a 50% decrease in reaction velocity) values of 0.56% and 0.52% (v/v), respectively. Lyophilized GFJ and powdered grapefruit also inhibited DLM α-hydroxytriazolam formation with IC50 values of 0.76 and 1.2 mg/mL, respectively. Consistent with mechanism-based enzyme inhibition, preincubation of DLM with any of the grapefruit products for 20 min resulted in significant enhancement of inhibition of triazolam α-hydroxylation by 8–20%. The results indicate that 16 g of lyophilized GFJ or 23 g of powdered grapefruit would be equivalent to dosing 100 mL of GFJ. In vivo pharmacokinetic interaction studies are needed to confirm these in vitro findings.
Background
Perianal fistulas are painful ulcers or sinus tracts that disproportionately affect German shepherd dogs and are proposed as a spontaneous animal model of fistulising Crohn's disease.
Objectives
To characterise the rectal and cutaneous microbiota in German shepherd dogs with perianal fistulas and to investigate longitudinal shifts with lesion resolution during immunomodulatory therapy.
Animals
Eleven German shepherd dogs with perianal fistulas and 15 healthy German shepherd dogs.
Materials and Methods
Affected dogs were evaluated and swabbed at three visits, 30 days apart, while undergoing treatment with ciclosporin and ketoconazole. Healthy German shepherd dogs were contemporaneously sampled. Sites included the rectum, perianal skin and axilla. The microbiome was evaluated following sequencing of the V4 hypervariable region of the 16S ribosomal RNA (rRNA) gene.
Results
Alpha diversity was not significantly different between healthy and affected dogs at each of the three body sites (p > 0.5), yet rectal and perianal beta diversities from affected dogs differed significantly from those of healthy dogs at Day 0 (p = 0.004). Rectal and perianal relative abundance of Prevotella spp. increased and perianal Staphylococcus spp. relative abundance decreased in affected dogs over time, coincident with lesion resolution.
Conclusions and Clinical Relevance
Changes in lesional cutaneous and rectal microbiota occur in German shepherd dogs with perianal fistulas and shift over time with lesion resolution during immunomodulatory therapy. Further investigations of the role of cutaneous and enteric microbiota in the pathogenesis of perianal fistulas, and whether manipulation of microbial populations may ameliorate disease, are needed.
A 10‐year‐old, 8.9‐kg, spayed, female Jack Russell Terrier, with previously well‐controlled diabetes mellitus, presented with hyporexia of 2‐day duration. Cranial abdominal pain and weight loss were detected on clinical examination. Blood tests, urinalysis, urine protein:creatinine ratio, blood pressure, abdominal ultrasound and liver aspirate cytology revealed hyperglycaemia, elevated serum liver enzyme activities, glucosuria, proteinuria, hypertension, rounded liver edges, irregular hyperechoic gall bladder wall thickening, irregular hyperechoic gall bladder content and vacuolar hepatopathy. Bile cytological examination demonstrated fungal organisms, which were identified as Candida albicans on bile fungal culture. No bacteria were detected on bile cytological examination or bile bacterial aerobic and anaerobic culture. The dog was diagnosed with Candida albicans cholecystitis and recovered after a 12‐week course of oral ketoconazole. This case report highlights the value of performing bile cytology in suspect canine cholecystitis cases and is the first to describe Candida albicans fungal cholecystitis without bacterial coinfection in dogs.
Many previous studies presented the effectiveness of ketoconazole (KTZ) against leishmaniasis. However, the bioavailability and therapeutic efficacy of free KTZ are limited due to its low aqueous solubility. In this study, an inclusion complex (IC6HKTZ) was prepared with p-sulfonic acid calix[6]arene (CX6SO3H) to improve the solubility and efficacy of KTZ against Leishmania amazonensis and Leishmania infantum promastigotes. A linear increase in KTZ solubility as a function of CX6SO3H concentration was verified using the phase-solubility diagram. The resulting diagram was classified as AL-type and a 1:1 host-guest stoichiometry was assumed to prepare IC6HKTZ by freeze-drying. FTIR, TG/DSC, XRD, and solid-state 13C NMR spectroscopy analyses were performed to confirm the formation of IC6HKTZ. The solubility enhancement of KTZ by 120.00 μM CX6SO3H was about 95 times. The IC50 values of IC6HKTZ and free KTZ were 3.95 and 14.35 μM for Leishmania amazonensis and 6.74 and 17.47 μM for Leishmania infantum, respectively. The viability of DH82 macrophages was not affected by CX6SO3H. These results show that CX6SO3H is a new supramolecular carrier system that improves antileishmanial activities to KTZ for the treatment of cutaneous and visceral leishmaniasis.
Fungi may cause a wide variety of diseases from localized infections to fatal disseminated diseases in animals and humans. Fungal diseases have increased in importance over the last few decades and cause significant morbidity and mortality in dogs. Fungal infections may be confined to the surface of the body or may become systemic infection characterized by entry of the fungus into the dog and subsequent spread to various tissues of the body. Fungal infections are largely acquired via inhalation, ingestion, or through the skin. Some fungal diseases in the dogs are zoonotic, and the dogs can be responsible for transmission of these agents to the owner. Diagnosis of fungal infections in the dogs is challenging due to some limitations including the lack of specific signs and symptoms in the early stage of infection, diminishing number of clinical mycologists, cost, and lack of fast and accurate diagnostic tests. Early diagnosis of fungal infection is critical for effective treatment and reduces morbidity, mortality, and treatment cost. Chemotherapy is generally used for the treatment of fungal diseases. Antifungal drugs licensed for systematic use in dogs have been limited to a few agents and are often expensive and highly toxic to the dogs. Thus, limited therapeutic options exist for systemic form. Therapy with these drugs is often more prolonged than antibacterial therapy. The aim of this chapter is to review the most common fungal infections in dogs, including aspergillosis, dermatophytosis, blastomycosis, histoplasmosis, rhinosporidiosis, sporotrichosis, geotrichosis, and phaeohyphomycosis, and antifungal agents currently available for therapy.
Objective:
To characterize clinical, clinicopathologic, and hepatic histopathologic features and outcome for dogs with probable ketoconazole-induced liver injury.
Animals:
15 dogs with suspected ketoconazole-induced liver injury that underwent liver biopsy.
Procedures:
Medical record data were summarized regarding signalment, clinical signs, clinicopathologic and hepatic histopathologic findings, concurrent medications, ketoconazole dose, treatment duration, and outcome.
Results:
Median age and body weight were 8.2 years (range, 5 to 15 years) and 13.0 kg (28.6 lb; range, 8.2 to 38.0 kg [18.0 to 83.6 lb]), respectively. The most common breed was Cocker Spaniel (n = 5). All dogs received ketoconazole to treat cutaneous Malassezia infections. Median daily ketoconazole dose was 7.8 mg/kg (3.5 mg/lb; range, 4.4 to 26.0 mg/kg [2.0 to 11.8 mg/lb]), PO. Treatment duration ranged from 0.3 to 100 cumulative weeks (intermittent cyclic administration in some dogs); 6 dogs were treated for ≤ 10 days. Common clinical signs included lethargy, anorexia, and vomiting. All dogs developed high serum liver enzyme activities. Hepatic histopathologic findings included variable lobular injury, mixed inflammatory infiltrates, and conspicuous aggregates of ceroid-lipofuscin-engorged macrophages that marked regions of parenchymal damage. Five dogs developed chronic hepatitis, including 3 with pyogranulomatous inflammation. Of the 10 dogs reported to have died at last follow-up, survival time after illness onset ranged from 0.5 to 165 weeks, with 7 dogs dying of liver-related causes.
Conclusions and clinical relevance:
Findings for dogs with hepatotoxicosis circumstantially associated with ketoconazole treatment suggested proactive monitoring of serum liver enzyme activities is advisable before and sequentially after initiation of such treatment.
A 6-year-old, spayed female, mixed breed boxer dog was presented for decreased appetite, polyuria and polydipsia, and lethargy 9 days after treatment with ketoconazole for Malassezia pododermatitis. Ketoconazoleinduced hypoadrenocorticism was confirmed with an adrenocorticotropic hormone (ACTH) stimulation test, and ketoconazole was discontinued. Clinical signs resolved 48 hours after initiation of prednisone, and resolution of glucocorticoid insufficiency was confirmed with a repeat ACTH stimulation test 48 hours after a 10-day course of prednisone. Glucocorticoid insufficiency after administration of a commonly used dermatological dose of ketoconazole has not been previously reported in veterinary medicine but should be considered in patients with adverse effects while receiving ketoconazole. Key clinical message: Iatrogenic hypoadrenocorticism may occur in dogs treated with commonly used dermatological doses of ketoconazole. The disease is likely transient, but steroid supplementation may be required in some patients to resolve clinical signs, especially in the presence of concurrent illness or stress.
Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.
A 10-year-old spayed female cocker spaniel dog was referred for an evaluation of acute-onset generalized pustular cutaneous lesions following application of ketoconazole shampoo. Cytologic and histopathologic examinations of the lesions revealed intra-epidermal pustules with predominantly neutrophils and acantholytic, cells. This is the first description of putative contact ketoconazole shampoo-triggered pemphigus foliaceus in a dog.
A randomised, double-blinded, placebo-controlled multicentre trial was conducted in 36 dogs with atopic dermatitis to evaluate the cyclosporine-sparing effect of polyunsaturated fatty acids. Dogs were stable on their individual cyclosporine dosage and received either a mainly omega-3 fatty acid product with a minor omega-6 fatty acid fraction or placebo, orally for 12 weeks. Dogs were examined every 4 weeks and the Canine Atopic Dermatitis Extent and Severity Index (CADESI-03) was determined by a clinician. Pruritus, quality of life, global condition and coat quality were scored by the owner. If the dog's CADESI-03 and/or pruritus score improved by at least 25% compared with the previous visit, the cyclosporine dosage was decreased by approximately 25%. If the scores deteriorated by at least 25%, the cyclosporine dosage was increased by the same percentage. The median daily cyclosporine dosage/kg bodyweight decreased in the active group from 4.1 mg to 2.6 mg and in the placebo group from 3.5 mg to 3.3 mg over the study period. The difference between the two groups was significant (P = 0.009). The improvement in median pruritus score from inclusion to completion was significantly greater in the active group than in the placebo group (P = 0.04). There was no significant difference in CADESI-03 changes between groups (P = 0.38). The results of this study indicate a cyclosporine-sparing effect of a mainly omega-3 fatty acid supplement in dogs with atopic dermatitis.
Terbinafine (TBF) is known to concentrate and persist in human skin. Its use is increasing in veterinary medicine, but there are limited data concerning its tissue concentration and efficacy in dogs.
(i) Describe TBF accumulation in canine skin; (ii) Integrate pharmacokinetic data with historical minimum inhibitory concentration (MIC) results for Malassezia pachydermatis to verify the currently used dosage of TBF for the treatment of Malassezia dermatitis.
Ten healthy, client-owned dogs.
Dogs were given TBF (generic preparation, 250 mg tablets) 30 mg/kg per os (p.o.) once daily for 21 days. Serum, sebum and stratum corneum (SC) samples were collected on days 1, 5, 7, 11, 14, 21, 28 and 35. High-pressure liquid chromatography was used to determine drug concentrations in samples.
Relevant (mean ± standard deviation) parameters for TBF in serum, paw SC, thorax SC and sebum, respectively, were: maximum concentration (Cmax , μg/mL) 23.59 ± 10.41, 0.31 ± 0.26, 0.30 ± 0.32 and 0.48 ± 0.25; half-life (t1/2 , d) 4.49 ± 2.24, 6.34 ± 5.33, 4.64 ± 3.27 and 5.12 ± 3.33; time to maximum concentration (Tmax , d) 10.40 ± 6.98, 13.20 ± 5.16, 11.90 ± 8.62 and 10.60 ± 3.69.
These results suggest that TBF does not achieve high concentrations in canine SC or sebum compared to serum. The mean Cmax of all skin tissues (paw SC, thorax SC and sebum) barely exceeded the reported Malassezia MIC90, of 0.25 μg/mL, which indicates that doses higher than 30 mg/kg p.o. once daily may be necessary.
© 2015 ESVD and ACVD.
Le traitement des dermatophytoses du chien et du chat repose sur des principes thérapeutiques validés selon les recommandations de la médecine factuelle. Cet article expose les recommandations d’un groupe d’experts quant aux différentes modalités thérapeutiques systémiques, topiques et environnementales des dermatophytoses canines et félines et propose une classification des principales molécules disponibles en médecine vétérinaire.
Fungi are emerging as important nosocomial pathogens causing considerable morbidity and mortality in hospitalized patients. In vitro antifungal susceptibility tests differ from the usceptibility tests performed against bacteria in that a given fungal species may be in the form of yeast or of filamentous fungi. In vitro and laboratory animal model studies have begun to define the pharmacodynamic characteristics of antifungal agents. This chapter discusses the antifungal drugs for systemic administration. These drugs include allylamines, polyenes, flucytosine, azoles, imidazoles, triazoles, and echinocandins. It outlines the mechanism of action, antimicrobial activity, resistance, pharmacokinetic properties, drug interactions, toxicity and adverse effects, administration and dosage, and clinical applications of antifungal drugs. The chapter talks about the topical applications of griseofulvin, iodides, lufenuron, natamycin, nystatin, and azole antibiotics.
Malassezia dermatitis was seen in 2 of 91 atopic dogs and in 20% of food-allergic dogs, while earlier studies omit yeast-related disease. The yeast Malassezia pachydermatis began to be recognized as an important canine skin pathogen in the early 1990s. The aim to prevent recurrences of microbial skin infections in allergic patients should focus in the first instance on an optimization of treatment of the primary hypersensitivity. Thus, in some allergic dogs, once microbial infection has been resolved, relapses of infection may be prevented using anti-inflammatory medications. Dogs with a history of meticillin-resistant Staphylococcus aureus (MRSA) or meticillin-resistant Staphylococcus pseudintermedius (MRSP) infection require more complex follow-up procedures in order to prevent recurrences of infection with multidrug-resistant bacteria. Around 80% of staphylococcal infections are thought to be caused by endogenous bacteria, i.e. those that are found colonizing the patient as part of the microflora.
A Chinese shar pei with a 2 yr history of episodic fever, lethargy, and shifting lameness was presumptively diagnosed with familial shar pei fever but had never been treated for the syndrome. After being presented for a superficial pyoderma with possible dermatophyte coinfection, treatment with a cephalosporin and ketoconazole were prescribed. One wk later, colchicine was initiated for familial shar pei fever using cautious dose escalation. Nevertheless, gastrointestinal toxicity, skeletal muscle myopathy, and hepatotoxicity developed within 2 wk. Abrupt resolution of gastrointestinal toxicity and myopathy followed drug withdrawal. However, escalating liver enzyme activity and hyperbilirubinemia led to liver biopsy to rule out an antecedent hepatopathy. Biopsy characterized canalicular cholestasis and colchicine-associated metaphase arrest and ring mitoses reflecting repression of mitotic spindle formation. Signs of illness completely resolved 3 mo after drug discontinuation. Although avoidable adverse interactions between ketoconazole and drugs reliant on cytochrome oxidase biotransformation and/or drug efflux mediated by multiple drug-resistant transporters are well documented in humans, these are rarely reported in veterinary patients. This case exemplifies an important and avoidable ketoconazole/colchicine drug interaction from which the patient completely recovered. The dog tested negative for the canine MDR1 loss of function mutation that also might potentiate colchicine toxicity.
Nausea is a subjective sensation, which often acts as a signal that emesis is imminent. Nausea is a widespread problem that occurs as a clinical sign of disease or as an adverse effect of a drug therapy or surgical procedure. The mechanisms of nausea are complex and the neural pathways are currently poorly understood. This review summarises the current knowledge of nausea mechanisms, the available animal models for nausea research and the anti-nausea properties of commercially available anti-emetic drugs. The review also presents subjective assessment and scoring of nausea. A better understanding of the underlying mechanisms of nausea might reveal potential clinically useful biomarkers for objective measurement of nausea in species of veterinary interest.
Rifampicin has been reported to have potent activity against Staphylococci, including meticillin-resistant Staphylococcus pseudintermedius. There is limited documented information regarding adverse effects and recommendations for serum biochemistry monitoring.
The aims of this retrospective study were as follows: (i) to document the occurrence of adverse events in dogs receiving oral rifampicin; (ii) to determine the relationship between adverse events and the dosage/duration of therapy and concurrent medications; and (iii) to report findings associated with changes on serum alanine aminotransferase (ALT).
Client-owned dogs.
A retrospective review of 344 medical records was carried out. Serum ALT concentrations and adverse effects were recorded and analysed. Correlations between different time intervals (days 0-9, 10-18, 19-27, 28-36 and >36) and serum ALT elevation were compared.
Dogs received 2.9-16 mg/kg/day of rifampicin. Adverse events occurred in 16.27% of dogs (56 of 344) and included vomiting (6.97%), anorexia (6.10%) and lethargy (3.77%). Adverse events were significantly more common in dogs concurrently treated with trimethoprim-sulfamethoxazole (P = 0.018), doxycycline (P = 0.044), levothyroxine sodium (P = 0.044), cephalosporins (P = 0.002) and nonsteroidal anti-inflammatories (P < 0.001). Twenty-five of 94 dogs (26.59%) had serum elevations of ALT. These increases were significantly associated with the duration of therapy during two time periods, 19-27 days (P = 0.04) and >36 days (P = 0.01).
Significant adverse events were noted in association with concurrent drug administration and with serum ALT elevations. Pretreatment and weekly serum biochemistry monitoring is recommended to identify dogs at risk for hepatotoxicosis.
Background:
Ciclosporin (CSA) is approved for the treatment of canine atopic dermatitis. Ciclosporin is metabolized by liver cytochrome P450 enzymes, a process inhibited by ketoconazole (KTZ).
Hypothesis/objectives:
The aims of this study were to determine skin and blood CSA concentrations when CSA was administered alone at 5.0 (Treatment 1) or 2.5 mg/kg (Treatment 2) and when CSA was administered at 2.5 mg/kg concurrently with KTZ at 5 (Treatment 3) or 2.5 mg/kg (Treatment 4). We hypothesized that skin and blood CSA concentrations in Treatment 1 would not differ from those obtained with T3 or T4.
Animals:
In a randomized cross-over study, six healthy research dogs received each of the treatments (Treatment 1, 2, 3 and 4) once daily for 7 days.
Methods:
After the first, fourth and seventh dose for each treatment, a peak and trough skin punch biopsy sample and whole blood sample were collected and analysed with high-performance liquid chromatography-tandem mass spectrometry. Data were analysed using a repeated measures approach with PROC MIXED in SAS. Pairwise comparisons were performed with least squares means and Tukey-Kramer adjustment for multiple comparisons.
Results:
Mean blood CSA concentrations in Treatment 1 were not different from those in Treatment 2 or 4, but were less than in Treatment 3. Mean skin CSA concentrations in Treatment 1 were greater than in Treatment 2, not different from those in Treatment 4, and less than those in Treatment 3.
Conclusions and clinical importance:
Administration of CSA and KTZ concurrently at 2.5 mg/kg each may be as effective as CSA alone at 5.0 mg/kg for treatment of canine atopic dermatitis.
To evaluate the impact of modulation of the membrane-bound efflux pump P-glycoprotein (P-gp) on plasma concentrations of orally administered prednisolone in dogs.
7 healthy adult Beagles.
Each dog received 3 treatments (control [no treatment], rifampicin [100 mg/d, PO, for 21 days, as an inducer of P-gp], and ketoconazole [100 mg/d, PO, for 21 days, as an inhibitor of P-gp]). A single dose of prednisolone (1 mg/kg, PO) was administered on day 8 of each treatment period. There was a 7-day washout period between subsequent treatments. Plasma concentrations of prednisolone were determined by use of a validated liquid chromatography-tandem mass spectrometry method. Duodenum and colon biopsy specimens were obtained endoscopically from anesthetized dogs and assessed for P-gp protein labeling via immunohistochemical analysis and mRNA quantification via real-time PCR assay. Total fecal collection was performed for evaluation of effects of P-gp modulation on digestion of nutrients.
Rifampicin treatment upregulated duodenal P-gp in dogs and significantly reduced the area under the plasma concentration-time curve of prednisolone. Ketoconazole typically downregulated expression of duodenal P-gp, with a subsequent increase in the area under the plasma concentration-time curve of prednisolone. There was a noticeable interindividual difference in response. Digestion of nutrients was not affected. Conclusions and Clinical Relevance: Modulation of P-gp expression influenced plasma concentrations of prednisolone after oral administration in dogs. Thus, treatment response to prednisolone may be influenced by coadministration of P-gp-modulating medications or feed ingredients.
This double-blinded noninferiority clinical trial evaluated the use of oral fluconazole for the treatment of Malassezia dermatitis in dogs by comparing it with use of an accepted therapeutic agent, ketoconazole. Dogs presenting with Malassezia dermatitis were treated with either fluconazole or ketoconazole in addition to cephalexin for concurrent bacterial dermatitis. Statistically significant improvements in cytologic yeast count, clinical signs associated with Malassezia dermatitis, and pruritus were seen with both antifungal treatments. There was no statistical difference between the treatments with regard to the magnitude of reduction in these parameters. These results suggest that fluconazole is at least as effective as ketoconazole for the treatment of dogs with Malassezia dermatitis.
Antifungal therapy has progressed significantly with the development of new drugs directed at various processes in fungal cell metabolism. Within veterinary medicine, treatment options for systemic mycoses remain limited to amphotericin B, ketoconazole, fluconazole, and itraconazole. However, newer triazoles, echinocandins, and lipid-based formulations of amphotericin B are now approved for use in humans. This article provides a comprehensive review of the antifungal medications available for veterinary patients, and includes a brief discussion of the newer, presently cost-prohibitive, antifungal therapies used for systemic mycoses in humans.
The antiparasitic activity of ivermectin depends on the presence of an active drug concentration at the site of parasites location for an adapted length of time. Ivermectin interactions with another concurrently administered drug can occur. Concomitant administration of some drugs can increase the bioavailability of simultaneously administered ivermectin. This can, in some cases, become a useful pharmacological strategy to improve its antiparasitic efficacy and to delay the development of resistance in livestock or, in other cases, lead to adverse drug reactions and toxicities. On the other hand, other interactions can result in lower levels of this drug, determining that moderate resistant residual populations of the parasites may persist to contaminate pastures. The characterisation of ivermectin interactions can be used to predict and optimise the value of the parasiticide effects. This article reviews the pharmacological interactions of ivermectin in several domestic animal species.
The aim of this systematic review was to evaluate the efficacy of antifungal treatments for Malassezia dermatitis in dogs and, when possible, to propose recommendation for or against their use.
Electronic searches were carried out using PubMed MEDLINE®, CABDirect and CONSULTANT database. The volumes of Advances in Veterinary Dermatology , the proceedings of ESVD/ECVD and AAVD/ACVD congresses were hand‐searched for studies relevant to this review. All articles and book chapters discussing treatment of Malassezia dermatitis were scanned for additional citations. Lastly, a request was sent to the Vetderm Listserv to share recent clinical trials. The analysis evaluated study design, methodology quality, subject enrolment quality, type of interventions and outcome measures.
The searches identified 35 articles, and 14 trials that fulfilled the following selection criteria: (i) in vivo clinical trials, (ii) dogs showing clinical lesions of Malassezia dermatitis and (iii) enrolment of at least five dogs. Among these, only eight studies fulfilled the following additional criterion: (iv) prospective in vivo clinical trials reporting clinical and mycological outcome measures. A total number of 14 different treatment protocols included four blinded, randomized and controlled trials (quality of evidence grade A), four controlled studies lacking blinding and/or randomization (grade B), five open uncontrolled trials (grade C) and one descriptive study (grade D).
This systematic review allowed us to recommend, with good evidence, the use of only one topical treatment of Malassezia dermatitis (2% miconazole nitrate +2% chlorhexidine, twice a week for 3 weeks) and with fair evidence the use of two systemic treatments with azole derivatives (ketoconazole, 10 mg kg ⁻¹ day ⁻¹ and itraconazole, 5 mg kg ⁻¹ day ⁻¹ for 3 weeks).
In previous papers we demonstrated that cyclosporin A (CsA) was specifically oxidized in rabbit and human liver by cytochrome P-450IIIA. We therefore anticipated that any drug that is an inducer or an inhibitor of this cytochrome should lead to interaction with CsA when given in association with it. In order to confirm this hypothesis, primary cultures of human hepatocytes and human liver microsomes were used to "reproduce" in vitro clinically significant interactions observed between CsA and drugs known either as specific inducers (i.e., rifampicin) or as specific inhibitors (i.e., erythromycin) of P-450IIIA. Our results were in close agreement with the clinical reports. Human hepatocytes maintained in primary cultures for 72 hr in the presence of 50 microM rifampicin exhibited increased levels of P-450IIIA, determined by Western blot using specific antibodies, and concomitant increase in CsA oxidase activity, determined by HPLC analysis of extra and intracellular media. Conversely, these cultures exhibited erythromycin concentration-dependent decreases in CsA oxidase activity when incubated in the presence of 5, 20, and 100 microM erythromycin. In addition, a Lineweaver-Burk analysis of the erythromycin-mediated inhibition of CsA oxidase activity in human liver microsomes revealed competitive inhibition (with Ki of 75 microM) as expected, this macrolide being a specific substrate of P-450IIIA. Using this experimental approach, 59 molecules representative of 17 different therapeutic classes were screened for inducers and inhibitors of CsA oxidase activity. Our results allowed us to elucidate the molecular mechanism of previously observed, but unexplained, drug interactions involving CsA, and to detect drugs that should interfere with CsA metabolism as inducers or inhibitors. Drugs detected as potential inducers of CsA oxidase included: rifampicin, sulfadimidine, phenobarbital, phenytoin, phenylbutazone, dexamethasone, sulfinpyrazone, and carbamazepine. Drugs detected as potential competitive inhibitors included: triacetyloleandomycin, erythromycin, josamycin, midecamycin, ketoconazole, miconazole, midazolam, nifedipin, diltiazem, verapamil, nicardipine, ergotamine, dihydroergotamine, glibenclamide, bromocriptine, ethynylestradiol, progesterone, cortisol, prednisone, prednisolone, and methylprednisolone. Finally, cefoperazone, cefotaxime, ceftazidime, isoniazide, doxycycline, spiramycin, sulfamethoxazole, norfloxacin, pefloxacin, vancocin, trimethoprim, amphotericin B, valproic acid, quinidine, cimetidine, ranitidine, omeprazole, diclofenac, aspirin, paracetamol, debrisoquine, guanoxan, captopril, furosemide, acetazolamide, sparteine, gliclazide, and imipramine were found not to interfere with the hepatic metabolism of CsA.
Both eucaryotic and procaryotic cells are resistant to a large number of antibiotics because of the activities of export transporters. The most studied transporter in the mammalian ATP-binding cassette transporter superfamily, P glycoprotein (P-gp), ejects many structurally unrelated amphiphilic and lipophilic xenobiotics. Observed clinical interactions and some in vitro studies suggest that azole antifungals may interact with P-gp. Such an interaction could both affect the disposition and exposure to azole antifungal therapeutics and partially explain the clinical drug interactions observed with some antifungals. Using a whole-cell assay in which the retention of a marker substrate is evaluated and quantified, we studied the abilities of the most widely prescribed orally administered azole antifungals to inhibit the function of this transporter. In a cell line presenting an overexpressed amount of the human P-gp transporter, itraconazole and ketoconazole inhibited P-gp function with 50% inhibitory concentrations (IC(50)s) of approximately 2 and approximately 6 microM, respectively. Cyclosporin A was inhibitory with an IC(50) of 1.4 microM in this system. Uniquely, fluconazole had no effect in this assay, a result consistent with known clinical interactions. The effects of these azole antifungals on ATP consumption by P-gp (representing transport activity) were also assessed, and the K(m) values were congruent with the IC(50)s. Therefore, exposure of tissue to the azole antifungals may be modulated by human P-gp, and the clinical interactions of azole antifungals with other drugs may be due, in part, to inhibition of P-gp transport.
Compounds known to modulate P-glycoprotein (P-gp) activity were evaluated in cell monolayers expressing P-gp for their effects on the secretory transport of P-gp substrates paclitaxel, vinblastine, and digoxin. Paclitaxel has been proposed to selectively interact with a binding site on P-gp that is distinct from the vinblastine and digoxin-binding site. Using Madin-Darby canine kidney (MDCK)-multidrug resistance-1 (MDR1), MDCK-wild-type (WT), and Caco-2 cell monolayers, the basal-to-apical (BL-AP) apparent permeability (Papp) of [3H]paclitaxel, [3H]vinblastine, and [3H]digoxin in the presence of various concentrations of a series of structurally diverse P-gp substrates and modulators of P-gp function were determined. MDCK-WT cell monolayers demonstrated active secretory transport of all P-gp substrate probes, although the sensitivity to inhibition by verapamil was lower than that demonstrated in MDCK-MDR1 cell monolayers. When evaluated as competitive inhibitors, several known P-gp substrates had no effect or only a slight modulatory effect on the BL-AP Papp of all probe substrates in MDCK-MDR1 cells. The secretory transport of P-gp substrates in MDCK-WT cells was more sensitive to inhibition by known P-gp modulators compared with MDCK-MDR1 cells. Low concentrations of ketoconazole (1-3 microM) activated the BL-AP Papp of [3H]vinblastine and [3H]digoxin in MDCK-MDR1 cells but not in MDCK-WT or Caco-2 cells. Determination of secretory transport in P-gp expressing cell monolayers, such as MDCK-MDR1 and Caco-2, may be complicated by substrate cooperativity and allosteric binding, which may result in the activation of P-gp. In addition, expression of other efflux transporters in these cell lines introduces additional complexity in distinguishing which transporter is responsible for substrate recognition and transport.
The many methods proposed for causality assessment of adverse drug reaction (ADR) generally rely on algorithms. They have no clear relationship to probabilities, however, a situation we attempted to improve.
Thirty ADR cases corresponding to 32 suspect drugs were randomly selected from the French pharmacovigilance database. The statistical weighting was performed by using a multilinear regression with logit(p) as the dependent variable and seven judgment criteria as independent variables. The best model (i.e., giving the best correlation with the gold standard) was retained for the new causality assessment method.
The weights [logit(p)] for the 21 choices, on average three for each of the seven criteria, ranged from -3.95 to 0.86, secondarily rounded to multiples of 0.5. The correlation between the probability obtained from the final method and the gold standard was quite good (R(2) = .92).
This method based on the rational weighting of seven causality criteria is straightforward to use and provides very good agreement with experts' judgment. Moreover, unlike most classical algorithms, it respects one basic rule of probabilities-namely, a symmetrical probability distribution for drug causation around the .5 neutral position (maximum uncertainty).
Sirolimus is an immunosuppressive drug currently used alone or in combination with cyclosporine. Both drugs undergo extensive metabolism by the CYP 3A enzymes. This study aimed at comparing the activity of recombinant CYP (rCYP) 3A4 and 3A5 toward sirolimus, investigating the effect of cyclosporine on the metabolic rate of these two cytochromes P450 (P450s), as well as the impact of the CYP 3A5*3 polymorphism on that of human liver microsomes (HLMs). Two distinct approaches were used; i.e., the measurement of (1) hydroxy-sirolimus and desmethyl-sirolimus production, and (2) sirolimus depletion by the in vitro half-life method. rCYP 3A5 exhibited a lower intrinsic clearance (CL(int)) for both hydroxylation (0.11 versus 0.24 microl/pmol P450/min) and depletion of sirolimus (0.64 versus 2.36 microl/pmol P450/min) than rCYP 3A4. Similar CL(int) values for hydroxylation, demethylation, and depletion were found when comparing a pool of HLMs carrying at least one CYP 3A5*1 (active) allele with a pool of HLMs not expressing CYP 3A5. This was further confirmed for sirolimus depletion using individual microsome preparations (p = 0.42). A deeper inhibitory effect of cyclosporine on the CL(int) of sirolimus depletion was found for rCYP 3A4 than for rCYP 3A5 (i.e., -44% versus -8% at 0.62 microM, 750 microg/l cyclosporine), and sirolimus metabolism was slightly less inhibited for HLMs expressing CYP 3A5 than not (-38% versus -56%). In the absence of cyclosporine, the CYP 3A5*3 polymorphism may not influence significantly sirolimus metabolism at the hepatic level. However, strong CYP 3A4 inhibition by cyclosporine could unveil the influence of this polymorphism.
A companion article discussed the pharmacology and clinical uses of the more traditional antifungal therapies: polyenes, griseofulvin, and iodides. The availability of newer antifungal drugs, which are often more efficacious with fewer side effects, has led to many safe and effective applications in the management of small animal cutaneous fungal infections. This article describes the pharmacokinetics, modes of action, principal adverse effects, and clinical uses of antifungal agents of the azole (triazoles, imidazoles) and allylamine (terbinafine) classes for treating cutaneous fungal diseases in small animals. Clinical experience gained with the newer antifungals will aid practitioners in choosing appropriate drugs from an expanded armamentarium.
This all-new, comprehensive resource features the latest medical and surgical interventions for cattle, sheep, and goats. Addressing treatment of both the individual animal and herd populations, the book is completely revised to contain only the most current treatments and techniques, written by leading researchers, practitioners, and educators in food animal practice.
A companion article discussed the pharmacology and clinical uses of the more traditional antifungal therapies: polyenes, griseofulvin, and iodides. The availability of newer antifungal drugs, which are often more efficacious with fewer side effects, has led to many safe and effective applications in the management of small animal cutaneous fungal infections. This article describes the pharmacokinetics, modes of action, principal adverse effects, and clinical uses of antifungal agents of the azole (triazoles, imidazoles) and allylamine (terbinafine) classes for treating cutaneous fungal diseases in small animals. Clinical experience gained with the newer antifungals will aid practitioners in choosing appropriate drugs from an expanded armamentarium.
Synopsis: Ketoconazole1 is an imidazole antifungal drug structurally related to the earlier compounds in this series, such as miconazole and econazole. However, while retaining a similarly broad spectrum of antifungal activity, it differs from the earlier members of this group in that it can be administered orally to treat a wide variety of superficial or ‘deep’ fungal infections. In open studies in superficial mycoses orally administered ketoconazole was effective in patients with dermatophyte or yeast skin infections, pityriasis versicolor, onychomycoses and oral or vaginal candidosis. Additionally, results were encouraging in chronic mucocutaneous candidosis. In open studies in systemic mycoses it was effective in patients with systemic candidosis, paracoccidioidomycosis and histoplasmosis, and moderately effective in patients with coccidioidomycosis, chromomycosis or asymptomatic candiduria. Few controlled studies have been performed, and a small number of well-designed comparative studies are needed to more clearly establish the relative efficacy of ketoconazole, particularly with regard to amphotericin B in the systemic mycoses in which amphotericin B has proved useful. Despite some aspects of the drug’s use which require further clarification, ketoconzole will make a major impact in the treatment of fungal infections. The extent to which it may become an ‘agent of choice’ in such conditions will be clarified by wider clinical experience. Antimicrobial Activity: Ketoconazole is active in vitro against a wide range of fungi, with a spectrum of activity which qualitatively resembles that of miconazole, an earlier imidazole antifungal drug. The spectrum of activity includes dermatophytes (e.g. Microsporum, Trichophyton, Epidermophyton), yeasts (e.g. Candida, Cryptococcus neoformans), dimorphic fungi (e.g. Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis) and various other fungi. However, quantitatively ketoconazole was often less active in vitro than other imidazole antifungal drugs with quantitative results showing considerable variation depending on factors such as culture medium, inoculum size, conditions of incubation, etc. Thus, with ketoconazole, in vitro tests in agar media are not necessarily reliable indicators of useful in vivo activity (see below). As with other imidazole antifungals, ketoconazole has some activity in vitro against Gram-positive cocci. Interestingly, it is also active in vitro against some parasites, including chloroquine-sensitive and -resistant Plasmodium falciparum and Leishmania tropica. In in vivo animal models ketoconazole was effective in treating dermatophytic infections in guinea-pigs, and a wide variety of superficial and systemic candidal infections. In mice infected intravenously with Candida albicans, ketoconazole (160mg/kg/day) given orally was more effective than the same dose of miconazole and as comparably effective as amphotericin B given intravenously (0.25 or 1 mg/kg/day). In coccidioidomycosis in mice ‘higher’ doses of ketoconazole (40 to 160mg/kg daily) were effective in preventing mortality, but lower doses were not. In experimental murine cryptococcosis the drug was variably effective depending on the dose and model used. Combined treatment of cryptococcosis with ketoconazole plus amphotericin B tended to be more effective than either drug alone in reducing mortality, but ketoconazole combined with flucytosine was no more effective than ketoconazole alone in eradicating the fungus from spleen tissue of infected animals. ‘Higher’ doses of ketoconazole (160mg/kg/day) reduced mortality in murine blastomycosis and histoplasmosis, in the latter case a combination of ketoconazole and amphotericin B again tending to be more effective than single drug treatment. The mechanism of action of ketoconazole at a biochemical level may be related to disturbances in sterol or fatty acid metabolism, or to effects on oxidative and peroxidative systems resulting in accumulation of toxic endoperoxides within the cell. There is also preliminary evidence suggesting the possibility of a complementary action between imidazole antifungal drugs and host defence cells, but the clinical importance of this (and whether such effects also occur with other antifungal drugs) is not yet clear. Pharmacokinetic Studies: Although the oral bioavailability relative to intravenous administration has not been determined, ketoconazole appears to be well absorbed from the gastrointestinal tract. Peak serum concentrations after a single 200mg dose (about 3 to 4µg/ml) should be clinically useful against many fungal infections. Under conditions of markedly reduced gastric acidity, for example treatment with cimetidine or some antacids, absorption of ketoconazole may be impaired. In animal studies the drug was widely distributed in the body, including to the fur of both rats and guinea-pigs. In man ketoconazole has been detected in urine, saliva, sebum and cerumen after a single dose of 200mg given orally. While the drug was present in varying concentrations in cerebrospinal fluid in a few patients so studied, the extent of penetration into cerebrospinal fluid needs additional clarification. In vitro, ketoconazole is about 99 % bound to human plasma proteins (primarily albumin) at a drug concentration of 1µg/ml. Ketoconazole is extensively metabolised prior to elimination; about 2 to 4 % of total urinary excretion is in the form of unchanged drug. The elimination half-life of the drug in healthy subjects appears to be about 8 hours after a usual dose of 200mg, although shorter values have been reported and this requires further clarification. In patients with renal impairment the disposition of ketoconazole does not seem to be markedly altered, and dosage adjustment in such patients is probably unnecessary. Further studies are needed to clarify the effects of hepatic disease on ketoconazole elimination. Therapeutic Trials: Most of the clinical experience with ketoconazole to date is derived from a series of open international multicentre studies. Many of the patients involved had previously been treated unsuccessfully with other antifungal drugs. In a large proportion of patients, both the initial diagnosis and the evaluation of treatment were based on clinical evaluation confirmed by mycological or serological evidence. Most patients received a dose of ketoconazole 200mg once daily. In superficial mycoses the response rates (remission/marked improvement) in the open multicentre studies were as follows: dermatophytic or yeast skin infections 67 % /21 %, onychomycosis or perionyxis 81% (remission or marked improvement), pityriasis versicolor 92 % /5 %, oral candidosis 77 % / 7 %, vaginal candidosis about 80 % to 90 % (negative cultures after 1 to 4 weeks) and chronic mucocutaneous candidosis 25 % /52 %. In ‘deep’ mycoses the following response rates, expressed similarly, occurred in the open multicentre studies: systemic candidosis about 70 % / 11 %, coccidioidomycosis 13 % / 22 %, paracoccidioidomycosis about 79 % / 16 %, histoplasmosis about 52 % / 32 % and chromomycosis about 24 % / 29 %. Ketoconazole has also been used in open studies in a few patients with various less common fungal infections such as mycetomas, sporotrichosis, lobomycosis, aspergillosis, alternariosis and cryptococcosis, often with encouraging results, but clinical experience in these areas is too limited to clearly evaluate the efficacy of the drug. Only a small number of controlled studies have been performed. Ketoconazole 200mg daily was more effective than griseofulvin 250mg daily (ultramicrosize) or 500mg daily (microsize) in a few small studies in patients with fungal skin infections usually due to Trichophyton, and was more effective than a placebo in single small studies in patients with pityriasis versicolor or chronic mucocutaneous candidosis. A small number of additional well-designed comparative studies are needed to more clearly define the relative efficacy of ketoconazole, particularly in ‘deep’ fungal infections in which amphotericin B has been useful. Most patients treated to date have not been followed up for adequate periods to determine the likelihood of relapse after ketoconazole therapy. Similarly, the prophylactic use of ketoconazole to prevent relapse has not been adequately studied, although preliminary findings suggest this may be worthwhile in some conditions. Only limited information exists on the treatment of fungal meningitis with orally administered ketoconazole, and it is unclear at present whether use of this drug alone is appropriate in such patients. Side Effects: Ketoconazole is well tolerated by most patients. Gastrointestinal reactions (about 5 % ) or pruritus (about 2 % ) occur most frequently, occasionally necessitating a dosage reduction or discontinuing treatment. Gynaecomastia has been reported in a few male patients on either usual or ‘higher’ doses. Transiently elevated liver enzymes occurred in about 10 % of patients, and symptomatic liver dysfunction during ketoconazole administration has occurred in a few patients but resolved on discontinuing therapy. Various other ‘side effects’, including dizziness, somnolence, arthralgia, myalgia, headache and many others have been reported, but only in 1 or a few of 1361 patients studied, and their association with drug treatment is open to question. Overall, treatment was permanently discontinued due to side effects in 1.5 % of these patients and temporarily discontinued in 1.3 %. In 62 children treated with the drug 2 cases of side effects were reported —transient fever and chills in one child and persistent nausea and vomiting in another, the latter necessitating discontinuation of therapy. Dosage and Administration: For all conditions except vaginal candidosis the initial recommended adult dosage is 200mg once daily. If the clinical response is inadequate, the dose may be increased to 400 or 600mg once daily, but there is little evidence to support an improved response with ‘higher’ doses. In vaginal candidosis the recommended dosage schedule is 200mg twice daily for 5 days. The duration of treatment should be individualised, and based on clinical and mycological response. Generally, in ‘deep’ mycoses treatment should be continued for at least 1 week after apparent eradication of the infecting fungus. Continued prophylactic use to prevent relapse may be appropriate in some conditions, although this has not been well studied. In children the recommended dose is 20mg 3 times daily for those weighing up to 15kg, 100mg once daily for those weighing between 15 and 30kg and 200mg once daily for those weighing 30kg or more.
Given the limited data available from clinical trials, it is not easy to make an early, accurate assessment of a new drug. Ketoconazole, initially known by its development number, R 41400, is no exception. At this point, ketoconazole seems to be a highly efficacious, broadspectrum, oral antifungal agent that may be the most important drug of its class ever developed.
Résumé— Cet article est une revue des antifongiques systémiques communément utilisés. Sont présentés les origines des diverses substances, leur pharmacocinétique, leur mode d'action, leurs effets secondaires et enfin, leurs indications en médecine vétérinaire. [Hill, P.B., Moriello, K.A., Shaw, S.E. A review of systemic antifungal agents (Antifongiques systémiques: une revue).
Abstract— This paper is a review of commonly used systemic antifungal antibiotics. Included is a review of the origins of the drugs, pharmacokinetics, modes of action, adverse effects and clinical uses in veterinary medicine.
Publicado en 1982 Incluye bibliografía e índice
Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p greater than 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p greater than 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p less than 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p greater than 0.05). We conclude from these new observations that the KC-induced decrease in CsA Cl(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5-10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.
Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.
The most serious side effect of ketoconazole is hepatitis, which has proved fatal in seven reported cases. We present a case of fulminant hepatic failure in a 45-year-old Oriental woman that probably would have been fatal except for a successful liver transplant. A review of the literature of fatalities associated with ketoconazole is presented.
Several reports have demonstrated the efficacy of topical ketoconazole in dermatologic conditions that are not exclusively related to fungi. Some basic pharmacologic studies have indicated effects of ketoconazole on cholesterol production in keratinocytes, on the 5-lipoxygenase enzyme, and on the metabolism of all-trans-retinoic acid in the skin. These observations have led to the hypothesis that topically applied ketoconazole may possess antiinflammatory properties. This hypothesis was tested in an animal model in which living and killed Staphylococcus aureus applied to the backs of guinea pigs resulted in inflammation with erythema and hyperkeratosis. Ketoconazole 0.5% or 2% was applied topically once daily in an ointment base, either as monotherapy or in combination with hydrocortisone acetate 1%. In addition, untreated, excipient-treated, and hydrocortisone acetate-treated animals were included in the study design. All groups consisted of 10 animals that were observed and scored daily up to 3 days after the experimental therapy was stopped. In the animal model involving killed bacteria (i.e., no infection), topical ketoconazole had antiinflammatory activity comparable to that of hydrocortisone acetate. The activity of ketoconazole on the skin of animals infected with living bacteria (i.e., active bacterial infection) was superior to that of steroid therapy, which suggests some antibacterial effect of topically applied ketoconazole. The combination therapy was highly active under both conditions. These results suggest that, apart from the known antimycotic effects of ketoconazole, this molecule might also have effects against gram-positive bacteria at the high concentrations obtained after local application.(ABSTRACT TRUNCATED AT 250 WORDS)
The ergosterol biosynthesis-inhibiting (EBI) antifungals constitute the most important group of compounds developed for the control of fungal diseases in man. Currently, representatives of two classes of EBI antifungals are available: the squalene epoxidase inhibitors and those that interfere with cytochrome P450-dependent ergosterol synthesis. The allylamines (eg, terbinafine) inhibit squalene epoxidase in sensitive fungi, Trichophyton mentagrophytes being the most sensitive species. The most important developments have come from the introduction of the N-substituted imidazoles and triazoles, the so-called azole antifungals. Most of the currently available imidazoles (eg, miconazole, clotrimazole, econazole) and the triazole derivative terconazole are mainly for topical treatment. Ketoconazole was the first azole derivative orally active against yeasts, dermatophytes and dimorphic fungi. The new triazole, itraconazole, appears to be among the most promising orally active systemic agents. All the azole antifungals inhibit the cytochrome P450-dependent, 14 alpha-demethylase, a key enzyme in the synthesis of ergosterol, the main sterol in most fungal cells. Of all the azoles tested, itraconazole shows the highest affinity for the cytochrome P450 involved. It is about three and ten times more active in vitro than miconazole and the bis-triazole, fluconazole, respectively. Itraconazole's high affinity for the fungal P450 originates from its triazole group as well as from the nonligating lipophilic tail.
Study of influence of ketonazole ou cyclosporin blood concentrations after it had reached steady-state levels in rats. The possibilities that the site of interaction is during metabolism or during absorption were investigated
This article has no abstract; the first 100 words appear below.
Ketoconazole is an imidazole derivative that is chemically related to miconazole (Fig. 1). It is an oral antimycotic agent with broad-spectrum activity and low toxicity.¹²³ The drug is considered to represent an important innovation in the treatment of fungal disease and has been used extensively in clinical practice for the past five years. The development of gynecomastia in some patients treated for mycosis first led to the investigation of the drug's effect on the production of testosterone.⁴,⁵ Thereafter, ketoconazole was shown to be a potent inhibitor of gonadal and adrenal steroid synthesis in vitro and in vivo.⁵⁶⁷⁸⁹¹⁰ The finding of . . .
I am indebted to Dr. Alexander C. Brownie for his comments and suggestions and to Mrs. Esther Olczak for assistance in the preparation of the manuscript.
Source Information
From the Department of Biochemistry, State University of New York at Buffalo, Buffalo, N.Y., and the Institute of Medical Semiotics, University of Padua. Padua, Italy. Address reprint requests to Dr. Sonino at the Institute of Medical Semiotics, University of Padua, via Ospedale 105, 35100 Padua, Italy.
The effect of five imidazole derivatives (metronidazole, tinidazole, clotrimazole, miconazole and ketoconazole) on human polymorphonuclear leucocytes (PMNL) was examined in vitro. Metronidazole and tinidazole had no apparent effect on either PMNL chemotactic response or PMNL fungal/bacterial killing. In contrast, clotrimazole, miconazole and ketoconazole inhibited PMNL chemotaxis. In addition, miconazole and ketoconazole were shown to depress the ability of PMNL to kill bacteria and fungi.
Ketoconazole is a new, orally effective, antifungal agent. It is an imidazole compound and like other antifungals of this group, has a wide spectrum of use. Effectiveness has been shown in a variety of deep fungal infections as well as in superficial infections such as candidiasis, dermatophytosis and tinea versicolor. Although it first appeared to be a remarkably safe agent associated with only minor side effects, with more use it has become apparent that symptomatic drug-induced hepatitis occurs in approximately 1 in 12,000 patients. This idiosyncratic side effect and potential effects on testosterone and cortisol synthesis may limit the use of ketoconazole to deep fungal infections and severe recalcitrant superficial infections of the skin.
Silent and symptomatic hepatic reactions have occurred during ketoconazole treatment. The silent reactions (transient asymptomatic elevations of serum transaminase or alkaline phosphatase levels) may occur at any time during ketoconazole treatment. Asymptomatic increases in liver enzymes may also occur in a sizeable number of patients with fungal disease without any treatment. Symptomatic hepatic reactions have occurred mainly during the first few months of treatment. The estimated incidence of symptomatic reactions is of the order of 1 in 10,000.
Ketoconazole is an imidazole antifungal drug structurally related to the earlier compounds in this series, such as miconazole and econazole. However, while retaining a similarly broad spectrum of antifungal activity, it differs from the earlier members of this group in that it can be administered orally to treat a wide variety of superficial or 'deep' fungal infections. In open studies in superficial mycoses orally administered ketoconazole was effective in patients with dermatophyte or yeast skin infections, pityriasis versicolor, onychomycoses and oral or vaginal candidosis. Additionally, results were encouraging in chronic mucocutaneous candidosis. In open studies in systemic mycoses it was effective in patients with systemic candidosis, paracoccidioidomycosis and histoplasmosis, and moderately effective in patients with coccidioidomycosis, chromomycosis or asymptomatic candiduria. Few controlled studies have been performed, and a small number of well-designed comparative studies are needed to more clearly establish the relative efficacy of ketoconazole, particularly with regard to amphotericin B in the systemic mycoses in which amphotericin B has proved useful. Despite some aspects of the drug's use which require further clarification, ketoconazole will make a major impact in the treatment of fungal infections. The extent to which it may become an 'agent of choice' in such conditions will be clarified by wider clinical experience.
Identifying selective inhibitors of cytochrome P450 isoforms is a useful tool in defining the role of individual cytochrome P450s in the metabolism process. In this study, nine chemical inhibitors were selected based on literature data and were examined for their specificity toward cytochrome P450-mediated reactions in human liver microsomes. Furafylline was a potent, mechanism-based inhibitor for CYP1A2-mediated phenacetin O-deethylation. The probes sulfaphenazole (CYP2C9) and quinidine (CYP2D6) selectively inhibited tolbutamide methylhydroxylation and bufuralol 1'-hydroxylation, respectively. Additionally, the CYP2E1-catalyzed chlorzoxazone 6-hydroxylation was significantly inhibited by diethyldithiocarbamate. Of the CYP3A4 inhibitor probes used, troleandomycin proved to be the most specific for testosterone 6 beta-hydroxylation.
The last decade has witnessed remarkable advances in the therapy for cutaneous fungal diseases. These will have a major impact on the choice of antifungal therapy. To understand these advances traditional therapies for fungal diseases, the polyenes, griseofulvin, older topical agents and the older azoles, will be reviewed first. Part II will focus on recent advances.
The purpose of this article is to review the risk/benefit ratio of the oral antifungals: griseofulvin, ketoconazole, fluconazole, itraconazole, and terbinafine. The reported side effects of each drug have been listed with particular emphasis on the possibility of hepatic damage. All oral antifungal agents cause minor gastrointestinal upset, as well as headache and skin reactions. There is also a rare incidence of reversible hepatic damage. Although the incidence of abnormal liver function tests from oral antifungal therapy is extremely low, patients should be advised to inform their physician if any warning symptoms are noticed.
Historically there has been considerable interest in comparing patterns of biotransformation of xenobiotic chemicals in experimental animal models and humans, e.g. in areas such as drug metabolism and chemical carcinogenesis. With the availability of more basic knowledge it has become possible to attribute the oxidation of selected chemicals to individual cytochrome P450 (P450) enzymes in animals and humans. Further, these P450s can be characterized by their classification into distinct subfamilies, which are defined as having > 59% amino acid sequence identity. Questions arise about how similar these enzymes are with regard to structure and function. More practically, how much can be predicted about reaction specificity and catalysis? In order to address these issues, we need to consider not only the relatedness of P450s from different species but also (i) functional similarity within P450 subfamilies and (ii) the effects of small changes imposed by site-directed mutagenesis. Relationships in the P450 1A, 2A, 2B, 2C, 2D, 2E, 3A, and 17A subfamilies are briefly reviewed. Overall functional similarity is generally seen in subfamily enzymes but many examples exist of important changes in catalysis due to very small differences, even a single conservative amino acid substitution. Some general conclusions are presented about predictability within various P450 subfamilies.
To determine the degree to which the dose of oral cyclosporine (CyA), in healthy dogs, can be decreased by concurrent oral administration of ketoconazole. Dogs in this study were observed for physical or biochemical side effects that might have been caused by the administration of CyA and ketoconazole.
Prospective research study.
Five healthy, intact female Beagle dogs.
CyA was administered orally twice daily to achieve stable whole blood trough levels of 400 to 600 ng/mL. Ketoconazole was added at a low therapeutic dose (average dose: 13.6 mg/kg/d) then at a subtherapeutic dose (average dose: 4.7 mg/kg/d). CyA whole blood trough levels were monitored every 3 to 4 days and maintained at 400 to 600 ng/mL by adjusting CyA doses accordingly. Physical examination, CBC, biochemical profile, and urinalysis were performed at 2-week intervals throughout the study period.
The initial mean dose of CyA required to achieve target blood levels was 14.5 mg/ kg/d. With concurrent ketoconazole (low therapeutic dose, average dose: 13.6 mg/kg/d) and CyA administration, the CyA dose declined to 3.4 mg/kg/day (range: 1.2 to 5.2 mg/kg/d), representing a 75% reduction in CyA dose and monetary savings of 57.8%. At a subtherapeutic dose of ketoconazole (average dose: 4.7 mg/kg/d), combination therapy resulted in a CyA dose of 10.1 mg/kg/day (4.9 to 10.6 mg/kg/d), representing a 38% reduction in CyA dose and monetary savings of 23.8%. Weight loss and transient hypoalbuminemia of unknown clinical significance were observed. Other physical and biochemical evaluations were unremarkable over the 12-week study period.
The oral administration of ketoconazole can be used to reduce substantially the oral CyA dose needed to maintain selected blood levels in healthy dogs.
The oral administration of ketoconazole can result in substantial cost savings to owners of dogs receiving CyA after renal allograft transplantation or for the treatment of autoimmune disease.
1. Ivermectin was extensively metabolized by human liver microsomes to at least 10 metabolites. The structure of many of them (mostly hydroxylated and demethylated) was determined by 1H-NMR and LC/MS. 2. To determine which human cytochrome P450 isoform(s) is responsible for the metabolism of ivermectin, chemical inhibitors including sulphaphenazole, quinidine, furafylline, troleandomycin (TAO) and diethyldithiocarbamate (DDC) were used to evaluate their effect on ivermectin metabolism. TAO, a specific inhibitor of cytochrome P4503A4, was the most potent inhibitor, inhibiting the total metabolism as well as formation of each metabolite. Metabolism was also inhibited by an anti-human cytochrome 3A4 antibody by 90%. 3. When ivermectin was incubated with microsomes from cells expressing CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at 4 mg/ml protein concentrations, metabolic activity was only detected with the microsomes containing CYP3A4. The metabolic profile from cDNA-expressed CYP3A4 microsomes was qualitatively similar to that from human liver microsomes. 4. Thus, cytochrome P4503A4 is the predominant isoform responsible for the metabolism of ivermectin by human liver microsomes.
Decisions on treatment are guided, not only by the potential for benefit, but also by the nature and severity of adverse drug reactions. However, some researchers have found numerous deficiencies in trial reports of adverse effects. We sought to confirm these findings by evaluating trials of drug therapy published in seven eminent medical journals in 1997.
Literature review to determine whether the definition, recording and reporting of adverse drug reactions in clinical trials were in accordance with published recommendations on structured reporting.
Of the 185 trials reviewed, 25 (14%) made no mention of adverse drug reactions. Data in a further 60 (32%) could not be fully evaluated, either because numbers were not given for each treatment arm (31 trials), or because a generic statement was made without full details (29 trials). When adverse drug reactions such as clinical events or patient symptoms were mentioned in the reports, details on how they had been recorded were given in only 14/95 (15%) and 18/104 (17%) trials respectively. Of the 86 trials that mentioned severity of adverse drug reactions, only 42 (49%) stated how severity had been defined. The median amount of space used for safety data in the Results and Discussion sections was 5.8%.
Trial reports often failed to provide details on how adverse drug reactions were defined or recorded. The absence of such methodological information makes comparative evaluation of adverse reaction rates potentially unreliable. Authors and journals should adopt recommendations on the structured reporting of adverse effects.
To evaluate the inhibitory potency of ketoconazole (KTZ) on the metabolic activities of isozymes of cytochrome P-450 (CYP) in dogs.
4 healthy 1-year-old male Beagles.
Hepatic microsomes were harvested from 4 dogs after euthanasia. To investigate the effects of KTZ on CYP metabolic activities, 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam hydrochloride were used as specific substrates for CYP1A1/2, CYP2C21, CYP2D15, and CYP3A12, respectively. The concentrations of metabolites formed by CYP were measured by high-performance liquid chromatography, except for the resorufin concentrations that were measured by a fluorometric method. The reaction velocity-substrate concentration data were analyzed to obtain kinetic variables, including maximum reaction velocity, Michaelis-Menten constant, and inhibitory constant (Ki).
KTZ competitively inhibited 7-ethoxyresorufin O-deethylation and midazolam 4-hydroxylation; it noncompetitively inhibited tolbutamide methylhydroxylation. Bufuralol 1'-hydroxylation was inhibited slightly by KTZ. The mean Ki values of KTZ were 10.6+/-6.0, 170+/-2.5, and 0.180+/-0.131 microM for 7-ethoxyresorufin O-deethylation, tolbutamide methylhydroxylation, and midazolam 4-hydroxylation, respectively.
In dogs, KTZ at a therapeutic dose may change the pharmacokinetics of CYP3A12 substrates as a result of inhibition of their biotransformation. Furthermore, no influence of KTZ on the pharmacokinetics of CYP1A1/2, CYP2C21, and CYP2D15 substrates are likely. In clinical practice, adverse drug effects may develop when KTZ is administered concomitantly with a drug that is primarily metabolized by CYP3A12.
Cyclosporine A and ketoconazole were used as a combined therapy to treat 19 dogs with anal furunculosis. Complete resolution of all lesions was achieved in three to 10 weeks, but recurrences occurred in seven of the 19 dogs (36.8 per cent), with remission periods extending from one to six months for these dogs. Adverse effects of treatment included excessive hair loss, intermittent lethargy, vomiting and decreased appetite in some dogs, but none of the signs were considered serious. The results of treatment are comparable with, if not better than, the surgical alternatives. There is an approximate 70 per cent cost saving over the use of cyclosporine alone.
Methadone is an opioid, which has a high oral bioavailability (>70%) and a long elimination half-life (>20 h) in human beings. The purpose of this study was to evaluate the effects of ketoconazole [a CYP3A and p-glycoprotein (p-gp) inhibitor] and omeprazole (an H+,K(+)-ATPase proton-pump inhibitor) on oral methadone bioavailability in dogs. Six healthy dogs were used in a crossover design. Methadone was administered i.v. (1 mg/kg), orally (2 mg/kg), again orally following oral ketoconazole (10 mg/kg q12 h for two doses), and following omeprazole (1 mg/kg p.o. q12 h for five doses). Plasma concentrations of methadone were analyzed by high-pressure liquid chromatography or fluorescence polarization immunoassay. The mean +/- SD for the elimination half-life, volume of distribution, and clearance were 1.75 +/- 0.25 h, 3.46 +/- 1.09 L/kg, and 25.14 +/- 9.79 mL/min.kg, respectively following i.v. administration. Methadone was not detected in any sample following oral administration alone or following oral administration with omeprazole. Following administration with ketoconazole, detectable concentrations of methadone were present in one dog with a 29% bioavailability. MDR-1 genotyping, encoding p-gp, was normal in all dogs. In contrast to its pharmacokinetics humans, methadone has a short elimination half-life, rapid clearance, and low oral bioavailability in dogs and the extent of absorption is not affected by inhibition of CYP3A, p-gp, and gastric acid secretion.
Antifungal dermatologic agents: azoles and allylamines. Compendium on Continuing Education for the Practicing
- De C Jaham
- Paradis M Papich
- Mg
De Jaham C, Paradis M, Papich MG. Antifungal dermatologic agents: azoles and allylamines. Compendium on Continuing Education for the Practicing Veterinarian Small Animal 2000; 22: 548–59.
Cataracts in dogs after long-term ketoconazole therapy
- P D De Costa
- R E Merideth
- R L Sigler
de Costa PD, Merideth RE, Sigler RL. Cataracts in dogs after
long-term ketoconazole therapy. Veterinary Compendium of
Ophthalmology 1995; 6: 176-80.
II ketoconazolo nella terapia della leishmaniosi del cane
- C D'ambrosio
- C Gallo
- A Agresti
D'Ambrosio C, Gallo C, Agresti A. II ketoconazolo nella terapia
della leishmaniosi del cane. Atti SISVET 1986; 40: 492-6