DISCLAIMER NOTE: Consult your veterinarian before treating your dog for Demodectic Mange. This article is for information purposes only and is not to be used as a substitute for proper veterinary care.

NEW APPROACHES TO THE TREATMENT OF CANINE DEMODICOSIS

Veterinary Clinics Of North America: Small Animal Practice

Manon Paradis, DMV, MScV

Canine demodicosis is an inflammatory parasitic skin disease characterized by an excessive proliferation of Demodex canis mites within the hair follicles. A complete description of canine demodicosis is beyond the scope of this article. The reader is referred to standard textbooks for detailed descriptions. This article concentrates on new therapeutical modalities in regard to this disorder; however, key points are presented to facilitate comprehension.

Canine demodicosis is classified as localized or generalized according to the extent of the disease, as the course and prognosis of the two types of demodicosis are vastly different. Canine localized demodicosis (CLD) is a benign disease, and the presence of secondary pyoderma and pruritus is rare. Most cases resolve spontaneously and uneventfully within 6 to 8 weeks. Although amitraz is approved for use in CLD in some countries (e.g., Canada), it is not a rational treatment. The use of acaricidal treatment does not seem to alter the course of CLD, and it may even favor the development of resistance. In contrast, canine generalized demodicosis (CGD) has been considered historically to be one of the most severe canine skin diseases and is one of the most frustrating diseases to treat. Although spontaneous resolution of CGD has been said to occur in up to 50% of cases in dogs less than 1.5 years of age, the prognosis for CGD is guarded. Fortunately, although euthanasia was common in the past, it is rarely necessary nowadays if a dedicated dog owner uses treatments currently available. With intense treatment (either with an approved protocol or with extralabel use of a drug), over 90% of CGD cases can be cured.

Typically, both CLD and GCD start during puppyhood, but true adult-onset demodicosis can also occur. The latter disease is even more difficult to treat than the juvenile onset CGD unless underlying immunosuppressive disease can be controlled or an exacerbating drug can be withdrawn. Most cases of CGD involve a secondary bacterial skin infection, which requires administration of systemic antibiotics for several weeks concomitantly with the acaricidal treatment.

Over the last few years, several new therapeutical options have become available for the treatment of CGD. The reported therapeutical efficacy of each drug varies greatly as a result of a number of factors, including differences in the populations studied, in the criteria used when differentiating CLD and CGD, in the way "cure" is defined, and in the length of follow-up periods. Therefore, results from various studies are not always easy to compare, but overall efficacy rates are presented and discussed.

LICENSED ACARICIDAL TREATMENT PROTOCOL

Amitraz

Although a number of products have been claimed to be effective in the treatment of CGD, amitraz revolutionized the treatment of CGD approximately two decades ago. Amitraz is an acaricide-insecticide from the formamidine family. Its pharmacological activities include monoamine oxidase inhibition, alpha₂ adrenergic agonist activity, and prostaglandin synthesis inhibition. In 1982, it was approved by the US Food and Drug Administration for use as a topical dip for the treatment of CGD. It still remains the only product licensed for this condition. It is marketed in the United States and Canada as Mitaban (Upjohn, distributed by Janssen-Animal Health, Ontario, Canada), a 19.9% amitraz liquid concentrate that is applied as a 250-ppm amitraz solution (0.025%; 10.6 mL in 7.6 L of water) to the dog's entire body every 2 weeks. Product information dictates that dogs with medium to long hair coats be clipped prior to treatment and that the dipping be continued for at least 2 treatments after negative scrapings, have been obtained. Treatments should be preceded by a shampoo to remove crusts, debris, and bacteria. A benzoyl peroxide shampoo is preferable because of its follicular flushing activity, which allows better penetration of the acaricide. Although it is not necessary to repeat clipping and shampooing before each treatment, it makes sense to shorten the hair coat or remove crusts before treatment when needed. The amitraz solution should be prepared fresh for each application. The solution degrades when exposed to air, and the degraded product may be more toxic. Slightly different amitraz formulations are marketed worldwide (e.g., Ectodex; Hoechst/Roussel, and Taktic). Protocols for its use may vary from country to country. For example, in France, amitraz solution (Ectodex) has been approved since 1995 for use at a final dilution strength of 500 ppm every 5 to 7 days.

Amitraz has reported cure rates ranging from 0% to 99%. This vast discrepancy of reported efficacy is probably related to the different treatment protocols (case selection, different concentrations of amitraz solution, frequency of application) and different criteria for cured cases, including long-term follow-up periods. When amitraz was introduced as a topical acaricide in the early 1980s, several reports stated that biweekly treatment with amitraz was almost 100% effective in resolving CGD. The validity of these reports is marred by a number of factors, however, including the facts that some of these reports included cases of CLD, the researchers defined effectiveness as a return to clinical normalcy, and long term cure was not assessed in follow-up studies. Currently, cure is defined as an animal being disease-free for at least 1 year after treatment is completed. Based on this definition, the actual cure in these early studies would have been less than that reported if any of the dogs subsequently relapsed. In any case, the actual long-term cure rates following biweekly amitraz treatments with a 1 year follow-up interval are probably in the range of 60% to 80% for the typical population of dogs with CGID under 1.5 years of age. Therefore, not all dogs respond to this approved amitraz treatment regimen. When cure is not achieved, the following options are available: increase the frequency of amitraz treatments to weekly or daily, increase the concentration of amitraz from 250 up to 1250 ppm, institute a maintenance program with 250-ppm amitraz dips every 2 to 4 weeks, or employ systemic macrocyclic lactone (ML) endectocides such as milbemycin oxime, ivermectin, or moxidectin.

EXTRA-LABEL PROTOCOLS

Amitraz

In an attempt to increase the clinical efficacy of amitraz, unlicensed protocols have been developed involving more concentrated solutions of the drug applied more frequently. One study reported that improved success rates (78% vs 22%) were achieved by doubling the frequency of treatment to once weekly. In Europe, weekly applications of amitraz at concentrations of 500 to 1000 ppm were reported to be effective and safe in the treatment of CGD. Although results suggest that better cure rates may be achieved when twice the recommended frequency of application is used, it is not known if weekly treatment decreases the time needed for a cure. A cost-effective approach is to start with the licensed biweekly 250-ppm amitraz applications and switch to weekly treatment if mite counts do not decrease over the following 4 to 8 weeks.

Because weekly and biweekly amitraz treatments for CGID were not always effective, daily amitraz applications have also been tried. Two independent studies evaluated the efficacy of a 1250-ppm (0.125%) amitraz solution applied to half of the body daily in dogs with CGD previously refractory to biweekly or weekly amitraz treatments. This treatment was effective in 73% of CGD cases. Thirteen of the 16 cases that resolved did so after one course of treatment, which - ranged from 1 to 5 months in duration. The other 3 cases initially relapsed but were cured after they were retreated. All cases deemed to be cured, including those that initially relapsed, were followed for at least 1 year after their last treatment. This more aggressive daily amitraz dip regimen never gained widespread popularity; because the results were published roughly at the same time that milbemycin and ivermectin were starting to show promising results in the treatment of CGD. Its use may be limited to dogs with refractory demodicosis if other forms of treatment (e.g., ML endectocides) are unacceptable or have failed.

Some cases of pododemodicosis can be chronic and resistant to therapy. In the past, more residual acaricidal activity has been achieved with amitraz mixed with propylene glycol or mineral oil (1:9-1:60 ratios) and painted onto the feet as needed to control the disease. Nowadays, the majority of these recalcitrant pododemodicosis cases are being treated with systemic ML endectocides.

Although the overall reported cure rate with amitraz dips, especially with the daily administration protocol, is relatively high, there are several disadvantages to its use in dogs with CGD, including the fact that topical treatment is tedious, time-consuming, and potentially hazardous, because the owner is exposed to a topical pesticide every time the drug is used. In addition, dogs with medium or long hair coats should be closely clipped on a regular basis throughout the course of the treatment to allow the aqueous solution to contact the skin and better penetrate the hair follicle. To minimize human exposure to the solution, protective clothing and gloves should be worn, and the treatment should be administered in a well-ventilated area. Contact with the animal should be avoided until the coat is dry.

The most common side effects attributed to amitraz treatment in dogs are sedation, pruritus, and hypothermia. Other less common side effects, including anorexia, polyuria, polydipsia, bradycardia, hypotension, hyperglycemia, seizures, ataxia, and, rarely, death, have also been reported. Severe reactions or intoxication can be reversed with alpha ₂ agonist inhibitors such as yohimbine or atipazole. The product information for Mitaban shows an increasing frequency of side effects as the topical concentration increases. Interestingly, none of the dogs treated with the 1250-ppm amitraz solution (i.e., five times the approved concentration) applied to half of their body daily developed side effects."' In that study, however, one human being showed signs of respiratory distress after being exposed to a dog just treated with amitraz solution. Drugs such as hydroxyzine should not be used with amitraz dips, because they both have a monoamine oxidase-inhibiting activity that may potentiate toxicity.

Systemic Macrocyclic Lactone Endectocides

ML endectocides are broad-spectrum antiparasitic agents produced by the fermentation of various actinomycetes. The dual activity of this class of compounds against endoparasites (anthelmintic) and ectoparasites (acaricide and insecticide) gave rise to the term endectocide. ML endectocides include two closely related groups of molecules: avermectins (e.g., ivermectin, abamectin, and eprinomectin) and milbemycins (e.g., milbemycin oxime and moxidectin). They essentially differ by the presence (avermectins) or the absence (milbemycin) of a disaccharide at the C13 position. Milbemycins are actually aglycone avermectins.

All ML endectocides share a similar mode of action. They bind selectively and with high affinity to the glutamate-gated chloride ion channels present in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions. The influx of chloride ions that follows inhibits the electrical activity of nerve cells in nematodes and that of muscle cells in arthropods, causing a rapid nonspastic paralysis and eventual death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels such as those gated by neurotransmitter gamma-aminobutyric acid. In mammals, this inhibitor neurotransmitter system is located within the central nervous system. The wide margin of safety for ML endectocides is attributable to the fact that mammals do not have glutamate-gated chloride channels; these compounds have a low affinity for other mammalian ligand-gated chloride channels and do not readily cross the blood-brain barrier.

Several studies have demonstrated an immunostimulatory effect of ivermectin in human beings and laboratory animals. Results of a recent study suggest that ivermectin does not have an immunostimulatory effect in healthy dogs, however.

Over the last decade, multiple studies have reported the efficacy of the extralabel use of ivermectin, milbemycin oxime, and, more recently, moxidectin in the treatment of CGD.

Milbemycin Oxime

Milbemycin oxime (Interceptor; Novartis), the fermentation product of Streptomyces hygroscopus aureolacrimosus, is approved for use in dogs only as a monthly heartworm and intestinal parasite preventative at a dose of 0.5 mg/kg. Recently, several studies showed that daily administration of milbemycin oxime was effective in the treatment of CGD. The overall remission rate was quite high, but the cure rate was as low as 42% with a dose of approximately 0.5 to 1 mg/kg daily. A reported cure rate of 84.6% has been obtained following an average daily dose of 2.2 mg/kg. The median treatment duration at the higher dose was 13 weeks (range, 9-26 weeks). Side effects were uncommon, but transient stupor, ataxia, and trembling that resolved after discontinuation of the treatment have been seen in two dogs.

Milbemycin oxime is a practical and relatively safe treatment for CGD; however, it is expensive when used for this purpose. Moreover, it is possible that some Collies sensitive to ML endectocides would not tolerate daily administration of milbemycin oxime. A toxicity study with milbemycin oxime was conducted on Collies sensitive to ivermectin. Reactions typical of avermectin toxicity (e.g., depression, ataxia, mydriasis, salivation) occurred in two of five Collies treated with a single dose of 5 mg/kg and in all five dogs treated with a single dose of 10 mg/ kg. Toxicity to daily administration of a relatively high dose (e.g., 2.2 mg/kg) of this compound has not been tested in that breed.

Ivermectin

In dogs, ivermectin (Heartgard; Merial Canada Inc., Baie d'Urfee, Quebec, Canada), the fermentation product of S. avermitilis, is licensed only for the prevention of dirofilariasis at a dosage of 6 pg/kg orally once a month. Ivermectin is widely used in dogs to treat various endo and ectoparasites, typically at dosages between 200 and 400 µg/ kg every 7 (orally) to 14 (subcutaneously or pour-on form) days for a treatment duration of up to 8 weeks. Approximately 15 years ago, various investigators used ivermectin for the treatment of CGD at a dosage of 400 µg/kg subcutaneously weekly, for a total of eight treatments, without any tangible benefit. Daily administration of milbemycin oxime was subsequently found to be effective; however, as ivermectin and milbemycin have a similar mode of action and spectrum of activity, the efficacy of ivermectin was reinvestigated using a higher dose administered daily in an adult dog with chronic CGD. This initial case report showed promising results and stimulated further research using high daily doses of ivermectin. Formulations used orally in these studies were either the 1% propylene glycol-based injectable product (Ivomec, Merial Canada Inc., Baie d'Urfee, Quebec, Canada) for cattle, sheep, and swine or the 1% equine aqueous solution (Eqvalan oral solution for horses, Merial Canada Inc., Baie d'Urfee, Quebec, Canada).

Typically, daily oral doses of ivermectin at 300 to 600 µg/kg of body weight were used in these various protocols, and, in most cases, treatment duration extended 1 month beyond negative skin scrapings. The cure rate was usually dose dependent, and ivermectin was found to be effective in up to 83.3% of dogs with CGD. Mean treatment duration varied between 10 and 18 weeks (range, 10-40 weeks). Transient side effects such as ataxia and mydriasis were seen occasionally a few days to a few weeks after initiating treatment but subsided following withdrawal of ivermectin or a decrease in the dose administered.

A starting dose of 450 to 600 µ/kg every other day has been suggested as a more cost-effective approach based on results of a recent study in which 8 of 12 dogs achieved negative skin scrapings on alternate-day therapy, with the goal of reserving daily dosing for refractory cases. Only 5 of these 12 dogs had been previously treated with amitraz, however, and the cure rate was unknown at the time of publication.

The therapeutical potential of the 0.5% alcohol-based pour-on formulation of ivermectin (Ivomec pour on for cattle, Merial Canada Inc., Baie d'Urfee, Quebec, Canada) for cattle in the treatment of chronic CGD has been evaluated in a recent study because of its presumed longer residual effect compared with that of orally administered ivermectin in dogs. Pour-on ivermectin was applied topically along the dorsal midline at 1500 µg/kg (0.3 mL/kg) three times per week for up to 6 months. Although all dogs had a substantial reduction in the severity of clinical signs and in the number of D. canis mites found on skin scrapings, only 1 of 12 (7%) dogs was cured. The treatment efficacy of the topical formulation may have been negatively affected by the fact that only 7 of 12 dogs completed the 6-month trial. In addition, it is possible that an increased frequency of administration (i.e., 1500 µg/kg every 24 hours) may be more effective. This would render the treatment less practical and similar in cost to the more convenient daily oral ivermectin treatment protocol; at a dose of 600 µg/kg, this has a reported cure rate of 83.3%, thus remaining a more effective and convenient route of administration for use in dogs.

The extra-label use of daily oral ivermectin is a relatively well-documented effective therapeutical alternative in cases of chronic CGD involving resistance or intolerance to amitraz. It is much less expensive than daily milbemycin oxime and easier to administer than daily amitraz applications. Ivermectin therapy can be initiated in several ways. Typically, a dose of 300 to 600 µg/kg daily (or every other day) is selected based on the chronicity and severity of individual cases. As with any other acaricides, dose or frequency of administration can be readjusted if mite counts do not decrease over the following weeks. It has been suggested that the bad taste of ivermectin can be masked by giving it with ice cream or in a cored hot dog.

Ivermectin is potentially toxic, however, and should be considered only if attempts with the conventional CGD treatment have failed. Idiosyncratic toxicity has been reported in Collies and other herding breeds such as Australian Shepherds, Old English Sheepdogs, and Shetland Sheepdogs, as well as in their outcrosses following a single dose as low as 100 µg/kg. These idiosyncratic toxicity reactions include ataxia, behavior disturbances, tremors, mydriasis, weakness/recumbency, apparent blindness, hypersalivation, depression, and, in severe cases, coma and death. A recessive autosomal gene may be responsible for these idiosyncratic reactions in Collies, and it is estimated that up to half of Collies are susceptible to ivermectin toxicity. Greater penetration of ivermectin across the blood-brain barrier occurs in Collies. In nonsusceptible breeds, ivermectin has a wide safety margin. In an acute oral toxicity study, the highest single oral dose without adverse effects was 2000 µg/kg. In a subchronic toxicity study, Beagles were given 500, 1000, and 2000 µg/kg orally once a day for 14 weeks. No drug-related adverse effects were seen at 500 µg/kg daily. Dogs given 1000 µg/kg or more developed mydriasis. At 2000 µg/kg, 50% of the dogs additionally lost a small amount of weight and developed tremors, ataxia, anorexia, and dehydration. One may expect that up to 10% of dogs with CGD (excluding breeds susceptible to ivermectin toxicity) treated with oral daily ivermectin at a dose ranging from 300 to 600 µg/kg may develop mydriasis and possibly ataxia within 2 to 3 weeks after initiation of treatment. The side effects usually subside within days following cessation of ivermectin administration or decrease of the dose.

Moxidectin

Moxidectin is a fermentation product from S. cyaneogriseus. It is available in some countries as a monthly canine heartworm preventative at an oral dose of 3 µg/kg. In addition, a 1% injectable aqueous solution (Cydectin injectable solution; Ayerst) for cattle has been used successfully in cases of CGD.1 A cure rate of 89% (16/18) was obtained following daily oral administration of 400 µg/kg of moxidectin. The mean duration of treatment was 5 months (range, 3-7 months). One dog was in clinical remission but relapsed 12 months after the end of treatment. The other failure was a result of undesirable side effects (lethargy, anorexia, ataxia, and tremors) noted 3 months into treatment. Moxidectin appears to be as effective as ivermectin and milbemycin oxime. The cost of treatment is comparable to that of ivermectin but is much lower than that of milbemycin. Until more information is gathered on its toxicity in dogs, one should take the same precautions as with extra-label use of ivermectin. As moxidectin is more lipophilic than ivermectin, it should be used carefully in thin or debilitated animals. There is indeed a warning in the product information that extra care be taken with calves weighing under 100 kg to ensure that the correct dose is used, particularly if the animals are in poor condition, debilitated, or suffering from infectious diseases, because they may be susceptible to an overdose of moxidectin.

Lufenuron

Lufenuron (Program; Novartis), a benzoylphenyl urea, is an insect development inhibitor for the cat flea Ctenocephalides felis. It acts by blocking the synthesis and deposition of chitin and is both ovicidal and larvicidal. The drug concentrates into the subcutaneous fat and is slowly released into the blood. Chitin is found in the eggshells of Demodex spp. as well as larval, nymphal, and adult exoskeletons. The efficacy of lufenuron for the treatment of CGD was recently investigated. Even at the higher dosage regimen (mean dose of 15.8 mg/kg three times a week for 2 to 3 months), it was found to be ineffective, despite the presence of high concentrations of lufenuron in the epidermis and dermis.

OTHER THERAPEUTICAL CONSIDERATIONS

Treatment of CGD must not focus only on the mites but also on concurrent bacterial pyoderma with topical therapy and systemic antibiotics as well as on identifying other problems such as inadequate nutrition, heavy parasite loads, stressful management situations, and intercurrent systemic disorders. All of these may contribute to the dog's immunosuppression and make it more difficult to resolve the demodicosis. Concurrent topical and systemic glucocorticoid. administration should be avoided. Female dogs should be spayed, as demodicosis may worsen or relapse during estrus, pregnancy, or the postpartum period. Moreover, because of the inheritable nature of juvenile-onset CGD, affected dogs and close relatives should not be used for breeding purposes.

Antimicrobial Therapy

Concurrent pyoderma is present in most cases of CGD and contributes to the dog's immunosuppression. In most cases of pyodemodicosis, the bacterial component must be addressed before topical acaricidal treatment is initiated to lessen skin irritation and to allow better penetration of the acaricidal solution.

Antibiotic selection varies from case to case and should be dictated by the severity and depth of the pyoderma. In most cases, bactericidal agents should be selected because of the probable immunosuppressed state of the dog. In addition, the antibiotic selected should achieve good concentration in the skin and have a low potential for the development of bacterial resistance. A first-generation cephalosporin (cephalexin or cephadroxil) is the antibiotic of choice in most cases of pyodemodicosis. Quinolones (e.g., enrofloxacin, orbifoxacin) are quite effective against staphylococcal infection as well as in many cases of gram-negative infections such as Pseudomonas spp., but they should not be administered to young growing dogs. A cytological examination of the exudate from draining tracts or pustules should be performed to detect the type(s) of bacteria present. Bacterial culture and sensitivity testing is often performed in the presence of deep pyoderma associated with CGD because of the possibility of mixed bacterial infections. The oral antibiotic must be administered at the proper dose and interval for a minimum of 4 weeks and for at least 2 weeks beyond complete healing of the lesions. Typically, antibiotics are administered for 6 to 8 weeks.

Topical Therapy

Topical treatment can be beneficial, especially in the initial management of CGD cases with deep draining infections and cellulitis. The hair coat must be clipped (mandatory for amitraz dips) to prevent the formation of sealing crusts and to allow topical agents to come into contact with the affected skin. Hydrotherapy (whirlpools, warm water soaks, hot packs) helps to remove crusts, decreases the number of bacteria, and promotes healing. Magnesium sulfate (Epsom salts), a mildy hypertonic drawing solution, is usually beneficial during the first few days of treatment when used at 30 mL/L of warm water in the form of soaks or hot packs. Antibacterial or antiseborrheic shampoos (e.g., benzoyl peroxide) can also be used as required.

PROGNOSIS

Although new therapeutical modalities have drastically improved the prognosis for CGD, it still remains impossible to predict which cases are likely to be more recalcitrant. In articles reporting the efficacy of new therapeutical alternatives, the majority of CGD cases were chronic and amitraz resistant. Based on this, one should realize that the overall success rate obtained would most likely have been higher for typical population of dogs with CGD without this selection bias. We can estimate that 10% or less of CGD cases may never obtain a permanent cure in spite of the use of adequately followed approved treatment protocols or new extra-label alternatives.

An important cause of relapse is premature cessation of therapy. Indeed, if relapse occurs within the first 3 months after treatment has been terminated, it is most likely that the duration of therapy was inadequate (considering the 30-day life cycle of the mite, it would be difficult for a few mites to replicate to a sufficient number to cause clinical disease within 3 months). When relapses occur late (e.g., several months after treatment has been terminated), it is the dog that failed rather than the treatment protocol (in spite of our current definition of cure and failure). In any case, in this situation, cure would be unlikely with a repetition of the same protocol. The recommendation would then be to either recommence the same protocol on an intermittent basis as required for the dog's entire life, to use the same drug on a maintenance level to prevent recurrence of clinical signs, to use a more effective alternative treatment regimen if available, or to consider simultaneous topical (e.g., amitraz) and systemic (e.g., ML endectocide) treatment. Drug interaction is unlikely, as the pharmacology of these two types of drugs is different. Nevertheless, no studies have proven that simultaneous topical and systemic treatment, with its added effort and expense, is more effective or significantly shortens the overall course of treatment.

SUMMARY

Topical amitraz is the only approved treatment for CGD; however, it is not always effective or well tolerated. Extra-label use of amitraz, milbemycin oxime, ivermectin, and moxidectin may be effective therapeutical alternatives for dogs with resistant CGD or dogs that have an intolerance to the licensed amitraz protocol. It appears that oral administration of milbemycin oxime (1-2 mg/kg), ivermectin (400-600 µg/kg), and moxidectin (400 µg/kg) daily is a practical therapeutical alternative and would provide similar cure rates. Nevertheless, milbemycin oxime is expensive, ivermectin is potentially more toxic, and only limited information is available on moxidectin. The average treatment duration with these new regimens is 4 months, with an expected range of 3 to 10 months. Treatment should be administered daily for a minimum of 3 months and for at least 1 month after a series of negative skin scrapings. For chronic cases or cases that take a relatively long time to respond to therapy, 2 to 3 months of treatment beyond negative scrapings may be more appropriate. Dogs with CGD always approach clinical normalcy weeks to months before negative skin scrapings are obtained. All dogs respond at their own rate; as long as the skin scrapings at each visit show fewer mites, the current therapy should be continued for an additional month. If the mite count starts to increase, this may suggest that the treatment protocol is not being followed or it may be that the therapy chosen was suboptimally effective. Although CGD is still a disease that is not easily treated, the prognosis for dogs with this disorder has dramatically improved in the past few years. It must be remembered, however, that the treatment alternatives for CGD described above are not approved and should not be used unless the approved therapeutical regimen has failed.