W e all get stumped now and then with a patient who has a difficult case of acne, but one case in particular will long stand out in my mind. I truly had to put on my detective’s hat to solve this mystery. T. R. is a 32-year-old Caucasian female who presented with the chief complaint of severe cystic acne of her face, chest and back for more than 5 years. She had been seen and treated numerous times, by numerous physicians, during this 5-year time period. However, she claimed that her treatment results were never satisfactory. She’d already tried oral medications such as, tetracycline, doxycycline (Vibramycin), minocycline (Minocin) and azithromycin (Zithromax). Topical preparations included clindamycin phosphate (Cleocin T) lotion, sodium sulfacetamide (Klaron) lotion and azelaic acid (Azelex) cream. The patient claimed that she used all of these medications as prescribed, but never saw any significant improvement in her cystic acne. The patient’s past medical history was significant only for severe cystic acne. She denied taking any medications besides those prescribed for her acne. She denied any allergies to medications and claimed that her menstrual periods were regular. In addition she denied any flare in her acne during or just prior to her menstrual period. Examining T.R. and Selecting a Treatment Regimen On examination, T.R. had numerous erythematous pustules, nodules and cysts of her face, chest and back. The lesions were inflammatory in nature; very few comedones and milia were observed. She showed an increase in oil production, which was predominantly located in the T-zone of her central face. In addition, she’d sustained significant scarring, both ice-pick and boxcar, on her face, chest and back as well. Treatment options were discussed with T. R., and a course of treatment with isotretinoin (Accutane) was agreed upon. It was explained that the patient would be subjected to blood testing prior to the start of her treatment, as well as periodically during the expected 5-month course of therapy. Initial blood tests were ordered. All laboratory work was acquired prior to the start of her therapy. Laboratory work consisting of complete blood cell count, routine chemistries, liver function tests, and thyroid and lipid profiles were all within normal limits. A urine pregnancy test was ordered, and a negative result followed. The patient was then counseled in great detail concerning the need for strict contraception and the danger of serious birth defects if she conceived a child during her 20-week treatment course. The patient was married, and claimed that she and her husband were not ready to have children at this time and that he wore condoms during all sexual encounters. T. R. was also counseled about the expected side effects of treatment, including, but not restricted to, dryness of the mucosal surfaces of her eyes, nose and mouth. The patient was also encouraged to eat, preferably a food high in fat, around the time of her isotretinoin (Accutane) dose, as Roche, the drug’s manufacturer, claims that fat increases the absorption of Accutane in the gastrointestinal tract. Finally, the patient was weighed. She weighed in at 70 kilograms, and we started a dose of Accutane 40 mg once daily. T. R. was instructed to continue her topical medication, Cleocin T lotion, twice daily and told to return to the office in 2 weeks. Two Weeks Later: Worse than Before In 2 weeks, T. R. returned for her first follow-up visit. She claimed that her skin wasn’t improving, and that “perhaps it was even a little worse.” She denied any dryness of her mucous membranes. She stated that she was taking her pill daily and had not missed any doses. She was told that Accutane doesn’t work immediately and that the drug would need to accumulate to a certain level in her blood before she would see a dramatic improvement in her acne. It was decided to increase her dose at this point to 40 mg of Accutane in the morning and 20 mg more in the evening. She was again told to return to the office in 2 weeks. On the next visit, T. R. complained that she was seeing a slight worsening of her condition. She claimed that she was seeing “new breakouts,” on her back and chest. Again, she was questioned about her compliance. Given her long history of treatment failures, the possibility of non-compliance as the reason for her lack of improvement needed to be addressed. She restated her frustration with the condition of her skin and her painful inflammatory acne for more than 5 years and reiterated that she was willing to do anything to see things improve. Again, she was questioned about side effects. She denied any. At this point, her dose was increased to 80 mg of Accutane — 40 mg twice daily. We scheduled another follow-up appointment for 2 weeks later. This scenario continued to repeat itself for the next two follow-up visits. T. R. received nearly 8 weeks of treatment without any improvement of her cystic acne, and without the appearance of any side effects, either. The need for a thorough and in-depth search to explain this patient’s situation was necessary. Looking for Clues So the following question was posed: Why does a patient with cystic acne not respond to Accutane treatment? Accutane is 13 cis retinoic acid. It is a vitamin A derivative with very high lipophilicity. The exact mechanism of action of isotretinoin is not entirely understood. It is suggested, however, that isotretinoin works against the major causative factors of acne. Specifically, it causes an involution of sebaceous glands and a reduction of sebum production, and acts against increased keratinization, which can lead to the development of the microcomedo. It is also believed that isotretinoin decreases the density of microflora of the skin, namely Propionibacterium acnes. The possibility also exists that isotretinoin works as an anti-inflammatory agent, thus preventing the creation of the inflammatory lesions of acne. Given the proposed mechanisms of action, one must still delve deeper to answer the question of why a patient with acne would not respond to treatment with isotretinoin. There is significant evidence in the literature to answer this question. In a study performed by Lehucher- Ceyrac et. al. on 188 acne patients from the years 1993 to 1999, researchers came to the following three conclusions: 1. The greatest predictive factor of isotretinoin resistance was the degree of closed comedonal acne. 2. Patients with hyperandrogenism were at an increased risk of isotretinoin failure. 3. In general, patients taking isotretinoin have an overall response rate of 95%. Other authors have postulated different reasons to explain isotretinoin treatment failure. In 1997, Dr. James Leyden identified four groups of patients that he labeled “Poor Responders to Isotretinoin (Accutane).” They included the following: 1. Pre-teens and young teenagers 2. Individuals with epithelial sinus tracts, such as those seen in pilonidal sinus or hidradenitis suppurativa 3. Patients with hemorrhagic or crusted lesions, which can develop into acne fulminans 4. Women with androgen excess states. According to Dr. Leyden, “By far the most common reason for a patient to fail isotretinoin (Accutane) treatment is the poor response of sinus tracks.” Our patient’s condition was not explained by any of the proposed mechanisms for failure found in the literature. She was neither a pre-teen nor a teenager, she did not show any of the expected signs or symptoms of epithelial sinus tracks, she did not have hemorrhagic or crusted lesions, which can lead to acne fulminans, and she did not suffer from an androgen excess state. So the question, why does a patient with acne not respond to isotretinoin treatment, remained unanswered. Digging Deeper According to the package insert for Accutane, Roche recommends a high-fat meal when one is taking a dose of Accutane, which T. R. was in fact instructed to do. That sparked a thought: Was T. R. somehow decreasing or preventing the dose of Accutane from being absorbed in the gastrointestinal tract through the consumption of a food? A more detailed history was needed to elucidate an answer to this question. At her next office visit, we questioned T.R. on this matter. She stated that approximately 8 weeks prior, at the time of her first visit to the office to seek treatment for her acne, she decided to go on an overall lifestyle improvement regimen. She decided to improve the appearance of her skin and to lose some weight. She joined a health club and decided to eliminate high-calorie snack foods from her diet. Her favorite food to eat was potato chips, and she was quite confident, given her new lifestyle improvement regimen, she would no longer be able to eat them. However, a new, low-calorie, low-fat replacement for her potato chips was on the market. She began eating these new chips, known as WOW! Potato Chips, daily, often as the recommended fatty meal when dosing her Accutane. Was there a relationship between the WOW! Potato chips and her Accutane treatment failure? WOW! Potato Chips are a popular product produced by Frito-Lay. The active ingredient is Olestra, also known as Olean. Olestra is the first non-caloric fat replacer to be used in snack foods. Chemically, it is a sucrose molecule to which are esterified as many as eight fatty acid residues, making it so large and fatty, that they cannot be metabolized by enzymes and bacteria in the gut. Therefore, the chemical is neither absorbed nor digested, merely excreted. The history behind Olestra is quite interesting. In 1968, Procter & Gamble researchers set out to create a food additive that would increase a premature infant’s intake of fat. Rather than proving to be a means of increasing an infant’s intake of fat, the product that was produced in the laboratory turned out to be a means of replacing fat and producing fat-free and low-fat foods. The product that was created in the laboratory was therefore a failure. However, the capitalistic minds at Procter & Gamble were committed to finding a new niche for this failed product. The market that was suggested for Olestra was the highly lucrative and competitive market of low-fat and fat-free snack foods. Thus, WOW! was born. However, over the next few years, some other important facts concerning Olestra and its interactions in vivo were identified. In addition to inhibiting the absorption of fat, Olestra inhibits the absorption of some vitamins and other nutrients, Procter & Gamble acknowledged in 1987. Being such a fatty molecule, it was found to bind irreversibly to cholesterol, fat-soluble vitamins and fat- soluble molecules. Information acquired during the research and development phase of Olestra that was submitted to the FDA during its approval process in 1996, demonstrated an irreversible binding between Olestra and fat-soluble vitamins, therefore decreasing the absorption of all fat-soluble vitamins, including retinol, in the gut. Therefore, it is hypothesized that the efficacy of isotretinoin (a retinol and vitamin A derivative) could be adversely affected by the consumption of any product containing Olestra. Putting Our Hypothesis to the Test In order to test and confirm this hypothesis, we instructed T.R. to discontinue the consumption of Olestra, which she did, and complete her 20-week course of Accutane treatment. T. R. experienced dramatic improvement of her acne, and she was discharged with excellent cosmetic results. This is, therefore, the first reported case of isotretinoin treatment failure secondary to the irreversible binding of the fat substitute Olestra, with isotretinoin, thus inhibiting the systemic absorption of the drug. This case clearly demonstrates that the failure of Accutane treatment due to the absorption blockade created by the binding of Olestra with retinol in the gastrointestinal tract, is a real and significant interaction. We encourage our colleagues to consider this potential interaction when treating patients with Accutane and generic versions of isotretinoin.
Can You Guess the Cause of this Drug Interaction?
W e all get stumped now and then with a patient who has a difficult case of acne, but one case in particular will long stand out in my mind. I truly had to put on my detective’s hat to solve this mystery. T. R. is a 32-year-old Caucasian female who presented with the chief complaint of severe cystic acne of her face, chest and back for more than 5 years. She had been seen and treated numerous times, by numerous physicians, during this 5-year time period. However, she claimed that her treatment results were never satisfactory. She’d already tried oral medications such as, tetracycline, doxycycline (Vibramycin), minocycline (Minocin) and azithromycin (Zithromax). Topical preparations included clindamycin phosphate (Cleocin T) lotion, sodium sulfacetamide (Klaron) lotion and azelaic acid (Azelex) cream. The patient claimed that she used all of these medications as prescribed, but never saw any significant improvement in her cystic acne. The patient’s past medical history was significant only for severe cystic acne. She denied taking any medications besides those prescribed for her acne. She denied any allergies to medications and claimed that her menstrual periods were regular. In addition she denied any flare in her acne during or just prior to her menstrual period. Examining T.R. and Selecting a Treatment Regimen On examination, T.R. had numerous erythematous pustules, nodules and cysts of her face, chest and back. The lesions were inflammatory in nature; very few comedones and milia were observed. She showed an increase in oil production, which was predominantly located in the T-zone of her central face. In addition, she’d sustained significant scarring, both ice-pick and boxcar, on her face, chest and back as well. Treatment options were discussed with T. R., and a course of treatment with isotretinoin (Accutane) was agreed upon. It was explained that the patient would be subjected to blood testing prior to the start of her treatment, as well as periodically during the expected 5-month course of therapy. Initial blood tests were ordered. All laboratory work was acquired prior to the start of her therapy. Laboratory work consisting of complete blood cell count, routine chemistries, liver function tests, and thyroid and lipid profiles were all within normal limits. A urine pregnancy test was ordered, and a negative result followed. The patient was then counseled in great detail concerning the need for strict contraception and the danger of serious birth defects if she conceived a child during her 20-week treatment course. The patient was married, and claimed that she and her husband were not ready to have children at this time and that he wore condoms during all sexual encounters. T. R. was also counseled about the expected side effects of treatment, including, but not restricted to, dryness of the mucosal surfaces of her eyes, nose and mouth. The patient was also encouraged to eat, preferably a food high in fat, around the time of her isotretinoin (Accutane) dose, as Roche, the drug’s manufacturer, claims that fat increases the absorption of Accutane in the gastrointestinal tract. Finally, the patient was weighed. She weighed in at 70 kilograms, and we started a dose of Accutane 40 mg once daily. T. R. was instructed to continue her topical medication, Cleocin T lotion, twice daily and told to return to the office in 2 weeks. Two Weeks Later: Worse than Before In 2 weeks, T. R. returned for her first follow-up visit. She claimed that her skin wasn’t improving, and that “perhaps it was even a little worse.” She denied any dryness of her mucous membranes. She stated that she was taking her pill daily and had not missed any doses. She was told that Accutane doesn’t work immediately and that the drug would need to accumulate to a certain level in her blood before she would see a dramatic improvement in her acne. It was decided to increase her dose at this point to 40 mg of Accutane in the morning and 20 mg more in the evening. She was again told to return to the office in 2 weeks. On the next visit, T. R. complained that she was seeing a slight worsening of her condition. She claimed that she was seeing “new breakouts,” on her back and chest. Again, she was questioned about her compliance. Given her long history of treatment failures, the possibility of non-compliance as the reason for her lack of improvement needed to be addressed. She restated her frustration with the condition of her skin and her painful inflammatory acne for more than 5 years and reiterated that she was willing to do anything to see things improve. Again, she was questioned about side effects. She denied any. At this point, her dose was increased to 80 mg of Accutane — 40 mg twice daily. We scheduled another follow-up appointment for 2 weeks later. This scenario continued to repeat itself for the next two follow-up visits. T. R. received nearly 8 weeks of treatment without any improvement of her cystic acne, and without the appearance of any side effects, either. The need for a thorough and in-depth search to explain this patient’s situation was necessary. Looking for Clues So the following question was posed: Why does a patient with cystic acne not respond to Accutane treatment? Accutane is 13 cis retinoic acid. It is a vitamin A derivative with very high lipophilicity. The exact mechanism of action of isotretinoin is not entirely understood. It is suggested, however, that isotretinoin works against the major causative factors of acne. Specifically, it causes an involution of sebaceous glands and a reduction of sebum production, and acts against increased keratinization, which can lead to the development of the microcomedo. It is also believed that isotretinoin decreases the density of microflora of the skin, namely Propionibacterium acnes. The possibility also exists that isotretinoin works as an anti-inflammatory agent, thus preventing the creation of the inflammatory lesions of acne. Given the proposed mechanisms of action, one must still delve deeper to answer the question of why a patient with acne would not respond to treatment with isotretinoin. There is significant evidence in the literature to answer this question. In a study performed by Lehucher- Ceyrac et. al. on 188 acne patients from the years 1993 to 1999, researchers came to the following three conclusions: 1. The greatest predictive factor of isotretinoin resistance was the degree of closed comedonal acne. 2. Patients with hyperandrogenism were at an increased risk of isotretinoin failure. 3. In general, patients taking isotretinoin have an overall response rate of 95%. Other authors have postulated different reasons to explain isotretinoin treatment failure. In 1997, Dr. James Leyden identified four groups of patients that he labeled “Poor Responders to Isotretinoin (Accutane).” They included the following: 1. Pre-teens and young teenagers 2. Individuals with epithelial sinus tracts, such as those seen in pilonidal sinus or hidradenitis suppurativa 3. Patients with hemorrhagic or crusted lesions, which can develop into acne fulminans 4. Women with androgen excess states. According to Dr. Leyden, “By far the most common reason for a patient to fail isotretinoin (Accutane) treatment is the poor response of sinus tracks.” Our patient’s condition was not explained by any of the proposed mechanisms for failure found in the literature. She was neither a pre-teen nor a teenager, she did not show any of the expected signs or symptoms of epithelial sinus tracks, she did not have hemorrhagic or crusted lesions, which can lead to acne fulminans, and she did not suffer from an androgen excess state. So the question, why does a patient with acne not respond to isotretinoin treatment, remained unanswered. Digging Deeper According to the package insert for Accutane, Roche recommends a high-fat meal when one is taking a dose of Accutane, which T. R. was in fact instructed to do. That sparked a thought: Was T. R. somehow decreasing or preventing the dose of Accutane from being absorbed in the gastrointestinal tract through the consumption of a food? A more detailed history was needed to elucidate an answer to this question. At her next office visit, we questioned T.R. on this matter. She stated that approximately 8 weeks prior, at the time of her first visit to the office to seek treatment for her acne, she decided to go on an overall lifestyle improvement regimen. She decided to improve the appearance of her skin and to lose some weight. She joined a health club and decided to eliminate high-calorie snack foods from her diet. Her favorite food to eat was potato chips, and she was quite confident, given her new lifestyle improvement regimen, she would no longer be able to eat them. However, a new, low-calorie, low-fat replacement for her potato chips was on the market. She began eating these new chips, known as WOW! Potato Chips, daily, often as the recommended fatty meal when dosing her Accutane. Was there a relationship between the WOW! Potato chips and her Accutane treatment failure? WOW! Potato Chips are a popular product produced by Frito-Lay. The active ingredient is Olestra, also known as Olean. Olestra is the first non-caloric fat replacer to be used in snack foods. Chemically, it is a sucrose molecule to which are esterified as many as eight fatty acid residues, making it so large and fatty, that they cannot be metabolized by enzymes and bacteria in the gut. Therefore, the chemical is neither absorbed nor digested, merely excreted. The history behind Olestra is quite interesting. In 1968, Procter & Gamble researchers set out to create a food additive that would increase a premature infant’s intake of fat. Rather than proving to be a means of increasing an infant’s intake of fat, the product that was produced in the laboratory turned out to be a means of replacing fat and producing fat-free and low-fat foods. The product that was created in the laboratory was therefore a failure. However, the capitalistic minds at Procter & Gamble were committed to finding a new niche for this failed product. The market that was suggested for Olestra was the highly lucrative and competitive market of low-fat and fat-free snack foods. Thus, WOW! was born. However, over the next few years, some other important facts concerning Olestra and its interactions in vivo were identified. In addition to inhibiting the absorption of fat, Olestra inhibits the absorption of some vitamins and other nutrients, Procter & Gamble acknowledged in 1987. Being such a fatty molecule, it was found to bind irreversibly to cholesterol, fat-soluble vitamins and fat- soluble molecules. Information acquired during the research and development phase of Olestra that was submitted to the FDA during its approval process in 1996, demonstrated an irreversible binding between Olestra and fat-soluble vitamins, therefore decreasing the absorption of all fat-soluble vitamins, including retinol, in the gut. Therefore, it is hypothesized that the efficacy of isotretinoin (a retinol and vitamin A derivative) could be adversely affected by the consumption of any product containing Olestra. Putting Our Hypothesis to the Test In order to test and confirm this hypothesis, we instructed T.R. to discontinue the consumption of Olestra, which she did, and complete her 20-week course of Accutane treatment. T. R. experienced dramatic improvement of her acne, and she was discharged with excellent cosmetic results. This is, therefore, the first reported case of isotretinoin treatment failure secondary to the irreversible binding of the fat substitute Olestra, with isotretinoin, thus inhibiting the systemic absorption of the drug. This case clearly demonstrates that the failure of Accutane treatment due to the absorption blockade created by the binding of Olestra with retinol in the gastrointestinal tract, is a real and significant interaction. We encourage our colleagues to consider this potential interaction when treating patients with Accutane and generic versions of isotretinoin.
W e all get stumped now and then with a patient who has a difficult case of acne, but one case in particular will long stand out in my mind. I truly had to put on my detective’s hat to solve this mystery. T. R. is a 32-year-old Caucasian female who presented with the chief complaint of severe cystic acne of her face, chest and back for more than 5 years. She had been seen and treated numerous times, by numerous physicians, during this 5-year time period. However, she claimed that her treatment results were never satisfactory. She’d already tried oral medications such as, tetracycline, doxycycline (Vibramycin), minocycline (Minocin) and azithromycin (Zithromax). Topical preparations included clindamycin phosphate (Cleocin T) lotion, sodium sulfacetamide (Klaron) lotion and azelaic acid (Azelex) cream. The patient claimed that she used all of these medications as prescribed, but never saw any significant improvement in her cystic acne. The patient’s past medical history was significant only for severe cystic acne. She denied taking any medications besides those prescribed for her acne. She denied any allergies to medications and claimed that her menstrual periods were regular. In addition she denied any flare in her acne during or just prior to her menstrual period. Examining T.R. and Selecting a Treatment Regimen On examination, T.R. had numerous erythematous pustules, nodules and cysts of her face, chest and back. The lesions were inflammatory in nature; very few comedones and milia were observed. She showed an increase in oil production, which was predominantly located in the T-zone of her central face. In addition, she’d sustained significant scarring, both ice-pick and boxcar, on her face, chest and back as well. Treatment options were discussed with T. R., and a course of treatment with isotretinoin (Accutane) was agreed upon. It was explained that the patient would be subjected to blood testing prior to the start of her treatment, as well as periodically during the expected 5-month course of therapy. Initial blood tests were ordered. All laboratory work was acquired prior to the start of her therapy. Laboratory work consisting of complete blood cell count, routine chemistries, liver function tests, and thyroid and lipid profiles were all within normal limits. A urine pregnancy test was ordered, and a negative result followed. The patient was then counseled in great detail concerning the need for strict contraception and the danger of serious birth defects if she conceived a child during her 20-week treatment course. The patient was married, and claimed that she and her husband were not ready to have children at this time and that he wore condoms during all sexual encounters. T. R. was also counseled about the expected side effects of treatment, including, but not restricted to, dryness of the mucosal surfaces of her eyes, nose and mouth. The patient was also encouraged to eat, preferably a food high in fat, around the time of her isotretinoin (Accutane) dose, as Roche, the drug’s manufacturer, claims that fat increases the absorption of Accutane in the gastrointestinal tract. Finally, the patient was weighed. She weighed in at 70 kilograms, and we started a dose of Accutane 40 mg once daily. T. R. was instructed to continue her topical medication, Cleocin T lotion, twice daily and told to return to the office in 2 weeks. Two Weeks Later: Worse than Before In 2 weeks, T. R. returned for her first follow-up visit. She claimed that her skin wasn’t improving, and that “perhaps it was even a little worse.” She denied any dryness of her mucous membranes. She stated that she was taking her pill daily and had not missed any doses. She was told that Accutane doesn’t work immediately and that the drug would need to accumulate to a certain level in her blood before she would see a dramatic improvement in her acne. It was decided to increase her dose at this point to 40 mg of Accutane in the morning and 20 mg more in the evening. She was again told to return to the office in 2 weeks. On the next visit, T. R. complained that she was seeing a slight worsening of her condition. She claimed that she was seeing “new breakouts,” on her back and chest. Again, she was questioned about her compliance. Given her long history of treatment failures, the possibility of non-compliance as the reason for her lack of improvement needed to be addressed. She restated her frustration with the condition of her skin and her painful inflammatory acne for more than 5 years and reiterated that she was willing to do anything to see things improve. Again, she was questioned about side effects. She denied any. At this point, her dose was increased to 80 mg of Accutane — 40 mg twice daily. We scheduled another follow-up appointment for 2 weeks later. This scenario continued to repeat itself for the next two follow-up visits. T. R. received nearly 8 weeks of treatment without any improvement of her cystic acne, and without the appearance of any side effects, either. The need for a thorough and in-depth search to explain this patient’s situation was necessary. Looking for Clues So the following question was posed: Why does a patient with cystic acne not respond to Accutane treatment? Accutane is 13 cis retinoic acid. It is a vitamin A derivative with very high lipophilicity. The exact mechanism of action of isotretinoin is not entirely understood. It is suggested, however, that isotretinoin works against the major causative factors of acne. Specifically, it causes an involution of sebaceous glands and a reduction of sebum production, and acts against increased keratinization, which can lead to the development of the microcomedo. It is also believed that isotretinoin decreases the density of microflora of the skin, namely Propionibacterium acnes. The possibility also exists that isotretinoin works as an anti-inflammatory agent, thus preventing the creation of the inflammatory lesions of acne. Given the proposed mechanisms of action, one must still delve deeper to answer the question of why a patient with acne would not respond to treatment with isotretinoin. There is significant evidence in the literature to answer this question. In a study performed by Lehucher- Ceyrac et. al. on 188 acne patients from the years 1993 to 1999, researchers came to the following three conclusions: 1. The greatest predictive factor of isotretinoin resistance was the degree of closed comedonal acne. 2. Patients with hyperandrogenism were at an increased risk of isotretinoin failure. 3. In general, patients taking isotretinoin have an overall response rate of 95%. Other authors have postulated different reasons to explain isotretinoin treatment failure. In 1997, Dr. James Leyden identified four groups of patients that he labeled “Poor Responders to Isotretinoin (Accutane).” They included the following: 1. Pre-teens and young teenagers 2. Individuals with epithelial sinus tracts, such as those seen in pilonidal sinus or hidradenitis suppurativa 3. Patients with hemorrhagic or crusted lesions, which can develop into acne fulminans 4. Women with androgen excess states. According to Dr. Leyden, “By far the most common reason for a patient to fail isotretinoin (Accutane) treatment is the poor response of sinus tracks.” Our patient’s condition was not explained by any of the proposed mechanisms for failure found in the literature. She was neither a pre-teen nor a teenager, she did not show any of the expected signs or symptoms of epithelial sinus tracks, she did not have hemorrhagic or crusted lesions, which can lead to acne fulminans, and she did not suffer from an androgen excess state. So the question, why does a patient with acne not respond to isotretinoin treatment, remained unanswered. Digging Deeper According to the package insert for Accutane, Roche recommends a high-fat meal when one is taking a dose of Accutane, which T. R. was in fact instructed to do. That sparked a thought: Was T. R. somehow decreasing or preventing the dose of Accutane from being absorbed in the gastrointestinal tract through the consumption of a food? A more detailed history was needed to elucidate an answer to this question. At her next office visit, we questioned T.R. on this matter. She stated that approximately 8 weeks prior, at the time of her first visit to the office to seek treatment for her acne, she decided to go on an overall lifestyle improvement regimen. She decided to improve the appearance of her skin and to lose some weight. She joined a health club and decided to eliminate high-calorie snack foods from her diet. Her favorite food to eat was potato chips, and she was quite confident, given her new lifestyle improvement regimen, she would no longer be able to eat them. However, a new, low-calorie, low-fat replacement for her potato chips was on the market. She began eating these new chips, known as WOW! Potato Chips, daily, often as the recommended fatty meal when dosing her Accutane. Was there a relationship between the WOW! Potato chips and her Accutane treatment failure? WOW! Potato Chips are a popular product produced by Frito-Lay. The active ingredient is Olestra, also known as Olean. Olestra is the first non-caloric fat replacer to be used in snack foods. Chemically, it is a sucrose molecule to which are esterified as many as eight fatty acid residues, making it so large and fatty, that they cannot be metabolized by enzymes and bacteria in the gut. Therefore, the chemical is neither absorbed nor digested, merely excreted. The history behind Olestra is quite interesting. In 1968, Procter & Gamble researchers set out to create a food additive that would increase a premature infant’s intake of fat. Rather than proving to be a means of increasing an infant’s intake of fat, the product that was produced in the laboratory turned out to be a means of replacing fat and producing fat-free and low-fat foods. The product that was created in the laboratory was therefore a failure. However, the capitalistic minds at Procter & Gamble were committed to finding a new niche for this failed product. The market that was suggested for Olestra was the highly lucrative and competitive market of low-fat and fat-free snack foods. Thus, WOW! was born. However, over the next few years, some other important facts concerning Olestra and its interactions in vivo were identified. In addition to inhibiting the absorption of fat, Olestra inhibits the absorption of some vitamins and other nutrients, Procter & Gamble acknowledged in 1987. Being such a fatty molecule, it was found to bind irreversibly to cholesterol, fat-soluble vitamins and fat- soluble molecules. Information acquired during the research and development phase of Olestra that was submitted to the FDA during its approval process in 1996, demonstrated an irreversible binding between Olestra and fat-soluble vitamins, therefore decreasing the absorption of all fat-soluble vitamins, including retinol, in the gut. Therefore, it is hypothesized that the efficacy of isotretinoin (a retinol and vitamin A derivative) could be adversely affected by the consumption of any product containing Olestra. Putting Our Hypothesis to the Test In order to test and confirm this hypothesis, we instructed T.R. to discontinue the consumption of Olestra, which she did, and complete her 20-week course of Accutane treatment. T. R. experienced dramatic improvement of her acne, and she was discharged with excellent cosmetic results. This is, therefore, the first reported case of isotretinoin treatment failure secondary to the irreversible binding of the fat substitute Olestra, with isotretinoin, thus inhibiting the systemic absorption of the drug. This case clearly demonstrates that the failure of Accutane treatment due to the absorption blockade created by the binding of Olestra with retinol in the gastrointestinal tract, is a real and significant interaction. We encourage our colleagues to consider this potential interaction when treating patients with Accutane and generic versions of isotretinoin.
