Tretinoin toxicity

The metabolism of tretinoin can be inhibited by fluconazole, and a case report describes tretinoin toxicity as a result of this interaction. Ketoconazole may interact similarly. 

Mahmoud HH, Hurwitz CA, Roberts WM, Santana VM, Ribeiro RC, Krance RA (1993) Tretinoin toxicity in children with acute promyelocytic leukaemia. Lancet 342 1394-1395... 

The major toxic effect of tretinoin is erythema and irritation of the skin to which it is applied, especially if the skin is moist. This toxicity often decreases with continued therapy. 

Attractive alternative to oral retinoid therapy in psoriasis (e.g., etretinate), primarily due to less toxicity. Structural changes to the basic retinoid structure (e.g., conformational rigidity) are claimed to enhance therapeutic efficacy and reduce the local toxicity associated with topical tretinoin (retinoic acid). However, place in therapy should await direct comparisons vs standard regimens in terms of efficacy, toxicity, and cost... 

The past twenty years have witnessed considerable progress in the synthesis and use of other retinoid-like molecules related to vitamin A. The aromatic retinoid etretin (8.54) and its ester etretinate (8.55) had some effectiveness in the treatment of psoriasis, a disorder of skin. 13-cA-Retinoic acid (isotretinoin) produces sebaceous gland atrophy and could prove useful in the treatment of severe acne vulgaris. Although these compounds have toxic side effects and are not in regular use, they have opened up new therapeutic possibilities. Retinoic acid (tretinoin, 8.56) has been employed in the treatment of acne. 

Acne and psoriasis Dermatologic problems such as acne and psoriasis are effectively treated with retinoic acid or its derivatives (see Figure 28.21). Mild cases of acne, Darier disease, and skri aging are treated with topical application of tretinoin (all trans retinoic acid), as well as benzoyl peroxide and antibiotics. [Note Tretinoin is too toxic for systemic administration and is confined to topical application.] In patients with severe recalcitrant cystic acre... 

Tretinoin (Vesanoid] Acute promyelocytic leukemia Cardiac arrhythmias edema blood pressure abnormalities (hypotension, hypertension] phlebitis respiratory tract problems muscle pain paresthesias CNS toxicity (depression, anxiety, confusion] skin rash Gl distress (abdominal distension nausea, vomiting]... 

Retinoic acid (vitamin A acid), in which the alcohol group has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. Flowever, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A-deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-n.v-rctinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be as much as fivefold less potent in producing the toxic symptoms of hypervitaminosis A. 

RETINOIDS VITAMIN A Risk of vitamin A toxicity Additive effect tretinoin is a form of vitamin A Avoid co-administration... 

Topical tretinoin has also been used as an ophthalmic ointment 0.01% in the treatment of squamous metaplasia associated with dry eyes. In 161 patients with either keratoconjunctivitis sicca or conjunctival cicatricial diseases (Stevens-Johnson syndrome, inactive pemphigoid, radiation-induced dry eye, drug-induced pseudopemphigoid, and toxic epidermal necrolysis) there were no beneficial effects in the former, but significant reversal of conjunctival kerati-nization in the temporal bulbar site in the latter (1). Adverse effects were hmited to blepharoconjunctivitis and resolved on withdrawal. 

In 21 patients with squamous cell carcinomas of the head and neck randomized to tretinoin 45, 50, or 150 mg/ m either once daily or as divided doses every 8 hours for 1 year, severe adverse effects included headache in five patients, hypertriglyceridemia in six, mucositis in two, and hyperbilirubinemia, raised alkaline phosphatase, colitis, raised lipase, xerostomia, eczema, and arthritis in one patient each (9). The dose had to be reduced in seven of eight patients with severe toxicity at 90 mg/m / day. Three of nine patients taking 45 mg/m /day required dose reductions. The plasma AUC of tretinoin did not correlate with the severity or frequency of adverse effects. From these results it can be concluded that 15 mg/m /day every 8 hours is a tolerable dose for 1 year in patients with squamous cell carcinomas of the head and neck. 

Hepatomegaly is an adverse effect of retinol and tretinoin. Transient slight rises in liver enzymes, notably aspartate transaminase, alanine transaminase, and alkaline phosphatase, are common, but some cases of hepato-toxicity due to etretinate and acitretin (SEDA-20, 154) have also been reported (76), as has cholestatic jaundice due to etretinate (77). Etretinate may have played a role in a case of liver failure leading to death (76). 

As with ALL, the goal of remission induction for AML is to rapidly induce a CR. Compared to ALL, however, fewer patients with AML achieve CR. Since the CR rate in AML is related to the intensity of the remission induction regimen, the drugs used in AML are given at doses that uniformly cause severe marrow hypoplasia (except tretinoin). One reason for the lower CR rate in AML as compared to ALL is the inability to give optimal doses of chemotherapy because of marrow toxicity. With continued improvement of supportive care for patients... 

The first part of this chapter is devoted to the results of toxicologic, mutagenic, teratogenic, and carcinogenic studies with isotretinoin and etretinate when appropriate, a comparison with results for retinol and tretinoin (all-(rans-retinoic acid) is presented. The second part of this chapter is devoted to a description of clinical or human toxicity. 

Single large doses of retinoids are only moderately toxic. Table I presents some LDjq values for vitamin A alcohol, tretinoin, isotretinoin, and etretinate given orally or intraperitoneally to rats, mice, and rabbits. For comparison, the approximate LD5Q for botulinus toxin is 0.00001 mg/kg and for ethyl alcohol 10,000 mg/kg (Klaassen and Doull, 1980). 

An interesting observation for some retinoids is that toxicity, as deflned by their LD50, is cumulative. Thus Teelmann (1981) has reported that the singledose oral LD o for etretinate in rats and mice is greater than 4000 mg/kg. In contrast, in animals treated with repeated daily doses of etretinate for 10 days, the LD50 was about 50 mg/kg/day. Similar cumulative toxicity has been described for tretinoin (Kretzschmer and Leuschner, 1975). 

Kretzschmar and Leuschner (1975) studied the toxicity of tretinoin administered orally to rats and dogs for 13 weeks at doses of 5 and 50 mg/kg/day. In rats, the low dose produced hair loss, dermal and mucosal alterations (not defined), inhibition of spermatogenesis, and weight loss. At 50 mg/kg/day, serum transaminase and serum alkaline phosphatase activities were elevated and total serum protein declined about 20% of the rats died. In dogs, similar signs of toxicity were seen at 5 mg/kg/day 50 mg/kg/day was lethal to about 50% of the dogs after about 11 weeks of treatment. In mice, doses of — 150-250 mg/kg/day for 5 days caused alopecia, weight loss, and undefined skin and mucous membrane lesions. 

Hixson and co-workers have carried out direct comparative studies of the toxicity of tretinoin and isotretinoin in mice (Hixson and Denine, 1978) and in rats (Hixson et al., 1979). For the subchronic toxicity studies in mice, treatment was for 21 days at doses of tretinoin of 3-60 mg/kg/day intraperitoneally and 10-100 mg/kg/day orally for isotretinoin the doses were 30-300 mg/kg/day intraperitoneally and 60-400 mg/kg/day orally. A general conclusion of this study was that, dose for dose, tretinoin was more toxic than isotretinoin. The authors noted that isotretinoin produced the same number and incidence of fractures at doses three to five times that of tretinoin administered by the same route. It is of interest that fractures were not invariably accompanied by elevations in serum alkaline phosphatase. Dose-related decreases in red cell counts were observed with isotretinoin but not with tretinoin. Hixson and Denine (1978) concluded on the basis of differences in onset, severity, and frequency that tretinoin was more toxic than isotretinoin in the Swiss mouse. 

Comparative toxicity studies have been reported for tretinoin, isotretinoin, etretinate, and two retinamides, A -(4-ethoxycarbopheny)retinamide and N- 4-hydroxycarbophenyl)retinamide (Du etal., 1982). Two-week oral toxicity studies in mice at doses of 150 mg/kg/day of tretinoin and 175 mg/kg/day of etretinate resulted in weight loss, hair loss, and fractures these signs of toxicity were not seen with 150 mg/kg/day of isotretinoin, 600 mg/kg/day of N-(4-hydroxycarbophenyl)retinamide or 860 mg/kg/day of A/-(4-ethoxycarbophenyl)-retinamide. In another experiment, 60 and 300 mg/kg/day of tretinoin and/V-(4-ethoxycarbophenyl)retinamide, respectively, were administered for 3 months tretinoin proved to be more toxic than the retinamide. 

The comparative toxicity of retinoids and retinamides have also been studied by Sani and Meeks (1982). On the basis of clinical signs of toxicity, lethality, and histopathological findings in rats and mice, the toxicity of the retinoids and retinamides were ranked in the order tretinoin > 2-hydroxypropylretinamide > isotretinoin > 2-hydroxyethylretinamide > ethylretinamide > 3-hydroxypropyl-retinamide > 4-hydroxyphenylretinamide. Treatment with the retinoids (doses not stated) caused an anemia characterized by erythrocytopenia and decreases in hemoglobin concentration, packed-cell volume, and hematocrit. Dose-dependent increases in serum alkaline phosphatase activity and decreases in serum albumin were also observed. 

---