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At least 19 recordsLinked to original sources
PubMed2006

The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%.

Topical tretinoin is highly effective and widely used in the treatment of acne vulgaris. Tretinoin gel microsphere 0.1% (TGM)--alone or in combination with erythromycin-benzoyl peroxide (EBP) or clindamycin-benzoyl peroxide (CBP) topical gels-and tretinoin gel 0.025% (TG)--alone or, combined with EBP-were exposed to simulated solar UV irradiation to determine the degree of tretinoin photodegradation/isomerization. The investigation revealed that 94% and 84% of the initial tretinoin in the TGM formulation remained stable after 2 and 6 hours, respectively, of simulated solar UV irradiation. When combined with EBP topical gel, 89% and 81% of the initial tretinoin remained stable after 2 and 6 hours, respectively, of exposure to simulated solar UV irradiation; 86% and 80% of the tretinoin remained stable after 2 and 6 hours, respectively, when combined with CBP topical gel. In contrast, only 19% and 10% of the tretinoin remained unchanged after 2 and 6 hours, respectively, of simulated solar UV irradiation of TG. Combined with the EBP topical gel, undegraded tretinoin quantities were further reduced to 7% and 0% at 2 and 6 hours, respectively, with TG. These data suggest that the TGM formulation offers marked protection against tretinoin photodegradation compared with TG, even in the presence of a topical gel containing a potent antibiotic or a strong oxidizing agent. Although simulated solar UV irradiation is not entirely reflective of actual conditions, the results appear to be substantial.

Anti-Bacterial Agents↗
PubMed1998

Irritation potential of a new topical tretinoin formulation and a commercially-available tretinoin formulation as measured by patch testing in human subjects.

BACKGROUND: A novel tretinoin preparation uses polyolprepolymer-2, a compound designed to reduce skin irritation by helping retain drugs on and in the surface layers of the skin. OBJECTIVE: We used patch testing to measure the effect of polyolprepolymer-2 on tretinoin-associated irritation. METHODS: Two patch test studies were conducted. The first assessed the effect of polyolprepolymer-2 by comparing commercially-available tretinoin formulations with respective polyolprepolymer-containing formulations of 0.025% tretinoin gel and 0.025%, 0.05%, and 0.1% tretinoin creams. The second assessed the effect of the polyolprepolymer-2 concentration on the potential decrease in irritation by comparing: (1) a commercially-available tretinoin cream with prototype tretinoin creams containing 20% polyolprepolymer-2 at three different concentrations of tretinoin (0.025%, 0.05%, and 0.1%); and (2) the effect of three different polyolprepolymer-2 concentrations (10%, 15%, and 20%) in prototype tretinoin creams on cumulative irritation. Patch agents were assigned to subjects according to a randomization schedule, and during a period of 5 days each subject received three 24-hour exposures to the test materials. Twenty-four hours elapsed between old patch removal and new patch application. RESULTS: In the first study, the tretinoin gel and cream containing polyolprepolymer-2 caused significantly less irritation than all equivalent formulations of the commercially-available tretinoin gel and creams except the 0.025% cream formulation. Irritation scores were not significantly different in terms of irritation in the 0.025% creams although scores did indicate a trend towards lower irritation with 0.025% tretinoin cream containing polyolprepolymer-2. In the second study, the tretinoin gel containing polyolprepolymer-2 and the three tretinoin prototype creams also containing polyolprepolymer-2 caused significantly less irritation than comparable concentrations of the commercially-available tretinoin. In addition, the 0.025% tretinoin gel formulation containing polyolprepolymer-2 was no more irritating than the commercially-available 0.025% tretinoin cream. CONCLUSION: Tretinoin formulations containing polyolprepolymer-2 are, in general, less irritating than the currently marketed tretinoin formulations.

Administration, Topical↗
PubMed1997

The percutaneous absorption of topically applied tretinoin and its effect on endogenous concentrations of tretinoin and its metabolites after single doses or long-term use.

BACKGROUND: The percutaneous absorption of topically applied tretinoin cream and emollient cream formulations has not been comprehensively studied. OBJECTIVE: To assess tretinoin absorption and plasma levels of tretinoin and its metabolites after single and repeated topical tretinoin doses. METHODS: In study 1, 28 subjects were equally divided into four treatment groups that received a single dose of tritiated tretinoin in a 0.05% formulation of emollient cream (Renova, Retinova) or cream (Retin-A) alone or after 28 days of repeated nonradioactive doses. In study 2, subjects received single topical doses of tritiated tretinoin cream alone (n = 5) or after 1 year of nonradioactive applications (n = 4). Plasma, urine, and fecal samples were analyzed to determine absorption; plasma samples in study 1 were also analyzed for concentrations of tretinoin and its metabolites. RESULTS: Percutaneous absorption of tretinoin was approximately 2% after a single dose and after 28 days of daily application. In patients receiving long-term therapy (i.e., > 1 year), absorption averaged 1.1%. Mean plasma concentrations of tretinoin after 28 days of treatment with either tretinoin emollient cream or tretinoin cream were not significantly changed when compared with the corresponding endogenous concentrations before treatment. CONCLUSION: Minimal percutaneous absorption of tretinoin was obtained after its topical application in cream formulations. Neither single-dose nor long-term treatment with topical tretinoin formulations appeared to affect the endogenous levels of tretinoin or its metabolites.

Administration, Topical↗
PubMed1998

Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical control of facial acne.

BACKGROUND: A formulation containing agents affecting the non-inflammatory as well as the inflammatory lesions of acne vulgaris at the same time would be efficient, probably showing a high efficacy and possibly a considerable shortening of the duration of treatment. One single formulation would simplify drug administration thereby enhancing patient compliance and possibly leading to improved therapeutic results. In two studies this seems to have been corroborated for the fixed clindamycin phosphate-tretinoin gel formulation. OBJECTIVE: This study was designed to assess whether the recently developed fixed formulation of 1.2% clindamycin phosphate and 0.025% tretinoin in a gel base (Velac), further referred to as Clindamycin phosphate Tretinoin Gel is at least as effective as a proprietary 0.025% tretinoin gel formulation (Aberela, Janssen Cilag Ab, Sollentuna, Sweden; further defined as tretinoin) showing an additional anti-inflammatory effect in the treatment of moderate to severe acne vulgaris. METHODS: In a double-blind, randomised study 72 patients were treated with CTG and 73 with tretinoin gel in a once daily regimen for 12 weeks. Responses, irritation as well as possible systemic and other adverse effects were recorded after 4, 8 and 12 weeks of treatment and the improvement, compared to baseline, assessed in all included patients. An additional assessment of the safety parameters was carried out at week 2. Parameters of efficacy were the various acne lesion counts, the overall acne severity grade and the calculated totals of acne lesion counts. RESULTS: CTG was statistically significantly more effective than tretinoin at the P = 0.05 level in the papular and the total mean inflammatory lesion counts as well as in the estimated or calculated mean overall acne severity scores. CTG and tretinoin gel were equally effective in the remaining parameters: open and closed comedones, the calculated total mean comedone, the pustule as well as the nodule lesion counts. The onset of action was faster for CTG than for tretinoin gel and evident in all assessed parameters except in open comedone lesion counts. In the calculated total mean acne lesion counts, half of all acne lesions had disappeared by week 6 of treatment with CTG, whereas this was recorded at week 9 for tretinoin gel. No clinically relevant changes in the parameters of safety as a consequence of treatment were observed, although the burning component of irritation was shown to be significantly less for CTG than for tretinoin gel. The observed adverse effects were considered minor. Treatment had to be discontinued in five patients on CTG and three on tretinoin. CONCLUSION: The addition of clindamycin to tretinoin, as in CTG, enhances the comedolytic efficacy of tretinoin in moderate to severe acne of the face, maintaining at the same time its anti-inflammatory efficacy thus accelerating resolution of all types of acne lesions without affecting the safety of response to both components.

Acne Vulgaris↗
PubMed2002

The stability of tretinoin in tretinoin gel microsphere 0.1%.

Topical tretinoin is highly effective and widely used in the treatment of acne vulgaris. In studies to determine the degree of tretinoin photo degradation (isomerization), 2 tretinoin formulations, tretinoin gel microsphere 0.1% and tretinoin gel 0.025%, alone or in combination with erythromycin-benzoyl peroxide topical gel, were exposed to fluorescent light, incandescent light, or darkness for up to 24 hours. Results of the investigations revealed that after 24 hours of exposure to fluorescent light, 98% of the initial tretinoin in the tretinoin gel microsphere 0.1% formulation remained unchanged. When tretinoin gel microsphere 0.1% was combined with erythromycin-benzoyl peroxide topical gel and exposed to fluorescent light, 99% and 87% of the tretinoin was recovered after 4 and 24 hours, respectively, indicating only a limited amount of degradation. In contrast, exposure of tretinoin gel 0.025% to 24 hours of fluorescent light resulted in up to 69% tretinoin degradation and up to 89% degradation when the gel was combined with the erythromycin-benzoyl peroxide topical gel. The data suggest that the tretinoin gel microsphere 0.1% formulation offers marked protection against tretinoin photo degradation, even in the presence of a strong oxidizing agent such as benzoyl peroxide.

Acne Vulgaris↗
PubMed1995

Two concentrations of topical tretinoin (retinoic acid) cause similar improvement of photoaging but different degrees of irritation. A double-blind, vehicle-controlled comparison of 0.1% and 0.025% tretinoin creams.

BACKGROUND AND DESIGN: The efficacy of topical tretinoin (all-trans-retinoic acid) in treating photoaging is well established. Questions that remain are (1) whether irritation causes all or part of the improvement; (2) the concentration of tretinoin that maximizes clinical response with minimal side effects; and (3) the effects of long-term treatment on components of the cutaneous immune system. To address these issues, 99 photoaged patients completed a 48-week study using 0.1% tretinoin cream (n = 32), 0.025% tretinoin (n = 35), or vehicle (n = 32) once daily in a double-blind manner. Before and after treatment, we assessed histologic features, keratinocyte expression of HLA-DR and intercellular adhesion molecule-1, numbers of epidermal Langerhans' cells and epidermal and dermal T lymphocytes, and vascularity as measured by dermal endothelial cell area. RESULTS: Both 0.1% and 0.025% tretinoin produced statistically significant overall improvement in photoaging of the face compared with vehicle; there were no clinically or statistically significant differences in efficacy between the two concentrations of tretinoin. After 48 weeks, 0.1% and 0.025% tretinoin produced similar statistically significant epidermal thickening (by 30% and 28%, respectively) compared with vehicle (11% decrease) and increased vascularity (by 100% and 89%, respectively) compared with vehicle (9% decrease). By various analyses, irritant side effects (erythema and scaling) were statistically significantly greater with 0.1% tretinoin than with 0.025% tretinoin. No significant changes occurred in any immunologic markers when tretinoin and vehicle treatments were compared. CONCLUSIONS: Tretinoin 0.1% and 0.025% produce similar clinical and histologic changes in patients with photoaging, despite significantly greater incidence of irritation with the higher concentration. The separation between clinical improvement and irritation suggests that mechanisms other than irritation dominate tretinoin-induced repair of photoaging in humans.

Aged↗
PubMed1999

Percutaneous absorption of [3H]tretinoin and systemic exposure to mequinol after dermal application of 2% mequinol/0.01% [3H]tretinoin (Solagé) solution in healthy volunteers.

Solagé is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution, which is being studied for its safety and efficacy as a topical treatment for disorders of skin hyperpigmentation. The purpose of this study was to evaluate the extent of percutaneous absorption of [3H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 cm2 area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% [3H]tretinoin solution. After 12 h, the radiolabelled dose was removed and bid treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [3H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 h) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).

Administration, Topical↗
PubMed1998

Reduced skin irritation with tretinoin containing polyolprepolymer-2, a new topical tretinoin delivery system: a summary of preclinical and clinical investigations.

Novel tretinoin cream and gel formulations have been developed that incorporate polyolprepolymer-2, which is a material designed to help retain drug molecules in and on the skin when applied in topical vehicles. The results of preclinical and clinical investigations have confirmed the beneficial impact of such a vehicle on tretinoin tolerability. In vitro studies with selected polyolprepolymer-containing formulations have reduced initial and cumulative tretinoin percutaneous penetration, and guinea pig studies showed that the gel formulation containing polyolprepolymer-2 caused less erythema and edema than did the corresponding commercially-available tretinoin gel formulation. Human studies with tretinoin containing polyolprepolymer-2 have consistently demonstrated a favorable tolerability profile when compared with commercially-available tretinoin. Use of the polyolprepolymer-2-containing tretinoin formulation in human studies has resulted in reductions in peeling--a problem commonly associated with use of standard tretinoin formulations. These reductions in irritation have not been at the expense of efficacy; acne clinical trial results indicate comparable effectiveness between tretinoin containing polyolprepolymer2 and commercially-available tretinoin.

Acne Vulgaris↗
PubMed2000

A comparative evaluation of tretinoin gel microsphere, 0.1%, versus tretinoin cream, 0.025%, in reducing facial shine.

Tretinoin gel microsphere, 0.1%, is a highly effective anti-acne medication formulated with sponge-like microspheres encapsulating the active ingredient, tretinoin. In addition to minimizing cutaneous irritation, this system may also reduce facial shine. This single-center, double-blind, half-face study evaluated the potential of tretinoin gel microsphere, 0.1%, to reduce the appearance of facial shine compared to tretinoin cream, 0.025%. Thirty-five subjects (ages 12 to 24 years) with moderate acne vulgaris and moderate facial oiliness, were evaluated after 4 consecutive days of product use. On sides treated with tretinoin gel microsphere, 0.1%, investigators found significantly reduced facial shine at 3 and 6 hours posttreatment. Subjects' self-evaluations revealed a significant reduction in facial shine at 3 hours posttreatment. Photographic analyses showed reductions in facial shine for both treatments, but decreases were greater on tretinoin gel microsphere, 0.1%-treated sides. Both therapies were well tolerated, and no adverse events occurred. Tretinoin gel microsphere, 0.1%, has the added benefit of reducing the appearance of facial shine, which is a frequent concern in acne patients.

Acne Vulgaris↗
PubMed2006

Niosomes as carriers for tretinoin. III. A study into the in vitro cutaneous delivery of vesicle-incorporated tretinoin.

The influence of drug thermodynamic activity and niosome composition, size, lamellarity and charge on the (trans)dermal delivery of tretinoin (TRA) was studied. For this purpose, tretinoin was incorporated at saturated and unsaturated concentrations in both multilamellar (MLV) and unilamellar (UV) vesicular formulations using two different commercial mixtures of alkyl polyglucosides: octyl-decyl polyglucoside and decyl polyglucoside. Positively and negatively charged vesicular formulations were prepared using either stearylamine or dicetylphosphate as a charge inducer. Niosomes made with polyoxyethylene (4) lauryl ether and liposomes made with soy phosphatidylcholine were also prepared and studied. Vesicular formulations were characterised by transmission electron microscopy and optical and light polarized microscopy for vesicle formation and morphology, and by dynamic laser light scattering for size distribution. The effect of the vesicular incorporation of tretinoin on its (trans)dermal delivery through the newborn pig skin was also investigated in vitro using Franz cells, in comparison with a commercial formulation of the drug (RetinA). The amount of tretinoin delivered through and accumulated in the several skin layers was detected by HPLC. Overall, obtained results showed that tretinoin cutaneous delivery is strongly affected by vesicle composition and thermodynamic activity of the drug. In particular, small, negatively charged niosomal formulations, which are saturated with tretinoin, have shown to give higher cutaneous drug retention than both liposomes and commercial formulation. Moreover, interactions between skin and vesicles seem to depend on physico-chemical properties of the main component of the vesicular bilayer.

Administration, Cutaneous↗
PubMedDate not supplied

Comparison of clindamycin/benzoyl peroxide, tretinoin plus clindamycin, and the combination of clindamycin/benzoyl peroxide and tretinoin plus clindamycin in the treatment of acne vulgaris: a randomized, blinded study.

In the treatment of mild to moderate acne vulgaris, the combination of an antibiotic and benzoyl peroxide provides enhanced efficacy over the individual agents, with the potential to decrease the emergence of resistant strains of P. acnes. To evaluate treatment regimens combining the daily use of a clindamycin/benzoyl peroxide gel, a tretinoin gel, and a clindamycin gel, the current randomized, evaluator-blind study was conducted. Results demonstrate that once-daily administration of clindamycin/benzoyl peroxide gel (combination formulation) was as effective as clindamycin/benzoyl peroxide gel + tretinoin gel + clindamycin gel. Both of these regimens provided greater efficacy than tretinoin + clindamycin. Treatment with clindamycin/benzoyl peroxide demonstrated a significant benefit over other treatments at Week 2, highlighting its rapid onset of action. All regimens were safe and generally well tolerated, with less severe peeling seen in patients who received clindamycin/benzoyl peroxide. In conclusion, the regimens that included clindamycin/benzoyl peroxide were more effective than tretinoin + clindamycin in the treatment of acne vulgaris, with no clinical advantage of adding tretinoin + clindamycin to once-daily clindamycin/benzoyl peroxide treatment.

Acne Vulgaris↗
PubMed2003

Niosomes as carriers for tretinoin. II. Influence of vesicular incorporation on tretinoin photostability.

In this work, we compared the chemical stability of tretinoin (TRA) in methanol and in vesicular suspensions exposed both to UV and artificial daylight conditions with the aim of evaluating the potential of niosomes as topical carriers capable of improving the stability of photosensitive drugs. Tretinoin-loaded niosomes were prepared from polyoxyethylene (4) lauryl ether (Brij 30), sorbitan esters (Span 40 and Span 60) and a commercial mixture of octyl/decyl polyglucosides (Triton CG110). Liposomes made from hydrogenated (P90H) and non-hydrogenated (P90) soy phosphatidylcholines were also prepared and studied. In order to evaluate the influence of vesicle structure on the photostability of tretinoin, TRA-loaded vesicles were prepared by the film hydration method, extrusion technique and sonication. After UV irradiation, TRA dissolved in methanol degraded very quickly while the incorporation in vesicles always led to a reduction of the photodegradation process. The photoprotection offered by vesicles varied depending on the vesicle structure and composition. After fluorescent light irradiation for 21 days, not all the studied vesicular formulations improved TRA stability when compared with the free drug in methanol. Tretinoin incorporated in P90 or Span vesicles presented a half-life shorter or very close to that of the free drug. However, the inclusion of TRA in P90H liposomes and Brij 30 or Triton CG110 niosomes retarded the drug photodegradation.

Administration, Topical↗
PubMed1998

Comparative tolerance of adapalene 0.1% gel and six different tretinoin formulations.

Adapalene 0.1% gel (Differin gel) is a recently introduced topical treatment for mild to moderate acne which has been demonstrated to be much better tolerated and at least as effective as tretinoin 0.025% gel. We compared the tolerance of adapalene 0.1% gel with six different formulations and concentrations of tretinoin. A total of 55 healthy human subjects were enrolled in two controlled, randomized, observer blinded, intraindividual comparison studies. In the first study, adapalene 0.1% gel was evaluated for its 21-day cumulative irritation potential compared with tretinoin 0.025%, 0.05% and 0.1% cream, tretinoin 0.01% and 0.025% gel, and petrolatum (control). In the second study, adapalene 0.1% gel was evaluated for its 21-day cumulative irritation potential compared with tretinoin 0.025%, 0.05% and 0.1% cream, tretinoin 0.1% gel microsphere, and petrolatum (control). In both studies, cumulative irritation scores helped to define three groups of common irritancy potential, with significant differences between each group. In study A, the three groups were in descending order of irritancy: tretinoin 0.1% cream and tretinoin 0.05% cream; tretinoin 0.025% gel, tretinoin 0.01% gel and tretinoin 0.025% cream; adapalene 0.1% gel and petrolatum (control). In study B, the three groups were in descending order of irritancy: tretinoin 0.1% cream; tretinoin 0.05% cream, tretinoin 0.025% cream and tretinoin 0.1% gel microsphere; adapalene 0.1% gel and petrolatum (control). The experimental results show that adapalene 0.1% gel is significantly better tolerated than any of six formulations of tretinoin, including two gels, three creams and a microsphere formulation, ranging in potency from 0.01% to 0.1%.

Acne Vulgaris↗
PubMed1997

A developmental toxicity study of tretinoin emollient cream (Renova) applied topically to New Zealand white rabbits.

BACKGROUND: Embryofetal developmental toxicity associated with oral administration of vitamin A analogs has led to concern about risks from topical application. OBJECTIVE: This study was conducted to evaluate the potential developmental toxicity of tretinoin emollient cream when applied to the skin of pregnant New Zealand white rabbits during organogenesis (gestational days 7 through 19). METHODS: Twenty rabbits each were randomly assigned to a control group (group I) or to receive vehicle (group II) or tretinoin emollient cream topically at dosages of 10 (0.05 mg/kg*, group III) or 100 (0.5 mg/kg*, group IV) times that used clinically in humans. Does and fetuses were examined for tretinoin-induced toxic effects, and maternal plasma tretinoin and metabolite levels were measured. RESULTS: The rate of abortion was increased significantly in does in group IV (p < or = 0.01) compared with the control group. Dosage-dependent increases in incidence and severity of skin reactions occurred in groups administered the vehicle and the two dosages of tretinoin. Does in groups III and IV had clinical and necropsy observations that were considered direct or indirect effects of tretinoin administration, persistent weight loss, and reduced feed consumption. Maternal endogenous plasma tretinoin levels were below the lower limit of quantitation of 5 ng/ml and were not significantly altered with treatment. Group IV had significantly reduced mean fetal body weight (p < or = 0.01) and a greater frequency of resorptions compared with group I. Although external, visceral, or skeletal alterations occurred at significantly greater levels in group III, they were unrelated to tretinoin administration because the fetal incidences were not dosage dependent, and the litter incidence did not significantly differ from the control group values. CONCLUSION: Maternally toxic dosages of tretinoin were associated with an increased incidence of abortions and resorptions and reduced fetal body weight, two end points of developmental toxicity. Consistent with the absence of detectable tretinoin plasma levels, however, no changes in fetal morphology were attributable to tretinoin administration. *The milligrams per kilogram dosage refers to the amount of active ingredient (tretinoin). The 0.05 mg/kg and 0.5 mg/kg groups were treated with 0.005% and 0.05% wt/wt tretinoin emollient cream formulation. The 0.05% tretinoin emollient cream is the Renova clinical formulation. The 10 and 100 times clinical multiples refer to Renova clinical multiples and are based on a 50 kg adult patient's applying 500 mg of 0.05% tretinoin emollient cream formulation daily to yield a clinical dosage of 0.005 mg/kg.

Abnormalities, Drug-Induced↗
PubMed1997

A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats.

BACKGROUND: Although it is well established that oral tretinoin produces embryofetal developmental toxicity in various laboratory animals, the toxic potential of topical tretinoin has not been clearly established. OBJECTIVE: This study of tretinoin administration to pregnant Wistar rats was conducted to determine whether topical tretinoin is associated with adverse effects on reproductive function or embryofetal growth and development and to compare outcomes with topical and oral tretinoin. METHODS: Topical and oral tretinoin (1 to 20 mg/kg and 1 to 10 mg/kg, respectively) or vehicles alone were administered on gestational days 6 through 16 and 15, respectively. RESULTS: Topical tretinoin: After topical treatment, dams receiving 10 mg/kg daily or greater had severe local and systemic toxicity prompting discontinuation of tretinoin. At doses of 2.5 mg/kg or greater, dam weight gain and food consumption were significantly less than those of control dams. Offspring of dams receiving 5 mg/kg weighed significantly less, and offspring of dams receiving 2.5 mg/kg or greater had a significantly greater occurrence of supernumerary ribs compared with control offspring. Oral tretinoin: After oral treatment, in the absence of maternal toxicity, significantly more offspring of dams receiving 5 mg/kg or greater had supernumerary ribs, and offspring of the 10 mg/kg treatment group had a greater incidence of cleft palate than had control offspring. CONCLUSION: The local and systemic maternal toxicity found in association with supernumerary ribs and low weights in the offspring at topical tretinoin doses of 2.5 and 5 mg/kg suggests that these developmental effects may be nonspecific or maternally mediated. Oral tretinoin at doses of 10 mg/kg, however, is clearly associated with embryofetal alterations in the Wistar rat.

Abnormalities, Drug-Induced↗
PubMed2001

Liposomes with tretinoin: a physical and chemical evaluation.

The comedolytic activity of tretinoin, incorporated in liposomes, is five to ten times higher compared to the conventional preparations and also the local tolerability is much better. This implies the big interest of a study on tretinoin in liposomes. First, the encapsulation capacity of tretinoin in the liposomes was determined. Therefore, a series of liposomes was prepared with different concentrations of tretinoin (1-6 mg/ml buffer) and lipids (100-300 mg/ml buffer) (egg phosphatidyl choline/cholesterol) with buffers pH=5 and 7. These series of liposomes were evaluated microscopically on the presence of tretinoin crystals outside the liposomes. The highest incorporation capacity was obtained using 2 mg of tretinoin and 300 mg of lipids per milliliter of buffer pH=5. The chemical stability of tretinoin in the liposomes, evaluated during 1 year, revealed no remarkable loss in tretinoin content, even when stored at 25 degrees C. The photo-degradation of tretinoin in the liposomes was about two times slower than in castor oil, but tretinoin degraded to approximately 25% of its initial content. The chemical evaluation of the lipid fraction showed no oxidative degradation of the polyunsaturated fatty acids in EPC because the determined concentration of conjugated dienes and hydroperoxides, two oxidative degradation products, was <1%, which is negligible. Finally, the in-vitro release of tretinoin from the liposomes, evaluated with a dialysis technique, was very low, but this is not a problem for topical use.

Chromatography, High Pressure Liquid↗
PubMed1997

Clinical pharmacokinetics of tretinoin.

Recent reports of the dramatic antitumour effect of tretinoin (all-trans retinoic acid) in patients with acute promyelocytic leukaemia (APL) have generated a great deal of interest in the use of this drug as a chemopreventive and therapeutic agent. However, the biological efficacy of tretinoin is greatly impaired by (presumably) an induced hypercatabolism of the drug leading to reduced tretinoin sensitivity and resistance. Several pharmacokinetic studies have shown that plasma drug exposure [as measured by the plasma area under the concentration-time curve (AUC infinity)] declines substantially and rapidly when the drug is administered in a long term daily tretinoin regimen. These observations led to the hypothesis that the rapid development of acquired clinical resistance to tretinoin may have a pharmacological basis and result from an inability to present an effective drug concentration to the leukaemic cells during continuous treatment. The principal mechanisms proposed to explain the increased disappearance of tretinoin from plasma include: (i) decreased intestinal absorption; (ii) enhanced enzymatic catabolism; and (iii) the induction of cytoplasmic retinoic acid binding proteins (CRABP), which leads to increased drug sequestration. The most favoured explanation is that continuous tretinoin treatment acts to induce drug catabolism by cytochrome P450 (CYP) enzymes. Several strategies aimed at preventing or overcoming induced tretinoin resistance have been, and are being, planned. These strategies include intermittent dose administration, administration of pharmacological inhibitors of CYP oxidative enzymes, combination with interferon-alpha and intravenous administration of liposome-encapsulated tretinoin. As these strategies are now under investigation and the number of patients enrolled is small, further studies are needed to determine the efficacy and toxicity of these new schedules of drug administration. In this article we provide an overview of the relevant aspects of tretinoin physiology and pharmacokinetics, and summarise the current status of knowledge to help in the better optimisation of tretinoin administration.

Antineoplastic Agents↗