Source: Health Products and Food Branch (CA) Revision Year: 2022
DERMATOP (prednicarbate ointment/emollient cream, 0.1%) is a mid-potency, non-fluorinated topical corticosteroid. Topical corticosteroids are synthetic derivatives of cortisone which are effective when applied locally to control many types of inflammatory, allergic and pruritic dermatoses. The mechanism of anti-inflammatory activity of topical corticosteroids is unclear. However, corticosteroids are thought to induce phospholipase A2 inhibitor proteins, preventing arachidonic acid release and the biosynthesis of potent mediators of inflammation.
Effect on proliferative capacity of fibroblasts in culture by gluco-corticosteroids was evaluated. Growth inhibition was not observed with prednicarbate or hydrocortisone at a concentration of 10 mcg/mL while betamethasone valerate and clobetasol-17-propionate produced inhibition at concentrations of 5 and 2 μg/mL, respectively.
The anti-inflammatory activity of prednicarbate has been primarily compared with desoximetasone.
Prednicarbate and desoximetasone have been shown to be equieffective against the inflammatory response to the irritant croton oil when applied topically to the ears of rats or mice. The IC50 in mice was 0.08 mg/mL while in rats it was 1.4 mg/mL for both prednicarbate and desoximetasone. Rat thymus weight was reduced by both compounds at the 3 mg/mL dose although the percent reduction with prednicarbate (27%) was less than that produced by desoximetasone (60%).
In a model of delayed hypersensitivity, topical prednicarbate (IC50 = 0.03 mg/mL) was as potent as topical desoximetasone (IC50 = 0.06 mg/mL) at inhibiting oxazolone-induced ear edema in mice.
In the carrageenan-induced paw edema test in rats, prednicarbate and desoximetasone, when administered as admixtures with carrageenan, reduced paw swelling with approximate ED50's of 20 and 10 mcg, respectively.
In the cotton pellet granuloma model in rat, prednicarbate showed weak long-term effects when it was included in the cotton pellet at a dose of 0.3 mg/pellet: thymus and adrenal weights were unchanged when compared with controls. Desoximetasone was a potent inhibitor of granuloma at 0.003 mg/pellet. After 0.03 mg/pellet desoximetasone, thymus involution and reduced adrenal weights were observed.
To determine whether topical application results in systemic activity, prednicarbate and desoximetasone were used on hairless rats in the cotton-pellet granuloma model. Granuloma weight, adrenal and thymus involution were measured after application of doses up to 0.3 mg/day for seven days. At 0.3 mg/day, there was only a thymus involution with prednicarbate whereas all three parameters were significantly reduced by 0.03 mg/day of desoximetasone. Reduction in body weight was observed with desoximetasone at 0.03 and 0.01 mg doses but not with prednicarbate at doses of 0.03-0.3 mg.
In a seven-day study, in the cotton-pellet granuloma test in rat, a daily subcutaneous injection of prednicarbate significantly reduced the dry weight of granuloma and thymus gland only at doses of 1 mg/kg , but not at doses of 0.1 and 0.3 mg/kg. Desoximetasone at a dose of 0.1 mg/kg resulted in a significant reduction in granuloma and thymus weights, but not at a dose of 0.03 mg/kg. Retardation of body weight increase was also apparent with all doses of both compounds. These results indicate that after systemic administration, prednicarbate has 1/10 the activity of desoximetasone.
In the carrageenan-induced paw edema in rat, prednicarbate (ED50 = 0.4 mg/kg) subcutaneous was approximately seven times less potent than desoximetasone (ED50 = 0.06 mg/kg) by the same route.
To evaluate adrenal suppression following topical administration, prednicarbate or desoximetasone was applied to shaved backs of rats for seven days. Corticosterone release was decreased by approximately 50% after doses of 0.01-0.05 mg/kg/day of prednicarbate. Desoximetasone suppressed corticosterone release dose-dependently (ED50 = 0.004 mg/kg/day).
The gluconeogenic activity of prednicarbate and desoximetasone was assessed in adrenalectomized rats. Liver glycogen content was not altered by a subcutaneous dose of 0.3 mg/kg prednicarbate but a subcutaneous dose of 0.01-0.03 mg/kg of desoximetasone increased liver glycogen.
In adrenalectomized rats with free accessible sodium chloride 0.9% solution as drinking water, urine volume increases were approximately equal after prednicarbate (0.3-3mg/kg) or desoximetasone subcutaneous (0.03-0.3 mg/kg). Sodium, potassium and chloride excretion were elevated more by desoximetasone than prednicarbate compared to saline controls. In adrenalectomized rats with free accessible drinking water instead of sodium chloride 0.9% solution, diuresis and saluresis were increased at doses of 0.3-1.0 mg/kg of prednicarbate. Desoximetasone at 0.01 mg/kg increased diuresis and saluresis and had a prolonged action.
Pharmacokinetics of prednicarbate were examined in rats and pigs. Subcutaneous administration and topical application of fatty ointment were evaluated in the rat. Percutaneous absorption and localization in the skin of pig was also evaluated. Prednicarbate labelled with C14 was used in all studies.
Following subcutaneous administration of about 1 mg/kg body weight of prednicarbate to rats, peak blood levels reached 0.056 μg/mL in females, 1-2 hours post dosing and 0.056 μg/mL also in males, 2-6 hours post-dosing. In males, serum elimination half-lives were 19.4 and 204 hours while in females they were 4 and 15.3 hours; the difference is probably attributable to a more rapid absorption from the subcutaneous depot in females. The radioactivity administered with labelled prednicarbate was excreted by males about 65% in the faeces and 30% in the urine. In females these parameters were about 70% and 18%, respectively. About 68% in females and 57% in males of the radioactivity was recovered in urine and faeces after 24 hours. Recovery was almost completed by the seventh day. Excretion half-lives for urine in males and females were 7-8 and 37-39 hours. For faeces, they were between 11 and 42 hours in males and 16 hours in females. Residual radioactivity appeared primarily at injection site, gastro-intestinal tract and in the carcass of animals.
A dose of about 1.2 mg/kg body weight of prednicarbate was applied topically as a 0.25% fatty ointment to intact and abraded skin of male rats. Measurable blood levels appeared 0.5-2.0 hours after application. Peak blood levels were 0.0076 μg/mL in intact skin and 0.0099 in abraded skin. Between 5 and 6% of dose was excreted in urine and faeces in 24 hours irrespective of skin condition. At 24 hours, the intestinal tract contained 3-5% of the administered dose in depilated dorsal skin of rat. In intact, horny layer, the remaining organism contained less than 6% of the dose administered while a damaged horny layer contained around 11%. Irrespective of skin condition, around 17-18% was found at site of application. The absorption rate was estimated at 14% and 22% for intact and abraded skin, respectively.
The percutaneous absorption was evaluated in pigs. A dose of 0.19-0.29 mg in a 0.25% fatty ointment was applied onto shorn intact and abraded skin. Six hours post application, epithelium contained 3.7% and 5.4% of the dose administered in abraded and intact skin, respectively. There was a tendency for a higher transdermal absorption in abraded horny layer of epidermis.
Following subcutaneous administration of 1 or 10 mg/kg body weight to rats, about one-third of the renally eliminated metabolites was identified as 20-dihydroprednisolone and as 6-β-hydroxy20-dihydro-prednisolone. No unchanged prednicarbate was detectable in the urine. The presence of prednisolone and prednisone accounted for about 1%. The same metabolites appeared in the faeces but accounted for 1/10 of excreted dose. In addition, there were about 20 or more metabolites present in urine and faeces in very small concentrations. The metabolism of prednicarbate showed great similarity to that of prednisolone.
The acute toxicity of prednicarbate was determined orally in immature mouse and rat, subcutaneously in immature rat and topically in white rabbits. The oral LD50's were 3102 mg/kg (2475-3719) in mouse and greater than 8000 mg /kg in rat. The subcutaneous LD50 was 1366 mg/kg (1101-1695) in the rat. The topical LD50 was greater than 250 mg/kg in the white rabbit. Principal signs of systemic toxicity were considered typical of corticosteroids and included reduced body weight, ruffled hair or loss of hair, squatting, abdominal position, reduced motility and diarrhea. Pathological changes were also typical of a cortisone effect and included, for example, liver cell necrosis and fatty degeneration of the residual parenchyma, atrophy of the spleen, foci of necrotic myocardial fibers, fatty degeneration of epithelia of renal tubules.
The subacute toxicity of prednicarbate was determined subcutaneously and topically in immature rat, in rabbit and in dog for periods of 20 to 90 days.
Prednicarbate was administered, as suspension, subcutaneously to groups of 15 male and 15 female immature rats at doses of 0 (vehicle and saline), 0.05, 0.2 and 0.8 mg/kg daily for 90 days. Doses of 0.2 and 0.8 mg/kg produced a dose-dependent inhibition in gain of body weight and decreased lymphocytes and increased segmented neutrophils. A dose of 0.8 mg/kg produced slightly increased serum GOT and GPT levels and decreased weight of adrenals. These changes were reversible and considered typical of large doses of corticosteroids.
The main degradation product of prednicarbate (S 80 9402) was given subcutaneously for 2 weeks to rats (0.1, 0.5 and 2.5 mg/kg/day), and to dogs (0.1, 0.32 and 1.0 mg/kg/day). Observations included decreased weight gains, increased urine pH (rats only), and other findings consistent with the known effects of corticosteroids.
Prednicarbate was topically applied to abraded and intact back of 4 groups of 4 male and 4 female white rabbits at doses of 0, 200, 500 and 1000 mg/kg daily for 20 days. Four deaths occurred, unrelated to treatment, and comprised one female control, one male and one female of the 500 mg/kg group and one male of the 1000 mg/kg group. Changes considered typical of a corticosteroid administration were observed and affected the body weight, lymphocytes and leukocytes, transaminases and alkaline phosphatase, absolute and relative weight of liver and adrenals. Microscopic changes observed are representative of a corticosteroid administration and consisted of increased amounts of hepatic glycogen and accelerated thymic involution.
Prednicarbate was given subcutaneously into the nape area to four groups of 4 male and 4 female beagle dogs at doses of 0, 0.1, 0.32 and 1.0 mg/kg daily for 3 months. Ten deaths occurred: one control male at day 45 because of peritonitis secondary to incidental ileus with perforation of jejunum, one female of 0.32 mg/kg group at day 77 due to extensive abscesses in area of injection, and the 4 males and 4 females of 1.0 mg/kg groups, of which one female died at day 18; the others were killed at day 40 because of moribund condition due to bacterial infection secondary to corticosteroid administration. A dose-dependent inhibition of body weight and increased consumption of water was observed. Diarrhea was dose-dependent. There was also a dose-dependent degree of lymphopenia and neutrophilia, an effect typical of corticosteroids. Dose-dependent changes ranging from not significant to significantly different were observed for erythrocytes, haemoglobin, haematocrit, anemia and leukocytosis. A dose-dependent change was observed for serum GOT, GPT and alkaline phosphatase levels in 0.32 and 1.0 mg/kg groups. There were microscopic changes consisting of reduced adrenals, enlarged and clay brown discoloration of liver, reduced prostate, and dark brown discoloration of kidneys. Microscopic changes were attributed to the glucocorticoid activity and shown to be largely reversible during recovery period and included adrenals, thymus, lymphoreticular organs, liver and heart, and skeletal musculature and diaphragm at the 0.32 mg/kg dose level.
DERMATOP (prednicarbate ointment 0.1%) was topically applied to groups of 15 male and 15 female rats at doses of 0, 0.1, 0.3 and 1.0 mg/kg daily for 6 months. Two deaths, one male of 0.1 mg/kg dose at week 20 because of moribund condition and metastasizing lymphosarcoma and one male of 0.3 mg/kg dose at week 7 due to extensive hepatocellular necrosis. Compoundrelated changes consisted of increased incidences of alopecia and dermal findings at application sites with microscopic epidermis and dermis changes, and hair follicles and adnexa changes. Dose-related and more pronounced changes in males than females were observed for body weight, haematological parameters, liver enzymes and incidence and degree of urinary protein and of severity of thymic involution of 1.0 mg/kg group which may be a reflection of the overall toxic state of animals of this latest group.
Reproduction and teratological effects were assessed in three studies in the rat and one study in the rabbit following subcutaneous administration.
The effects on fertility-pregnancy, and post-natal development were determined in four groups of 30 male and 30 female rats receiving as suspension doses of 0, 0.05, 0.2 and 0.8 mg/kg daily. Males of 0.05 and of 0.2 mg/kg groups exhibited transiently a local thinning of coat in the region of the eyes, ears and nape of neck, while they persisted in males and 3 females of the 0.8 mg/kg dose. Males of the 0.8 mg/kg group exhibited piloerection that was compound-related. A dosedependent body weight reduction was observed in males and females of the 0.2 and 0.8 mg/kg dosage group. The 0.8 mg/kg dose produced slight retardation in growth of foetuses and placentas, reflected by a slight impairment of ossification of foetal skeleton. The dams rearing their offspring exhibited a slight increase in supernumerary implantation sites, a possible indication that some foetuses were consumed by mother at birth.
Toxic effects on embryos of prednicarbate were determined in four groups of 20 pregnant rats receiving, as suspension, doses of 0, 0.56, 2.24 and 9.0 mg/kg body weight daily from gestational day 7 through 16. A second control and 9.0 mg/kg groups were added to the study since especially high dose animals exhibited a reduction in placental weights. Doses of 2.24 mg/kg daily had a slight retardation in weight gain of dams and reduced liver and spleen weights. Foetuses were slightly stunted and frequently exhibited thickened and undulating ribs. Dams of 9.0 mg/kg dose experienced piloerection, moderate reduction of weight gain, reduced liver and spleen weights. Foetuses were moderately stunted which was apparent because of a poor ossification of skeleton. Umbilical hernias and skeletal deformations were also frequently encountered in foetuses. The added groups showed that the retardation of the foetuses and bone deformations were reversible postnatally. The pre and postnatal foetal death rate and the fragmented dorsal vertebral centers exhibited in numerous young were very slightly increased and especially in offspring reared to weaning age.
The effects of prednicarbate on peri and postnatal development were assessed in four groups of 20 pregnant rats receiving as suspension doses of 0, 0.1, 0.5 and 2.5 mg/kg daily from gestational day 17 to day 21 after parturition. Two dams died: one control and one of 0.1 mg/kg dose group unrelated to compound. Dams of 0.5 and 2.5 mg/kg doses exhibited slight to moderate reduction of body weight during lactation period. Dams of the 2.5 mg/kg group had reduced splenic weights. A slight reduction in birth weights was observed in offspring of the 2.5 mg/kg dose.
The effects of prednicarbate on the embryo were determined in four groups of 15 pregnant rabbits receiving as suspension doses of 0, 0.0056, 0.0180, and 0.0560 mg/kg daily from gestational day 7 through 19. One death occurred at 0.0560 mg/kg, unrelated to prednicarbate. Abnormalities were observed in posture of the forelimbs in three foetuses from two litters of 0.0180 mg/kg dose. One of the foetuses was stunted and also exhibited anomalies of head, abdomen and limbs and causal connection with the compound cannot be ruled out. Dams of 0.0560 mg/kg had increased liver weights. A slight increase in intrauterine foetal death rate was observed. Foetuses of the 0.056 mg/kg dose were stunted and exhibited lighter placental weights, frequently cleft palates, impairment of ossification of sternum, umbilical hernias and anomalies in posture of forelimbs. A slight decrease in viability of foetuses was noted.
In the Ames test, prednicarbate was assessed in five strains of Salmonella typhimurium and one strain of Escherichia coli. Prednicarbate, at concentrations ranging from 4 to 500 μg/plate, was negative for mutagenic activity.
In the HGPRT forward mutation assay, the ability of prednicarbate to cause mutations in cultured hamster lung fibroblasts was assessed with and without metabolic activation. Doses ranging from 10 to 75 μg/mL were not considered mutagenic.
In the micronucleus test, prednicarbate was given subcutaneously as a suspension to four groups of five male and female mice at single doses of 0, 1.0, 12.5 and 160.0 mg/kg. No increase in occurrence of polychromatic erythrocytes with micronuclei was observed and therefore, the compound was negative for mutagenicity.
DERMATOP potential for irritation was determined in guinea pig in four studies and in rabbit in five studies following a topical application.
In guinea pig, prednicarbate 0.25%, desoximetasone 0.25% and placebo solution in one study; prednicarbate 0.25%, desoximetasone 0.25% and placebo ointment in another study have been compared following topical application on the flanks. In the two other studies, prednicarbate 0.1% and 0.25% as fatty ointment, and prednicarbate 0.25% as cream were evaluated following topical application on flanks.
The tested sites comprised one half abraded and one-half intact skin of groups of three males and three females per testing formulation. Subsequently, the treated site was occluded. The irritation indexes for prednicarbate 0.25%, desoximetasone 0.25% and placebo solution were 0.04, 0.04 and 0 respectively, and for ointment 0.08, 0.08 and 0.0 respectively; for prednicarbate 0.1% and 0.25% as fatty ointment these were 0.29 and 0.25 respectively and for prednicarbate 0.25% cream it was 0.0; thus, preparations were found non irritant.
In rabbit, prednicarbate 0.25%, desoximetasone 0.25% and placebo solution in one study; prednicarbate 0.25%, desoximetasone 0.25% and placebo ointment in another study have been compared following a topical application on the flanks. In two other studies, prednicarbate 0.1% and 0.25% as fatty ointment, and prednicarbate 0.25% as cream were evaluated after application on flanks. The tested site comprised one half abraded and one-half intact skin of groups of three males and three females per testing formulation. Subsequently, the tested site was occluded. The irritation indexes for prednicarbate 0.25%, desoximetasone 0.25% and placebo solution were 0.1 and for the ointment 0.01, 0.2 and 0.2 respectively. For the fatty ointment, indexes for prednicarbate 0.1% and 0.25% were 0.0 and 0.08 respectively, and for the cream base it was 0.29; thus, the compound is a non irritant.
In a rabbit study, a single 100 mg dose of DERMATOP (prednicarbate ointment, 0.1%) was instilled in the right eye while the left served as control and remained untreated. No sign of ocular mucosal irritation was observed after 24-72 hours and the preparation was considered nonirritant in this model.
Primary irritation studies were performed in the rabbit using prednicarbate emollient cream, 0.1%. This was found not to be an eye irritant (0.1 mL/animal) or a dermal irritant (0.5 g/site) on either abraded or intact skin. DERMATOP EMOLLIENT CREAM 0.1% (commercial formulation) was also tested on rabbit skin and found to have a primary dermal irritation index of 0.0; no irritation was observed on either intact or abraded skin.
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