calcipotriene and Drug-Related-Side-Effects-and-Adverse-Reactions

Calcipotriol (calcipotriene) is a synthetic vitamin D3 derivative that is a standard treatment option for psoriasis. It is generally well tolerated with minimal side effects. Due to its ability to reduce keratinocyte proliferation and induce keratinocyte differentiation as well as its immunomodulatory effects, calcipotriol has been used to treat a variety of skin disorders such as atopic dermatitis, actinic keratoses, lichen planus, seborrheic keratoses, and vitiligo [1]. We surveyed the literature examining the use of calcipotriol for non-psoriatic dermatologic disease.

Topics: Calcitriol; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Psoriasis

This chapter covers the hazards that some topical pharmaceutical preparations pose to animals who consume them. Included are medications containing calcipotriene, vitamins A and D, zinc oxide, 5-fluorouracil, brimonidine, imidazoline decongestants, local anesthetics, corticosteroids, antibiotics, salicylates, and benzoyl peroxide.

Topics: Administration, Oral; Adrenal Cortex Hormones; Anesthetics, Local; Animals; Anti-Bacterial Agents; Benzoyl Peroxide; Brimonidine Tartrate; Calcitriol; Drug-Related Side Effects and Adverse Reactions; Fluorouracil; Imidazoles; Ointments; Quinoxalines; Salicylates; Vitamin A; Vitamin D; Zinc Oxide

Calcipotriol, a vitamin D analogue is widely used in the treatment of psoriasis. However, poor adherence to topical therapy has led to an ineffective use of the medication and built a barrier to the treatment's success. A water-free lipid-based formulation system has been developed to improve dosage and cosmetic properties along with patient compliance. This study was conducted to evaluate the efficacy and cutaneous safety of water-free lipid-based formulations containing calcipotriol (50 μg/g) as compared to their corresponding vehicles and marketed calcipotriol formulations in a psoriasis plaque test. In total, 24 subjects with chronic psoriasis vulgaris were enrolled in this single-center, randomized, vehicle, and comparator-controlled clinical trial and treated once daily over a 12-day period (10 applications). The anti-psoriatic effect was evaluated by sonographic measurement of psoriatic infiltrate and investigators' clinical efficacy assessments. The mean reduction in psoriatic infiltrate from baseline to day 12 (end of trial) with lipid-based calcipotriol formulations (-34% and -37%) was statistically significant (P<0.0001) when compared to their corresponding vehicles (6% and -4%) but not when compared with marketed calcipotriol solution and cream (-34% and -49% respectively). Mean total clinical assessment scores of these lipid-based calcipotriol formulations (1.7 each) were between those of the two comparators - greater than marketed calcipotriol solution (1.3) but lower than cream (2.0). Overall, nine mild non-serious treatment-emergent adverse effects related to all calcipotriol formulations were reported in four subjects, but all recovered at the follow-up visit. Therefore, novel lipid-based formulations of calcipotriol were clearly more efficacious than their corresponding vehicles and considered as safe therapy against psoriasis vulgaris. J Drugs Dermatol. 2023;22(2):197-202. doi:10.36849/JDD.7151Citation: Holmbäck J, Carlsson A, Rinwa P. Efficacy and safety of water-free lipid formulation system containing calcipotriol against psoriasis vulgaris. J Drugs Dermatol. 2023;22(2):197-202. doi:10.36849/JDD.7151  .

Topics: Calcitriol; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Emollients; Humans; Ointments; Psoriasis; Treatment Outcome

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration

Chemotherapy-induced alopecia is thought to result from cytotoxic and apoptosis-related damage to the hair follicle. This study was designed to confirm whether keratinocyte apoptosis is indeed induced in growing (= anagen) hair follicles of C57 BL/6 mice after the injection of cyclophosphamide, using improved methods for histologic detection of apoptotic cells in murine skin. More importantly, we asked whether topical calcitriol-analogs are able to modulate cyclophosphamide-induced apoptosis in vivo, because there are conflicting reports on the effects of calcitriols on apoptosis in vitro. Anagen was induced in telogen mice on day 0 by depilation. Starting on day 5 post-depilation, the back skin of mice was topically treated with either 0.2 microg 1,25-dihydroxyvitamin D3, 2.0 microg calcipotriol, 0.02 microg KH 1060, or vehicle (ethanol) only. On the last day of treatment (i.e., day 9 post-depilation), all mice received 150 mg cyclophosphamide i.p. per kg as a single dose to induce alopecia, or vehicle (aqua dist.). Analysis of the treated skin by in situ-end labeling (using a modified terminal UTP nucleotide end labeling technique suitable for murine skin), by Hoechst 33342 stain, and by DNA electrophoresis on days 10 and 14, revealed the induction of massive apoptosis in cyclophosphamide-treated anagen hair bulbs, which was most prominent on day 10, whereas controls showed no follicular apoptosis. The calcitriol-pretreated groups demonstrated a significant reduction of apoptosis, with a maximal inhibition seen on day 14. This confirms that cyclophosphamide indeed induces massive keratinocyte apoptosis in anagen hair follicles, and provides evidence that topical calcitriol-analogs can suppress epithelial cell apoptosis in vivo. The mouse model employed here offers an excellent tool for dissecting the as yet poorly understood controls of keratinocyte apoptosis in situ and its pharmacologic manipulation.

Topics: Administration, Topical; Alopecia; Animals; Apoptosis; Calcitriol; Cyclophosphamide; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Female; Hair Follicle; Immunosuppressive Agents; In Situ Nick-End Labeling; Mice; Mice, Inbred C57BL