Pathophysiological profile of awake and anesthetized pigs following systemic exposure to the highly lethal ricin toxin

Background: Skin is the largest organ of the body and helps to regulate several physiological functions. It acts as a barrier that protects the body against UV-radiation, toxic substances, infections, etc. The abnormal growth of the skin cells is called skin cancer. Different types of skin cancer can be classified as Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC); which mainly occur due to chronic exposure to UV- sunlight and pollution. Methods: The conventional topical treatments of skin cancer such as cream, gel, ointment, etc., are more occlusive and thus they do not penetrate deep into the skin (dermal layer) and remain at the upper part of the skin (epidermal layer). The stratum corneum acts as a physiological barrier for the drug-loaded in the conventional formulation. The novel carrier systems have the potential to facilitate the penetration of the drug deep into the skin (dermal layer) because these have less size and higher flexibility than conventional treatment. Conclusion: In the present review, we have discussed various novel carrier systems being investigated for the topical application of chemotherapeutic agents for efficient skin targeting and better dermatological as well as therapeutic benefits with minimal systemic exposure and toxicity.

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Metabolic Conversion from Co-existing Ingredient Leading to Significant Systemic Exposure of Z-butylidenephthalide, a Minor Ingredient in Chuanxiong Rhizoma in Rats

Current Drug Metabolism ◽

10.2174/1389200211209050524 ◽

2012 ◽

Vol 13 (5) ◽

pp. 524-534 ◽

Cited By ~ 13

Author(s):

Ru Yan ◽

Nga Ling Ko ◽

Bin Ma ◽

Yun Kau Tam ◽

Ge Lin

Keyword(s):

Systemic Exposure ◽

Metabolic Conversion ◽

A Minor

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The design, synthesis, pharmacokinetic and pharmacodynamic evaluation of acyloxyalkyl-substituted T705 prodrugs

Medicinal Chemistry ◽

10.2174/1573406415666191022143933 ◽

2019 ◽

Vol 15 ◽

Author(s):

Xingzhou Li ◽

Tianhong Zhang ◽

Wu Zhong

Keyword(s):

Plasma Concentration ◽

Development Strategy ◽

Parent Compound ◽

Systemic Exposure ◽

Parent Drug ◽

New Drugs ◽

Structure Modification ◽

Design Synthesis ◽

Pharmacokinetic Properties

Background: The pharmacokinetic properties of T705 are not optimal for the development of new drugs. Objective: To improve the pharmacokinetic properties of T-705, structure modification of T-705 was conducted using a prodrug strategy. Method: The acidic amide H atom (N4-H) of T705 was attempted to be replaced with acyloxyalkyl groups following the prodrugs development strategy for carboxylic acids, and the resulting compounds were investigated whether could work as prodrugs and contribute to improving the pharmacokinetic properties of the parent compound T705 in vivo. Results: 4-acyloxyalkyl-T705 (4a–e), did act as prodrugs in vivo. 4-iso-butyryloxymethyl-T705 (4a) and 4-acetoxymethyl-T705 (4b) could significantly improve the plasma concentration and systemic exposure for T705, compound 4a displayed non inferior anti-influenza activities, compared with its parent drug T705. Conclusion: Our prodrugs development strategy for T705 is feasible, which may serves as a reference to prodrugs development of similar heterocyclic amides compounds.

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Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

Medicinal Chemistry ◽

10.2174/1573406416666201120102905 ◽

2020 ◽

Vol 16 ◽

Author(s):

Xi He ◽

Wenjun Hu ◽

Fanhua Meng ◽

Xingzhou Li

Keyword(s):

Plasma Concentration ◽

Broad Spectrum ◽

Plasma Concentrations ◽

Antiviral Drug ◽

Systemic Exposure ◽

Pharmacokinetic Profile ◽

Hydroxyl Group ◽

First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

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Nickel Allergy: Epidemiology, Pathomechanism, Clinical Patterns, Treatment and Prevention Programs

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200128141900 ◽

2020 ◽

Vol 20 (7) ◽

pp. 992-1002 ◽

Cited By ~ 1

Author(s):

Marta Tramontana ◽

Leonardo Bianchi ◽

Katharina Hansel ◽

Daniela Agostinelli ◽

Luca Stingeni

Keyword(s):

Contact Dermatitis ◽

Contact Allergy ◽

Systemic Exposure ◽

Prevention Programs ◽

Nickel Allergy ◽

Type Iv ◽

Treatment And Prevention ◽

Typical Type ◽

Clinical Patterns ◽

Allergic Contact

Nickel is the most common cause of contact allergy in the general population and the most frequently detected allergen in patients patch tested for suspected allergic contact dermatitis (ACD). ACD from nickel is a typical type IV hypersensitivity. Nickel allergy is mostly caused by nonoccupational exposure, such as jewelry and clothing decorations, metal tools, medical devices (mainly orthopedic and orthodontic implants, cardiovascular prosthesis), eyeglasses, utensils, keys, pigment for paint, cosmetics, and food (mainly legumes, chocolate, salmon, peanuts). Occupational exposure can involve several workers (mechanics, metalworkers, platers, hairdressers, jewelers, workers in the constructions and electronic industries), classically involving hands and forearms. The classic clinical pattern of ACD caused by nickel is characterized by eczematous dermatitis involving the sites of direct contact with the metal. Non-eczematous-patterns are reported, including lichenoid dermatitis, granuloma annulare, vitiligo-like lesions, dyshidrosiform dermatitis, and vasculitis. In the case of systemic exposure to nickel, sensitized patients could develop systemic contact dermatitis. Patch testing represents the gold standard for the diagnosis of ACD from nickel. Treatment includes avoidance of contact with products containing nickel and the patient’s education about the possible use of alternative products. A recent EU nickel directive, regulating the content and release of nickel from products, has caused a decrease of nickel contact allergy in some European countries. Nickel allergy is a relevant issue of public health with significant personal, social, and economic impact. This review summarizes epidemiology, pathomechanism, clinical patterns, treatment, and prevention programs.

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