Critical Analysis of Corneal Cross-linking (Part-I): Formulas for Efficacy, Safety Dose, Minimum Thickness, Demarcation Line Depth and the Role of Oxygen

Purpose: To update and derive formulas for the efficacy and kinetics of corneal collagen crosslinking (CXL) including both type-I and oxygen-mediated type-II mechanisms, the role of oxygen, the initiator regeneration, safety dose, minimum corneal thickness and demarcation line depth. Study Design: Modeling the kinetics of CXL in UV light and using riboflavin as the photosensitizer. Place and Duration of Study: Taipei, Taiwan, between June, 2021 and July, 2021. Methodology: Coupled kinetic equations are derived under the quasi-steady state condition for the 2-pathway mechanisms of CXL. For type-I CXL, the riboflavin (RF) triplet state [T] may interact directly with the stroma collagen substrate [A] to form radical (R) and regenerate initiator. For type-II process, [T] interacts with oxygen to form a singlet oxygen [1O2]. Both reactive radical (R) and [1O2], can interact with the substrate [A]) for crosslinking. Based on a safety dose and a threshold dose, formulas for the minimum corneal thickness and demarcation line depth (DLD) are derived. Results: Our updated theory/modeling showed that oxygen plays a limited and transient role in the process, in consistent with that of Kamave. In contrary, Kling et al believed that type-II is the predominant mechanism, which however conflicting with the epi-on CXL results. For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. RF depletion in type-I is compensated by the RF regeneration term (RGE) which is a decreasing function of oxygen. For the case of perfect regeneration case (or when oxygen=0), RF is a constant due to the catalytic cycle. Unlike the conventional Dresden rule of 400 um thickness, thin cornea CXL is still safe as far as the dose is under a threshold dose (E*), based on our minimum thickness formula (Z*). Our formula for thin cornea is also clinically shown by Hafez et al for ultra thin (214 nm) CXL. Conclusion: For both type-I and type-II, the transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. CXL for ultra thin corneas are still safe, as far as it is under a threshold dose (E*), based on our minimum thickness (Z*) formula, which has a similar tend as that of demarcation line depth (Z').

Up-Dated the Critical Issues of Corneal Cross-Linking (Type-I and II): Safety Dose for Ultra-Thin Cornea, Role of Oxygen and Initiator Regeneration

Aims:To update analytic formulas for the overall efficacy of corneal collagen crosslinking (CXL) including both type-I and oxygen-mediated type-II mechanisms, the role of oxygen and the initiator regeneration. Study Design:modeling the kinetics of CXL in UV light and using riboflavin as the photosensitizer.Place and Duration of Study:New Taipei City, Taiwan, between June, 2021 and July, 2021.Methodology:Coupled kinetic equations are derived under the quasi-steady state condition for the 2-pathway mechanisms of CXL. For type-I CXL, the riboflavin (RF) triplet state [T] may interact directly with the stroma collagen substrate [A] to form radical (R) and regenerate initiator. For type-II process, [T] interacts with oxygen to form a singlet oxygen [1O2]. Both reactive radical (R) and [1O2], can relax to their ground state, or interact with the substrate [A]) for crosslinking. Based on a safety dose, the minimum corneal thickness formula is derived. Results:Our updated theory/modeling showed that oxygen plays a limited and transient role in the process, in consistent with that of Kamave [2]. In contrary, Kling et al [3] believed that type-II is the predominant mechanism, which however conflicting with the epi-on CXL results. For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. RF depletion in type-I is compensated by the RF regeneration term (RGE) which is a decreasing function of oxygen. For the case of perfect regeneration case (or when oxygen=0), RF is a constant due to the catalytic cycle. Unlike the conventional Dresden rule of 400 um thickness, thin cornea CXL is still safe as far as the dose is under a threshold dose (E*), based on our minimum thickness formula (Z*). Our formula for thin cornea is also clinically shown by Hafez et al forultra thin (214 nm) CXL. Conclusion: For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. Ultra thin cornea is still safe as far as it is under a threshold dose (E*), based on our minimum thickness formula.

Violet-blue light exposure of the skin: is there need for protection?

Advocates of skin protection against blue light express concern about exposure to indoor lighting and electronic screens as well as natural outdoor exposure. However, the nature of adverse effects in skin is unclear and the doses to induce effects are unknown. We aimed to reveal whether there is a scientific basis for promoting skin protection against violet-blue light (400–500 nm, VBL). Based on published literature, we determined the time to reach a threshold dose that induced a biological response in human skin. In the absence of an action spectrum for effects on skin, we used a hand held probe with a defined spectral response and measurements of the unweighted exposure between 400 and 500 nm to estimate the exposure by a selection of artificial light sources and solar light. For comparison, an outdoor threshold erythemally weighted UV dose was set to 1 SED (standard erythema dose). Outdoor, weighted irradiances were obtained using a radiative transfer model. Induction of pigmentation in human skin tissue was the only consistently reported endpoint after VBL exposure of about 65 Jcm−2. This threshold dose was reached in 0.5 to 20 months of exposure to indoor lighting sources. In comparison, specialised medical sources reached this dose in 0.5 min to 45 h. The time outdoors to reach 1 SED was shorter than the time to reach a VBL threshold dose throughout all seasons. Skin protection against VBL is superfluous for exposures to domestic lighting sources or screens and for solar radiation; however, it may be advantageous for patients suffering from photosensitive diseases or taking photosensitising medication.

Toxicological Characteristics Of N-Deacetyllappaconitine Under Chronic Administration In White Rats

In chronic experiments in laboratory animals, studied toxicological perspective new antiarrhythmic effect of N-deacetyllappaconitine for the treatment of arrhythmic states, an original herbal preparation based on Aconitum leucostonum, Ac.Septentrionale was created. During 2,5 months of intragastric administration in animals exposed to all doses of N-deacetyllappaconitine, no deviations in the parameters of the functioning of the nervous system were found, therefore, this value is the lowest effective (threshold) dose in a chronic experiment.