Nine van der Vange

Normal findings in vulvar examination and vulvoscopy

Objective To determine the normal vulvar findings by naked eye examination and by vulvoscopy in healthy women without vulvar complaints.

Photodetection with 5-Aminolevulinic Acid–induced Protoporphyrin IX in the Rat Abdominal Cavity: Drug-dose–dependent Fluorescence Kinetics¶

In 75% of cases, ovarian carcinoma has already metastasized in the abdominal cavity at the time of diagnosis. For determination of the necessity for a supplementary therapy, in addition to surgical resection, it is important to localize and stage microscopical intraperitoneal metastases of the tumor. Intraperitoneal photodetection of tumor metastases is based on preferential tumor distribution of a fluorescent tumor marker. The time‐dependent differences in drug concentration between tumor and normal (T/N) tissues can be used to visualize small tumors. We performed fluorescence measurements on abdominal organs and tumor in the peritoneal cavity of rats. 5‐Aminolevulinic acid (ALA)–induced protoporphyrin IX (PpIX) was used as the fluorescent marker. Three different drug doses (100, 25 and 5 mg/kg) were used and PpIX fluorescence profiles were followed up to 24 h after intravenous administration. Maximum T/N ratios were found 2–3 h after administration of ALA with all drug doses. A significant T/N tissue contrast was obtained for all abdominal organs tested after administration of 5 mg/kg.

A Mathematical Evaluation of Dose-dependent PpIX Fluorescence Kinetics In Vivo¶

The in vivo pharmacokinetics of protoporphyrin IX (PpIX) after administration of 5‐aminolevulinic acid (ALA) cannot be described accurately by mathematical models using first‐order rate processes. We have replaced first‐order reaction rates by dose‐dependent (Michaelis–Menten [MM]) reaction rates in a mathematical compartment model. Different combinations of first‐order and dose‐dependent reaction rates were evaluated to see which one would improve the goodness‐of‐fit to experimentally determined in vivo PpIX fluorescence kinetics as a function of concentration. The mathematical models that were evaluated are all based on a three‐compartment model for drug distribution, conversion to PpIX and subsequent conversion to heme. Implementation of dose‐dependent reaction rates improved the goodness‐of‐fit and enabled interpolation to other drug doses. For most data sets the time constant for delivery to the target cells turned out to be dose dependent. For all data sets the use of MM rates for the conversion of ALA to PpIX yielded better fits. The clearance of PpIX turned out to be a first‐order process for all doses and types of administration. Fluorescence curves measured on a specific tissue type but obtained in different studies with different measurement techniques could be described with a single set of parameters.

White-light toxicity, resulting from systemically administered 5-aminolevulinic acid, under normal operating conditions

This study has investigated damage to the intraperitoneal organs of the rat after systemic (intraperitoneal and intravenous) administration of low doses of 5-aminolevulinic acid (ALA) and illumination with a standard white-light operating-room (o.r.) lamp. The study has been done within the framework of a larger study in which the possibility of using ALA for localization of small-volume macroscopically nonvisible peritoneal metastasis of ovarian tumors is being investigated. Fluorescence diagnostics are done in addition to the standard staging and localization procedures, either through a laparoscope or during laparotomy. In these circumstances, fluorescence diagnostics involve some risk of photosensitization of critical organs since a broad-band (o.r.) light source is used during the surgical procedures for illumination of the operating area. The drug dose and the time interval between administration of ALA and illumination are varied and normal tissues are examined both macroscopically and microscopically for damage. A relationship is demonstrated between the maximum tolerable dose (MTD) of ALA (defined as the dose that does not cause any tissue damage) and the time interval between administration and illumination. The white light that is used for illumination of the operating area is sufficient to induce damage to the peritoneal organs at relatively low ALA doses. The MDTs for 2, 6 and 16 h intervals are found to be respectively 1, 10 and 100 mg kg-1. The results are similar for both intraperitoneal and intravenous administration.

Protoporphyrin IX Kinetics in Rat Peritoneal Organs and Tumor After Systemic 5-Aminolevulinic Acid Administration

This work was performed within the framework of a study investigating the possibility of using photodetection for localization of small volume, macroscopically non-visible peritoneal metastasis of ovarian tumors using 5-AminoLevulinic Acid (ALA) induced protoporphyrin IX. This technique is based on differences in protoporphyrin concentration between tumor tissue and normal tissue. We investigated the fluorescence kinetics of protoporphyrin IX (PpIX) in rat tumor and abdominal organs following intravenous administration of 100 and 25 mg/kg ALA. The highest level of fluorescence was achieved in the liver after 4 h of 100 mg/kg ALA administration. Peak fluorescence in the liver was about 5 times higher than maximum tumor fluorescence. Maximum fluorescence contrast between tumor and intestines was measured at 2.5 hours after administration of 25 and 100 mg/kg ALA.