Flunitrazepam, a highly potent benzodiazepines, has a wide safety margin and widely used for insomnia treatment. However, a number of fatal poisoning cases involving a combination of flunitrazepam and other drugs have been reported. In instances of drug overdose deaths involving flunitrazepam in Japan, antipsychotic drugs like chlorpromazine are frequently used concomitantly. This study seeks to elucidate the pharmacokinetic interactions during the overdose of concurrent drugs, with a specific focus on the toxic effects of elevated doses of flunitrazepam and chlorpromazine in mice. Male ICR mice were intraperitoneally administered chlorpromazine (90 mg/kg) and flunitrazepam (200 mg/kg) either alone or concurrently. Body temperature was measured up to 24 hr after administration, and the number of deaths within 24 hr was quantified for each group. Additionally, flunitrazepam, chlorpromazine, and its active metabolite 7-hydroxychlorpromazine concentrations in serum and brain extracellular fluid were measured up to 24 hr after administration. Flunitrazepam enhanced the hypothermic effect of chlorpromazine, and acute intoxication deaths occurred only in the combination group. Cmax and AUC0-24h of flunitrazepam in serum and brain were not affected by concomitant administration with chlorpromazine. While flunitrazepam significantly increased the AUC0-24h of chlorpromazine, and the Cmax and AUC0-24h of 7- hydroxychlorpromazine in serum. Flunitrazepam was shown to alter the toxicokinetics of chlorpromazine when administered in combination, thereby augmenting the toxicity of chlorpromazine and leading to lethal drug intoxication. This study underscores the significance of comprehending toxicokinetics not only for individual agents but also when utilized in combination.
Fucoidan, a sulfated polysaccharide found abundantly in brown algae such as mozuku seaweeds, is classified as a water-soluble dietary fiber. Fucoidan reportedly exerts antitumor, anti-inflammatory, immunomodulatory, antioxidant, whitening, antibacterial, and antiviral activities. Owing to these properties, fucoidan has been widely used as an active ingredient for skin care purposes, including quasi-drug serums and hair growth products. However, fucoidan effects differ depending on the algal species, molecular weight, and other factors. Thus, it is crucial to thoroughly test fucoidan preparations and determine their suitability for individual applications. In this study, we probed the effects of mozuku-derived ultra-high-molecular-weight fucoidan (1700 kDa, normally ~300 kDa) preparations on indigenous skin bacteria and general bacteria. We observed that fucoidan preparations derived from Tongan mozuku Cladosiphon novae-caledoniae and Amami mozuku Cladosiphon okamuranus inhibited the growth of skin bacteria, such as Staphylococcus aureus and Staphylococcus epidermidis. However, no growth inhibition was observed for the skin bacterium Cutibacterium acnes or general bacteria, such as Lactobacillus casei, Escherichia coli, and Bacillus subtilis. Given its ability to hinder the growth of skin disease-causing bacteria, mozuku-derived ultra-high-molecular-weight fucoidan holds promise for future applications in the pharmaceutical and cosmetic industries.