Synthesis of 1-O-acyl- and 1-oxo-kamebanin analogues and their cytotoxic activity.

A series of 1-O-acyl- and 1-oxo-kamebanin analogues were prepared from kamebanin, isolated from Rabdosia excisa and their cytotoxicity was assayed on HL60 promyelocytic leukemia cells and HCT116 human colon cancer cells. The structure-activity relationship study showed that the presence of 1-O-acyl groups of a C3-C5 carbon chain increased the cytotoxic activity.

Semisynthesis of Antitrypanosomal p-Quinone Analog Possesing the Komaroviquinone Pharmacophore.

A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.

Relationship between Physicochemical Properties of Medical Supplies and Serious Adverse Drug Reactions Listed in the Package Inserts.

We sought to clarify the relationship between the physicochemical properties of each medical supply and serious adverse drug reactions listed in the package inserts, by reviewing new information. We investigated 1) 1078 medicines currently available on the domestic Japanese market by using physicochemical data, such as cLogD, molecular weight (MW), and pKa and 2) the serious adverse drug reactions stated in the package inserts and the presence or absence of serious renal and liver disorders, as well as mental, extrapyramidal, and skin disorders. The renal disorders data showed: cLogD<0, adjusted odds ratio (aOR)=2.00; MW values ≥500, aOR=2.28; and pKa<7.4, aOR=1.95-2.06. The liver disorders data showed: pKa<8.4, aOR=1.83-1.95, and MW values ≥300, aOR=1.47-1.87. The mental disorders data showed: cLogD≥0, aOR=2.12, and MW values<400, aOR=2.46-2.85. The extrapyramidal disorders data showed: pKa≥6.4, aOR=4.50-11.32; cLogD≥0, aOR=4.71; and MW values<500, aOR=7.95-15.08. The skin disorders data showed: cLogD<0, aOR=1.46; MW values ≥500, aOR=1.69; and pKa<6.4, aOR=1.65 or<7.4-8.4, aOR=1.59. This information will be useful for investigating the relationships between new drugs entering the market and their potential future adverse drug reactions, and for establishing both precautionary and medical observational standards.

Iridium-Catalyzed Synthesis of Acylpyridines by [2 + 2 + 2] Cycloaddition of Diynes with Acyl Cyanides.

2-Acylpyridines were prepared by iridium-catalyzed [2 + 2 + 2] cycloaddition of α,ω-diynes with acyl cyanides. [Ir(cod)Cl]2/rac-BINAP or F-DPPE is an efficient catalyst for this reaction. The scope and limitations of this reaction have been disclosed.

Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.

A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity.

[Risk factors and subjective symptoms of drug-induced leucopenia].

The present study investigated risk factors and subjective symptoms associated with drug-induced leucopenia. We selected 248 patients with drug-induced leucopenia from the Case Reports of Adverse Drug Reactions and Poisoning Information System (CARPIS) database of over 47000 case reports of adverse drug reactions and assigned them to a case group. We also randomly selected 743 cases of adverse drug reactions not associated with leucopenia as a control group. A comparison of patient characteristic data between the two groups using logistic-regression analysis revealed that female sex, autoimmune disease and renal damage were background risk factors for drug-induced leucopenia. In addition, thiamazole, ritodrine, propylthiouracil, ticlopidine, allopurinol, minocycline and captopril administration significantly increased the risk of drug-induced leucopenia. A significant association was also found for fever, chills and pharyngeal abnormalities. Based on these findings, we developed two estimated regression equations to help prevent drug-induced leucopenia in the community pharmacy setting.

[Estimation of adverse drug reactions by the evaluation scores of subjective symptoms (complaints) and background of patients--VI. Drug-induced metabolic disorders].

OBJECTIVES: The purpose of this study was to develop, implement, and assess estimation procedures to prevent adverse drug reactions (ADRs), especially drug-induced metabolic disorders, based on the subjective symptoms (complaints) of patients. METHODS: Our own database called CARPIS (Case Reports of Adverse Drug Reaction and Poisoning Information System) was started in 1987 and now contains ca. 23,000 case reports of ADRs. We extracted 264 cases of drug-induced metabolic disorders from CARPIS, such as hyperglycemia, hypoglycemia, and hypokalemia. Evaluation scores were created based on the subjective symptoms and the backgrounds of these patients. The scores were applied to the 264 cases to demonstrate their efficiency in estimation of ADRs. RESULTS: The evaluation scores estimated ADRs as follows: 39.6% of the 96 hyperglycemia cases, 53.6% of the 84 hypoglycemia cases, and 59.5% of the 84 hypokalemia cases. The validity measures of the evaluation scores were estimated to be as follows: for hyperglycemia sensitivity (SE) = 39.6%, specificity (SP) = 99.0%, predictive value of positive test (PVP) = 97.4%, positive likelihood ratio (PLR) = 39.6, and negative likelihood ratio (NLR) = 0.61; for hypoglycemia, SE = 53.6%, SP = 93.0%, PVP = 86.5%, PLR = 7.7 and NLR = 0.50; and for hypokalemia, SE = 59.5%, SP = 99.0%, PVP = 98.0%, PLR = 59.5, and NLR = 0.41. CONCLUSIONS: The proposed evaluation scores are a reliable estimation method to detect ADRs related to drug-induced metabolic disorders. The scores should be incorporated into the integrated ADR estimation system available at a Web site our institution is developing, along with other evaluation scores of drug-induced liver disorders, extrapyramidal symptoms, and leakopenia, and druy eruptions.