Coenzyme Q10 (CoQ10) is a naturally occurring component present in living cells. Its physiological function is to act as an essential cofactor for ATP production, and to perform important antioxidant activities in the body. In most countries, CoQ10 has been widely used as a dietary supplement for more than 20 years. Recently, the use of CoQ10 as a dietary supplement has grown with a corresponding increase in daily dosage. The present review describes the safety profile of CoQ10 on the basis of animal and human data. The published reports concerning safety studies indicate that CoQ10 has low toxicity and does not induce serious adverse effects in humans. The acceptable daily intake (ADI) is 12mg/kg/day, calculated from the no-observed-adverse-effect level (NOAEL) of 1200 mg/kg/day derived from a 52-week chronic toxicity study in rats, i.e., 720 mg/day for a person weighing 60 kg. Risk assessment for CoQ10 based on various clinical trial data indicates that the observed safety level (OSL) for CoQ10 is 1200 mg/day/person. Evidence from pharmacokinetic studies suggest that exogenous CoQ10 does not influence the biosynthesis of endogenous CoQ9/CoQ10 nor does it accumulate into plasma or tissues after cessation of supplementation. Overall, these data from preclinical and clinical studies indicate that CoQ10 is highly safe for use as a dietary supplement. Additionally, analysis of CoQ10 bioavailability or its pharmacokinetics provides the pertinent safety evaluation for CoQ10.

Newly synthesized rifamycin derivatives, KRM-1648, KRM-1657, KRM-1668, KRM-1686, and KRM-1687, having the chemical structures of 3'-hydroxy-5'-(4-alkylpiperazinyl)-benzoxazinorifamycins (alkyl residues: isobutyl, propyl, sec-butyl, sec-butyl [R configuration], and sec-butyl [S configuration], respectively), were studied for their in vitro antimycobacterial activities. Representative (KRM-1648) MICs for 90% of the strains tested, determined by the agar dilution method on 7H11 medium, of various pathogenic mycobacteria (9 species, 174 strains) were as follows (in micrograms per milliliter): Mycobacterium tuberculosis (rifampin [RMP]-susceptible strains), <0.0125; M. tuberculosis (RMP-resistant strains), 12.5; M. kansasii, 0.05; M. marinum, .0.0125; M. scrofulaceum, 0.1; M. avium, 1.56; M. intracellulare, 0.1; M. fortuitum, >100; and M. chelonae subsp. abscessus and M. chelonae subsp. chelonae, >100. These values are more than 64 times lower than those of RMP, except for the values against RMP-resistant M. tuberculosis (8 times lower) and those against rapid growers, including M. fortuitum and M. chelonae (the same as those of RMP). The other derivatives had similar levels of in vitro activity against these mycobacteria. When murine peritoneal macrophages in which M. intracellulare was phagocytosed in vitro were cultured in the presence of the benzoxazinorifamycins (1 ,ug/ml), much more rapid killing of the organisms ingested in the macrophages was seen compared with when the same amount of RMP was added to the medium. The addition of benzoxazinorifamycins at the concentration of 0.05 ,ig/ml caused more marked suppression of intracellular growth of the organisms compared with addition of RMP. KRM-1648 and KRM-1657 inhibited intracellular growth of M. tuberculosis, and their efficacies were much greater than that of RMP.Rifampin (RMP), a rifamycin derivative, is highly active against a number of mycobacteria, especially slow growers such as Mycobacterium tuberculosis, M. kansasii, and M. marinum (3,22,23), and is used for the treatment of patients with tuberculosis and some atypical mycobacterial infections (4,8,17,21,27 (4,21,27) because of its considerably weak in vitro activity against the MAC (3, 22, 23), possibly because of the permeability barrier of the organisms (7,20). Although other types of rifamycin derivatives, e.g., rifabutin (RBT) (2), rifapentine (1), FCE22807 (6), CGP40/469A (6), CGP-7040 (10), and P-DEA (10), have been developed and although the drugs have higher in vitro antimycobacterial activities than RMP (2, 3, 5, 9, 23, 28), the drugs are generally not so active against MAC infection in humans, particularly immunocompromised hosts (12,14,29). Since MAC infections are increasing remarkably in immunocompromised hosts, particularly in AIDS patients (30), the need to develop new antimicrobial agents including rifamycin derivatives which have a strong activity against the MAC is urgent. In this study, we described the in vitro activities of newly synthesized benzoxazinorifamycins against various p...

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The in vitro and in vivo activities of a new benzoxazinorifamycin, KRM-1648 (KRM), against Mycobacterium tuberculosis were studied. The MIC at which 50% of the isolates are inhibited (MIC 50 ) and the MIC 90 of KRM for 30 fresh isolates of M. tuberculosis measured by the BACTEC 460 TB System were 0.016 and 2 g/ml, respectively. These values were much lower than those for rifampin (RMP), which were 4 and >128 g/ml, respectively, and considerably lower than those for rifabutin (RBT), which were 0.125 and 8 g/ml, respectively. A correlational analysis of the MICs of these drugs for the clinical isolates revealed the presence of crossresistance of the organisms to KRM and either RMP or RBT although the MICs of KRM were distributed over a much lower range than were those of the other two drugs. KRM and RMP at concentrations of 1 to 10 g/ml almost completely inhibited the bacterial growth of RMP-sensitive strains (H 37 Rv, Kurono, and Fujii) of M. tuberculosis phagocytosed in macrophage-derived J774.1 cells. KRM was more active than RMP in inhibiting the growth of the RMP-resistant (MIC ‫؍‬ 8 g/ml) Kurata strain but failed to show such an effect against the RMP-resistant (MIC >128 g/ml) Watanabe strain. When KRM was given to M. tuberculosis-infected mice at dosages of 5 to 20 mg/kg of body weight by gavage, once daily six times per week from day 1 after infection, it was much more efficacious than RMP against infections induced in mice by the RMP-sensitive Kurono strain, as measured by a reduction of rates of mortality, a reduction of the frequency and extent of gross lung lesions, histopathological changes in lung tissues, and a decrease in the bacterial loads in the lungs and spleens of infected mice. KRM also displayed significant therapeutic efficacy against infection induced by the RMPresistant Kurata strain, while neither KRM nor RMP was efficacious against infection by the RMP-resistant Watanabe strain. In the case of infection with the Kurono strain, the efficacy of the drugs in prolonging the time of survival was in the order KRM, RBT, RMP. KRM was much more efficacious than RMP, when given at 1-to 4-week intervals. These findings suggest that KRM may be useful for the clinical treatment of tuberculosis contracted through RMP-sensitive strains, even when it is administered at long intervals.

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDSassociated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracelulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracelulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDSassociated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in the present study.Rifampin (RMP) and other rifarmycins, including rifabutin (RBT), rifapentine, and so on, are highly active against slowly growing mycobacteria, particularly Mycobacterium tuberculosis and some nontuberculous mycobacteria (1,3,5,7,14,18,24,28,29,36). However, they are not so excellent in their in vitro activity against M. avium complex (MAC) (5,19,28), supposedly because of the permeability barrier of the organisms (11,25). Moreover, it is not known whether RMP and other rifamycins are really efficacious in the treatment of patients with MAC infections. Some investigators have reported that multidrug chemotherapy, including treatment with RMP, has been used in many cases of clinical management of AIDS-or non-AIDS-associated MAC patients with success (4, 6). In contrast, others have reported unavoidable difficulty in clinical control of MAC, even by using RMP combined with other drugs (36). For instance, Rosenzweig (27) reported that sustained conversion of sputum with such chemotherapy alone was achieved in only 41% of patients and, after a 6-month trial of drugs including RMP, 33% of the patients experienced relapse.Because rifamycin with a high in vitro anti-MAC activity and superior pharmacokin...