Heme-dependent radical generation: possible involvement in antimalarial action of non-peroxide microbial metabolites, nanaomycin A and radicicol

Antimalarial screening was performed for microbial metabolites that simulate artemisinin in their mode of action, a potent antimalarial component of an herbal remedy with a characteristic peroxide structure. Nanaomycin A was identified in this screen as an antimalarial compound, together with radicicol and several other compounds already reported (J. Antibiotics 51: 153 approximately 160, 1998). Nanaomycin A inhibited in vitro growth of the human malaria parasite Plasmodium falciparum with an IC80 value of 33.1 nM. It was as potent as radicicol and about 1/10 as potent as artemisinin. Studies on the mode of action suggested that the antimalarial action of the two non-peroxides, nanaomycin A and radicicol, involved heme-dependent radical generation, as is for the peroxide artemisinin. Namely, the inhibition of in vitro growth of malaria parasite by nanaomycin A or radicicol was reversed by tocopherol, a radical scavenger added to the assay mixture. Secondly, in a reaction system established for radical detection, in which a test radical donor and beta-alanylhistidine as a radical recipient were incubated with and without hemin, the two compounds caused heme-dependent decreases of beta-alanylhistidine, as did artemisinin. Among the 14 microbial metabolites identified during this screening, a correlation was observed between antimalarial activity and heme-dependent radical generating activity.     

Antitumor effect of hydrolyzed anthocyanin from grape rinds and red rice

When Balb/C mice that were fed with red glutinous rice, white ordinary rice, or commercially available standard food were inoculated with syngeneic Meth/A lymphoma cells i.p., the group fed the red rice survived longer than the other two groups. In order to determine if the anthocyanins contained in red-coloured seeds and fruit rinds were responsible for the tumor suppressive effect, we added anthocyanins extracted from grape rinds and glutinous red rice to petri dishes that had been seeded with HCT-15 cells. After 4 days of culture, cell counts were made. These anthocyanins were not effective in suppressing the tumor growth. However, anthocyanidins, which were generated by keeping anthocyanins in 5 to 6% HC1 methanol for 5 to 6 hours, were effective in the suppression of tumor growth. Flowcytometric histograms were made after 2 days of culture with these bioflavonoids. The histogram of cells treated with crude anthocyanin was similar to that of the control. Hydrolyzed anthocyanidins gave the elevation of S phase, suggesting a block in the step from S-phase to G2-phase. It seemed that the anthocyanidins contained in the grape rinds and red rice were effective on the suppression of cell growth as observed previously for anthocyanins extracted from the petals of higher plants.     

Inhibition of cell growth in culture by quinones

Quinones were studied for their growth inhibitory effect on cultured malignant cells. HCT-15 cells derived from human colon carcinoma were used for these experiments. Quinones used were arbutin in the benzoquinone group, juglone and lawsone in the naphthaquinone group, alizarin, emodin, 1,8-dihydroxyanthraquinone, and anthraquinone in the anthraquinone group, and xanthone. Cultured cells were incubated with various concentrations of the quinones for four days in a 5% CO2 incubator, after which cell numbers were counted and significance of differences was analyzed by Student's t test. Anthraquinones and naphthaquinones used in these experiments were more effective than the monocyclic quinone. The 50% suppression dose was less than 12.5 micrograms/ml for them. The number of OH groups seemed to play an important role in the degree of the cell growth inhibition: anthraquinones with 2 or 3 OH groups were more effective than those with no OH group like, 9,10-dioxoanthracene and xanthone. In fact, anthraquinones with no OH group and xanthone were not significantly effective. Flow cytometric histograms revealed a specific pattern; that is, lawsone and juglone in the naphthaquinone group and alizarin and 1,8-dihydroxy-anthraquinone in the anthraquinone group blocked mainly the S phase, and emodin in the anthraquinone group blocked the G1 to S phase of the cell cycle.     

Synthesis and biological activity of 1-N-[4-(substituted)amidino and guanidino-2-hydroxybutyryl]kanamycins A and B

The synthesis and biological properties of 1-N-[4-(substituted)amidino and guanidino-2-hydroxybutyryl]kanamycins A and B are described. Reaction of 3,3",6'-tri-N-tert-butoxycarbonyl-amikacin with an appropriate amidinating or guanidinating reagent and subsequent deblocking gave a series of amikacin derivatives having an amidino or guanidino group on the 4"'-position. The corresponding kanamycin B analogs were also prepared by a similar procedure. Among these derivatives, 1-N-(4-formamidino- and guanidino-2-hydroxybutyryl)kanamycins A (7a and 7k) and B (11 and 14) exhibited antibacterial activity similar to the corresponding 4-amino analogs. The nephrotoxic potential of selected compounds is also briefly discussed.     

Clinical studies on cefprozil granules in pediatric skin soft tissues infections]

Cefprozil (CFPZ), a newly developed cephalosporin in fine granular form, was administered to pediatric patients with skin and soft tissue infections. MICs were determined for 6 drugs including CFPZ, cephalexin (CEX), cefaclor (CCL), ampicillin (ABPC), methicillin (DMPPC), cloxacillin (MCIPC) against 53 clinical isolates of Staphylococcus aureus from these patients. An inoculum size of 10(6) CFU/ml was used in the MIC-determinations. CFPZ was given to 73 patients with ages ranging from 6 months to 10 years and 8 months and 71 cases were evaluable for clinical effects as follows; impetigo (65), Staphylococcal scalded skin syndrome (1), furuncle (1), subcutaneous abscess (3), and periproctal abscess (1). To study clinical efficacy, bacteriological effects and safety of this drug, a mean dose of 8.4 mg/kg with 3-4 daily dosages (57 cases of t.i.d. and 14 cases of q.i.d.) was administered for an average of 6 days. The results obtained are summarized as follows. 1. With regard to the 53 isolates of S. aureus, MICs of CFPZ against 52 strains (98.1%) ranged from 0.78 to 3.13 micrograms/ml. 45 strains (84.9%) were inhibited at 0.78 micrograms/ml. MIC90 of CFPZ was 1.56 micrograms/ml, but MIC against 1 strain of Methicillin-resistant S. aureus (MRSA) was 100 micrograms/ml. The MIC90 of CEX and CCL were 6.25 micrograms/ml and MIC of CEX and CCL against 1 MRSA strain were 200 and 100 micrograms/ml, respectively. The MIC90 of ABPC, DMPPC and MCIPC were 6.25, 3.13 and 0.39 micrograms/ml, respectively. CFPZ showed the second highest activity after MCIPC against S. aureus. 2. CFPZ showed very good clinical responses and clinical effects in 71 patients all of whom judged by doctors in charge as having "good" or better responses. 3. For impetigo patients, the evaluable cases by score 3, 5 and 7 days after administration of the drug were 52, 39 and 20 patients, respectively. The efficacy rates on these days were 90.4, 100 and 100%, respectively. The efficacy rate at a daily dose of 30.1-45.0 mg/kg on day 3 was 17.2% higher than that at 22.5-30.0 mg/kg, and the "excellent" response rate of 30.1-45.0 mg/kg group was 45.3% greater. Because of these results, it is expected that good clinical effects can be obtained at a daily dose of 22.5-30.0 mg/kg of CFPZ, but better responses can be expected at 30.1-45.0 mg/kg in 3-4 divided doses given for 5 days. 4. Bacteriological effects of CFPZ were determined against 60 strains of S. aureus.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of lateral head tilting on head-shaking nystagmus

We conducted a trial to determine whether or not head-shaking nystagmus (HSN) was influenced by lateral head tilting. Twenty-two patients with unilateral peripheral vestibular lesions were examined between July 1990 and June 1996. All of the patients were found to have horizontal HSN following horizontal head shaking in the upright head position. Eye movements were recorded by electronystagmography with the eyes open in complete darkness. Patients voluntarily tilted their heads to the lateral head positions with the assistance of the examiner as quickly as possible immediately after head shaking in the upright head position. Findings showed that monophasic horizontal HSN and the first phase of biphasic horizontal HSN were suppressed by lateral head tilting. The second phase of biphasic horizontal HSN was influenced differently by head tilting when compared with the first phase. Vertical (down-beating) components in horizontal HSN may appear in the peripheral vestibular lesions, but seem to have no definite relation to head positions.     

Severity of trauma changes expression of TNF-alpha mRNA in the brain of mice

BACKGROUND: The greater nitrogen loss that occurs with increasing severity of trauma is believed to occur because activation of the hypothalamus-pituitary axis is greater with severe injury. Cytokines in the brain stimulate the hypothalamus-pituitary-adrenal axis. This study was carried out to investigate whether the brain would recognize severity of trauma via TNF-alpha mRNA synthesis in the brain. METHODS: Male C57BL/6 mice (n = 70, BW: 20-28 g) were randomly assigned into four groups, (1) control (no anesthesia or incision), (2) anesthesia alone, (3) anesthesia plus laparotomy by short incision (short), and (4) anesthesia plus laparotomy by long incision (long). A laparotomy was carried out in the short and long groups by a 1.2-cm vertical incision and by a horizontal plus a vertical incision (2.4 x 2.4 cm), respectively. Exactly either 3 or 24 h after surgery, the animals were decapitated. TNF-alpha mRNA levels in the tissues were determined by semi-quantitative PCR. RESULTS: Nitrogen and catecholamine excretion were increased in the long wound group compared with the short wound group. Expression of TNF-alpha mRNA in the brain was greater in the long group after surgery than in the control, anesthesia, and short groups (brain, long: 0.150 +/- 0.005; P < 0.01 vs control, anesthesia alone, and short groups), but TNF-alpha levels in the plasma were the same in the short and long groups after surgery. CONCLUSION: Levels of TNF-alpha mRNA in the brain were enhanced according to the length of the wound probably because of greater neural stimuli from the wound site, and this elevation was involved in the greater nitrogen loss.     

Intraoperative management of heart transplantation in Japan--report of two cases

We experienced intraoperative anesthetic management of two cases of heart transplantation in Japan. Both patients were in the end stage of cardiac failure due to dilated cardiomyopathy. One patient had had implantation of left ventricular assist system, and another patient had had implantation of automated cardioveter defibrillator. Transesophageal echocardiography was useful for the monitoring of cardiac function during the operation. Anti-arrythmic therapy including heart pacing and protection of right heart failure are important for the circulatory management of heart transplantation. The anesthesiologist is needed not only for the management of respiration and circulation but also for the prevention of infection and control of the time schedule.     

Early introduction of allergenic foods for the prevention of food allergy from an Asian perspective—An Asia Pacific Association of Pediatric Allergy,Respirology & Immunology (APAPARI) consensus statement

Emerging evidence for the early introduction of allergenic foods for the prevention of food allergies, such as peanut allergy in Western populations, has led to the recent publication of guidelines in the USA and Europe recommending early peanut introduction for high‐risk infants with severe eczema or egg allergy. Peanut allergy is, however, much less prevalent in Asia compared to the West. Varying patterns of food allergy are seen even within Asian countries—such as a predominance of wheat allergy in Japan and Thailand and shellfish allergy in Singapore and the Philippines. Customs and traditions, such as diet and infant feeding practices, also differ between Asian populations. Hence, there are unique challenges in adapting guidelines on early allergenic food introduction to the Asian setting. In this paper, we review the evidence and discuss the possible approaches to guide the timely introduction of allergenic food in high‐risk infants in Asia.