In vitro activities of two new glycylcyclines, N,N-dimethylglycylamido derivatives of minocycline and 6-demethyl-6-deoxytetracycline, against 339 strains of anaerobic bacteria

The in vitro activities of the N,N-dimethylglycylamido derivatives of minocycline (DMG-MINO) and 6-demethyl-6-deoxytetracycline (DMG-DMDOT) were compared with those of minocycline, tetracycline, clindamycin, and metronidazole by using the National Committee for Clinical Laboratory Standards-approved Wadsworth agar dilution method. The MICs of DMG-MINO, DMG-DMDOT, and metronidazole at which 90% of the strains were susceptible (0.5, 1, and 1 micrograms/ml, respectively) were lower than those for clindamycin, minocycline, and tetracycline (4, 8, and 32 micrograms/ml, respectively). All of the strains of anaerobes tested, except one strain of Bacteroides ovatus (MIC, 16 micrograms/ml), were susceptible to DMG-MINO and DMG-DMDOT at 8 micrograms/ml.     

In vitro activities of two glycylcyclines against gram-positive bacteria

The glycylcyclines designated CL 329,998 and CL 331,002 are N,N-dimethylglycylamido derivatives of minocycline and 6-demethyl-6-deoxytetracycline, respectively. In vitro activities of these two antimicrobial agents were compared with those of tetracycline, minocycline, and seven other antimicrobial agents against 412 gram-positive organisms. Both new drugs were significantly more active than minocycline against methicillin-resistant Staphylococcus aureus (MICs for 90% of isolates tested, 0.25 and 0.5 microgram/ml versus 4 micrograms/ml). CL 329,998 inhibited all streptococci, lactobacilli, and Leuconostoc spp. at concentrations of < or = 0.5 microgram/ml, with CL 331,002 slightly less active against some species. All enterococci, including minocycline-resistant and multidrug-resistant isolates, were inhibited at < or = 0.5- and < or = 1.0-microgram/ml concentrations of the new drugs, respectively. Only bacteriostatic activity was evident by time-kill curves. The two glycylcyclines demonstrated activities in vitro that were superior to those of minocycline against several gram-positive bacterial species, and at relatively low concentrations, they inhibited isolates resistant to both tetracycline and minocycline.     

Comparative in-vitro activity of ketolide HMR 3647 and four macrolides against gram-positive cocci of known erythromycin susceptibility status

BACKGROUND: The purpose of this study was to describe infertile patients' experiences and assessment of infertility treatment. METHODS: Sixteen couples undergoing infertility treatment at the Fertility Clinic, Herlev Hospital in Copenhagen County. Denmark, were interviewed using a semi-structured qualitative interview. The participants were selected by purposeful sampling with maximum variation. The interviews were audiotaped and transcribed in full. Data were analyzed by the Grounded theory method. RESULTS: Infertility patients preferred treatment that was organized in a separate clinic where there were only a few staff-members, proceeded without waiting time, and followed a plan known to both the doctor and the couple. Satisfaction or dissatisfaction with treatment was not related to length of infertility, sex, or social class. Surprisingly, assessment of treatment was not related to either outcome or type of treatment. The participants experienced infertility treatment as a psychological strain and they felt that their emotional needs were not met in the health care system. The desire for services from the health care system was related to how the participants managed their infertility problem in relation to other people. The more open-minded the participant was, the more was expected from the professionals. These participants wanted detailed information about technical aspects of infertility and treatment as well as psychosocial and sexual advice and support. CONCLUSION: The public health care system does not meet the needs of infertile couples for information, psychological and sexual counselling, and discussions of alternative ways of becoming parents. High-quality treatment has to consider the patients' different needs and ensure successful pregnancies as well.     

Comparative antimicrobial activity of RP 59,500 (quinupristin-dalfopristin), the first semisynthetic injectable streptgramin, against gram-positive cocci and other recent clinical pathogens

RP 59,500 (Quinupristin-Dalfopristin) is the first semisynthetic injectable streptogramin antimicrobial agent, which is a combination of quinupristin and dalfopristin in a 30:70 ratio. The components of RP 59,500 act synergically to provide bactericidal activity through action at different sites on bacterial ribosomes. In the present study, the antimicrobial activity of RP 59,500 was compared with those of four macrolides (erythromycin, clarithromycin, azithromycin, roxithromycin). Susceptibility testing was carried out by microdilution method on 303 strains of 10 species, especially antibiotic-resistant Gram-positive cocci. RP 59,500 was active against a wide range of Gram-positive cocci including methicillin-resistant Staphylococci and penicillin-resistant Streptococcus pneumoniae. The MICs90 of RP 59,500 against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis were both 0.25 microgram/ml, although those of four macrolides were higher than 32 micrograms/ml. The MICs90 of RP 59,500 against penicillin-sensitive, -intermediate and -resistant S. pneumoniae were all 0.5 microgram/ml, although those of four macrolides against penicillin-resistant S. pneumoniae were higher than 32 micrograms/ml. RP 59,500 also exhibited equivalent activities to the four macrolides against strains of Streptococcus pyogenes. Streptococcus agalactiae and Moraxella catarrhalis. RP 59,500 exhibited the highest activities against Enterococcus faecalis, Enterococcus faecium and Enterococcus avium strains which are intrinsically resistant to most antimicrobial agents. No cross-resistance was observed between RP 59,500 and the four macrolides, which will merit attention in future clinical trials of the agent. The effect of human serum on the MIC of RP 59,500 was studied with strains of S. aureus, S. epidermidis and E. faecalis. The presence of 20% (V/V) serum had little or no effect on the MIC, although 50% (V/V) serum increased MICs by 4-8 folds. Laboratory-induced resistance to RP 59,500 occurred in a stepwise fashion in broth cultures of S. aureus, S. epidermidis and E. facalis strains and the induction rate was slow and no more than four fold increases were observed. Population analysis was performed on RP 59,500 and the reference macrolides against S. aureus ATCC 25,923 strain. Although low frequencies (less than 0.01%) of resistant sub-population were detected with EM, CAM, AZM and RXM, no RP 59,500-resistant sub-population was detected in this study.     

In vitro activity of RU 64004, a new ketolide antibiotic, against gram-positive bacteria

The comparative in vitro activity of RU 64004 (also known as HMR 3004), a new ketolide antibiotic, was tested by agar dilution against approximately 500 gram-positive organisms, including multiply resistant enterococci, streptococci, and staphylococci. All streptococci were inhibited by < or = 1 microg of RU 64004 per ml. The ketolide was more potent than other macrolides against erythromycin A-susceptible staphylococci and was generally more potent than clindamycin against erythromycin A-resistant strains susceptible to this agent. Clindamycin-resistant staphylococci (MIC, > 128 microg/ml) proved resistant to the ketolide, but some erythromycin A- and clindamycin-resistant enterococci remained susceptible to RU 64004.     

E-4695, a new C-7 azetidinyl fluoronaphthyridine with enhanced activity against gram-positive and anaerobic pathogens

E-4695, (-)-7-[3-(R)-amino-2-(S)-methyl-1-azetidinyl]-1-cyclopropyl-1,4- dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid, is a new fluorinated naphthyridine with an azetidine moiety. The MICs of E-4695 at which 90% of the isolates were inhibited (MIC90s) were 0.06 to 0.5 microgram/ml for gram-positive cocci, including species of the genera Staphylococcus, Streptococcus, and Enterococcus, and the MIC90s against gram-negative pathogens such as members of the family Enterobacteriaceae (with the exception of Providencia spp. [MIC90, 8 micrograms/ml]) and Pseudomonas aeruginosa were 0.015 to 0.5 microgram/ml. E-4695 inhibited 90% of the Clostridium perfringens and Bacteroides fragilis isolates at 0.25 and 4 micrograms/ml, respectively. Against gram-positive cocci the potency of E-4695 was 2- to 8-fold higher than that of ciprofloxacin, 4- to 8-fold higher than that of ofloxacin, and 8- to 16-fold higher than that of fleroxacin. Against enteric bacteria and P. aeruginosa the potency of E-4695 was, in general, similar to that of ciprofloxacin and eightfold higher than those of ofloxacin and fleroxacin. E-4695 was four- and eightfold more potent than ciprofloxacin against C. perfringens and B. fragilis isolates, respectively. E-4695 and ciprofloxacin showed similar properties when the effects of pH or magnesium concentration were tested on them. E-4695 and ciprofloxacin had substantial reductions of activity only when pH decreased below 4.8. E-4695 and ciprofloxacin activities were not markedly affected by the presence of 5 or 10 mM Mg2+. The presence of serum and human urine at pH 7.2 decreased the activity of E-4695 between two- and fourfold. After an oral dose of 50 mg/kg of body weight, the maximum level in serum, the biological half-life, and the area under the concentration-time curve from 0 to 10 h for E-4695 were 13.2 microgram/ml, 3.3 h, and 45.6 microgram . h/ml, respectively. The area under the concentration-time curve from 0 to 4 h for ciprofloxacin was 2.3 microgram . h/ml at the same dose. Fifty-percent effective doses (ED50S) against Staphylococcus aureus HS-93 infections in mice were 4.5 mg/kg with E-4695 and 37.6 mg/kg with ciprofloxacin. Infection with Streptococcus pneumoniae 29206 was more effectively treated with E-4695 (ED50, 41,2 mg/kg) than with ciprofloxacin (ED50, 200 mg/kg). The ED50 of E-4695 for infections with Streptococcus pneumoniae 1625 was 132.2 mg/kg; ciprofloxacin was ineffective at 400 mg/kg against this strain. E-4695 was also more potent than ciprofloxacin in treatment of infections caused by gram-negative organisms such as Escherichia coli HM-42 (ED50S, 1.0 and 3.9 mg/kg, respectively). The ED50S of E-4695 and ciprofloxacin were 33.0 and 145.5 mg/kg against P. aeruginosa HS-116 and 9.6 and 18.9 mg/kg against P. aeruginosa B-120, respectively. The therapeutic efficacy of E-4695 may depend not only on its in vitro activity but also on its improved pharmacokinetic properties.     

简便高效测定熔盐电导率的新方法

提出一种简便高效的测定熔盐电导率的新方法———管式电导池法。该方法采用热解氮化硼管自制电导池,以钨丝作为工作电极,石墨作为对电极,采用阻抗仪测定nNaF·AlF3-Al2O3-CaF2熔盐的电阻,并与Wang 经验公式和Choudhary 经验公式计算所得电导率数据进行比较。结果表明,自制的管式电导池法所测得数据与经验公式计算得数据相近,并且有较好的准确性和重现性。管式电导池法是一种准确度高、结构简单、造价便宜、能扩大应用范围测定熔盐电导率的有效测试手段。     

Phase II trial of docetaxel: a new, highly effective antineoplastic agent in the management of patients with anthracycline-resistant metastatic breast cancer

PURPOSE: To determine the efficacy (objective response rate and duration of response and survival) and toxicity of docetaxel in patients with strictly defined anthracycline-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-five patients with bidimensionally measurable MBC who had progressive disease while receiving anthracycline-containing chemotherapy were registered onto the phase II trial. Docetaxel was administered at a dose of 100 mg/m2 over 1 hour every 21 days. RESULTS: Thirty-four patients were assessable for disease response; 18 (53%; 95% confidence interval [CI], 35% to 70%) achieved a partial response. The median times to disease progression and survival duration were 7.5 and 13.5 months, respectively, for responding patients. The median overall survival duration was 9 months. Two hundred eight cycles (median, five) of docetaxel were administered. Neutropenia with less than 500 cells/microL developed in 31 of 35 patients; it was complicated by fever in 30 (14%) of 208 cycles and in 18 (51%) of 35 patients, including one treatment-related death. Fluid retention was seen in 15 (43%) of 35 patients, including pleural effusions in 11 patients (31%). Moderate skin toxicity, asthenia, and myalgia were observed in 16%, 58%, and 37% of cycles, respectively. CONCLUSION: Docetaxel has the highest reported antitumor activity in anthracycline-resistant MBC. High objective response rates were seen in patients with visceral-dominant involvement, multiple metastatic sites, or extensive previous therapy. Docetaxel is associated with severe but reversible neutropenia, asthenia, and cumulative dose-related fluid retention. Dexamethasone decreased the frequency and severity of skin toxicity and appeared to ameliorate fluid retention.     

A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin

Camptothecins are the only available antitumor agents which target the nuclear enzyme topoisomerase I. 9-Aminocamptothecin (9-AC) is a water-insoluble derivative of camptothecin which has demonstrated impressive antitumor activity in preclinical models. While two other water-soluble derivatives, CPT-11 and topotecan, have successfully completed Phase I and Phase II testing, biochemical and tissue culture studies suggest that camptothecin analogues differ in characteristics which may be important in determining antitumor activity. We performed a Phase I trial of 9-AC to determine the pharmacokinetics, dose-limiting toxicity, and maximum tolerated dose of this agent when administered as a 72-h continuous i.v. infusion. Thirty-one patients with resistant solid cancers received 5-60 microgram/m2/h 9-AC for 72 h, repeated at 3-week intervals. The drug was administered in a vehicle containing dimethylacetamide, polyethylene glycol, and phosphoric acid. Blood samples were collected and the lactone (closed ring) form of 9-AC was quantitated. The maximum tolerated dose of 9-AC was determined to be 45 microgram/m2/h. Dose-limiting toxicity consisted of neutropenia. Thrombocytopenia was also prominent. There were no significant nonhematological toxicities. Minimal responses were seen in patients with gastric, colon, and non-small cell lung cancer. Although significant interpatient variation in plasma 9-AC lactone levels was observed, pooled data were fit to a two-compartment model, with a terminal half-life of 36 h. Analyses of topoisomerase protein levels in peripheral blood cells indicated decreases in topoisomerase I accompanied by increases in topoisomerase II in two of three patients. 9-AC is an active antitumor agent and may be administered safely as a 72-h infusion in patients with cancer. Although Phase II trials with a 72-h infusion of 9-AC are warranted, alternate schedules should be evaluated given the dramatic preclinical activity seen with more prolonged administrations.     

Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without rifampin, against Mycobacterium leprae in mice and in lepromatous patients

To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bactericidal effect of a single-dose combination of ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP), against Mycobacterium leprae was studied in the mouse footpad system and in previously untreated lepromatous leprosy patients. Bactericidal activity was measured by the proportional bactericidal method. In mouse experiments, the activity of a single dose of the combination OFLO-MINO was dosage related; the higher dosage of the combination displayed bactericidal activity which was significantly inferior to that of a single dose of RMP, whereas the lower dosage did not exhibit a bactericidal effect. In the clinical trial, 20 patients with previously untreated lepromatous leprosy were treated with a single dose consisting of either 600 mg of RMP plus 400 mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO. The OFLO-MINO combination exhibited definite bactericidal activity in 7 of 10 patients but was less bactericidal than the RMP-OFLO-MINO combination. Both combinations were well tolerated. Because of these promising results, a test of the efficacy of multiple doses of ROM in a larger clinical trial appears justified.     

Vaccination against rabies: construction and characterization of SAG2, a double avirulent derivative of SADBern

Both the G (VP7) and P (VP4) serotypes of human rotaviruses collected over a 10-year period from Japanese children with diarrhea were determined by recently-developed polymerase chain reaction-based typing assays. The combination of G1 and P8 was found in 65.2% and the combination of G2 and P4 was found in 15.2%. For the rest of the specimens, only a few other combinations occurred and their relative frequencies were less than 10%. The viruses carrying P9 were always associated with G3 as is the prototype strain AU-1.     

Antitrypanosomal activity of a new triazine derivative, SIPI 1029, In vitro and in model infections

A recently developed diaminotriazine derivative [O,O'-bis(1, 2-dihydro-2,2-tetramethylene-4,6-diamino-S-triazin-1-yl)-1, 6-hexanediol dihydrochloride; T-46; SIPI 1029] was examined for activity against African trypanosomes in in vitro and in vivo model systems. In vitro, SIPI 1029 was 50% inhibitory for growth of bloodstream trypomastigotes of four strains of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense at 0.15 to 2.15 nM (50% inhibitory concentrations). In in vivo mouse laboratory models of T. b. rhodesiense clinical isolate infections, SIPI 1029 was curative for 12 of 13 isolates at /=60% curative, and in six of these, a dose of /=60% cure rates. A number of these isolates were resistant to the standard trypanocide melarsoprol (Arsobal) and/or the diamidines diminazene aceturate (Berenil) and pentamidine. SIPI 1029 was also curative in combination with DL-alpha-difluoromethylornithine (Ornidyl) in a T. b. brucei central nervous system model infection. Some evidence of toxicity was found in dosage regimens of 10 mg/kg/day for 2 or 3 days in which deaths were observed in 6 of 65 animals given this dosage regimen. The activity of SIPI 1029 in this study indicates that this class of compounds (diaminotriazines) should be explored as leads for new human and veterinary trypanocides.     

Beditine, a new benzodioxane derivative, as a suppressor of human polymorphonuclear leukocyte and platelet activation

Beditine, 2-(2-amino-4-thiazolyl)-1,4-benzodioxane hydrochloride is a new substance which reduced platelet activation and degranulation, prevented aggregation and superoxide generation by activated human polymorphonuclear leukocytes (PMNL) and inhibited the activation of arachidonate 5-lipoxygenase. Beditine may, therefore, be a useful agent in the treatment of cardiovascular disease.     

In vitro and in vivo antibacterial activities of T-3761, a new quinolone derivative

T-3761, a new quinolone derivative, showed broad and potent antibacterial activity. Its MICs for 90% of the strains tested were 0.20 to 100 micrograms/ml against gram-positive bacteria, including members of the genera Staphylococcus, Streptococcus, and Enterococcus; 0.025 to 3.13 micrograms/ml against gram-negative bacteria, including members of the family Enterobacteriaceae and the genus Haemophilus; 0.05 to 50 micrograms/ml against glucose nonfermenters, including members of the genera Pseudomonas, Xanthomonas, Acinetobacter, Alcaligenes, and Moraxella; 0.025 micrograms/ml against Legionella spp.; and 6.25 to 25 micrograms/ml against anaerobes, including Bacteroides fragilis, Clostridium difficile, and Peptostreptococcus spp. The in vitro activity of T-3761 against these clinical isolates was comparable to or 2- to 32-fold greater than those of ofloxacin and norfloxacin and 2- to 16-fold less and 1- to 8-fold greater than those of ciprofloxacin and tosulfoxacin, respectively. When administered orally, T-3761 showed good efficacy in mice against systemic, pulmonary, and urinary tract infections with gram-positive and gram-negative bacteria, including quinolone-resistant Serratia marcescens and Pseudomonas aeruginosa. The in vivo activity of T-3761 was comparable to or greater than those of ofloxacin, ciprofloxacin, norfloxacin, and tosufloxacin against most infection models in mice. The activities of T-3761 were lower than those of tosufloxacin against gram-positive bacterial systemic and pulmonary infections in mice but not against infections with methicillin-resistant Staphylococcus aureus. The activities of T-3761 against systemic quinolone-resistant Serratia marcescens and Pseudomonas aeruginosa infections in mice were 2- to 14-fold greater than those of the reference agents.     

A comparison of the efficacy of new asymmetric bispyridinium oxime BI-6 with other oximes (obidoxime, HI-6) against soman in rats

BACKGROUND: Causes of death have changed greatly in the United States during the 20th century. OBJECTIVE: To detail these changes in elderly people during 1950-1990. METHODS: The source of data was 'Vital Statistics of the United States' for the years discussed. Mortality rates for several causes were calculated for the 85-89 age group, and the percentage of deaths attributed to several causes was calculated. RESULTS:There are large peaks about 1970 in both the mortality rate of ischemic heart disease and the percentage of total deaths attributed to this cause. The peaks have been followed by declines. Death rates from cancer and the percent of deaths attributed to cancer have increased during 1950-1990. CONCLUSIONS: The above changes coincide with major changes in medical science and care, the identification of the risk factors predisposing to ischemic heart disease and cerebrovascular diseases, and the implementation of Medicare, a program of health care benefits to all people 65 and over that is supported by the United States government.     

Effect of a new rifamycin derivative, rifalazil, on liver microsomal enzyme induction in rat and dog

1. The effect of a new rifamycin derivative, rifalazil (KRM-1648), on liver microsomal enzyme induction was studied in rat and dog with repeated oral administration of the compound. Relative liver weight, cytochrome b5 and P450 contents, enzyme activities of NADPH-cytochrome c reductase, aniline hydroxylase, p-nitroanisole O-demethylase, aminopyrine N-demethylase, and erythromycin N-demethylase were measured. 2. In rat, rifalazil treatment at 300 mg/kg/day for 10 days increased cytochrome b5 content but it did not affect liver weight, P450 content or enzyme activities. In contrast, rifampicin and rifabutin increased relative liver weights, cytochrome contents and enzyme activities under similar conditions. 3. In dog, rifalazil did not affect any parameters at 30 or 300 mg/kg/day for 13 weeks. 4. These findings indicate that rifalazil is not an enzyme inducer in rat and dog. This property differs from other rifamycin derivatives such as rifampicin and rifabutin.     

Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections

The evolution of fitness in experimental clonal populations of vesicular stomatitis virus (VSV) has been compared under different genetic (fitness of initial clone) and demographic (population dynamics) regimes. In spite of the high genetic heterogeneity among replicates within experiments, there is a clear effect of population dynamics on the evolution of fitness. Those populations that went through strong periodic bottlenecks showed a decreased fitness in competition experiments with wild type. Conversely, mutant populations that were transferred under the dynamics of continuous population expansions increased their fitness when compared with the same wild type. The magnitude of the observed effect depended on the fitness of the original viral clone. Thus, high fitness clones showed a larger reduction in fitness than low fitness clones under dynamics with included periodic bottleneck. In contrast, the gain in fitness was larger the lower the initial fitness of the viral clone. The quantitative genetic analysis of the trait "fitness" in the resulting populations shows that genetic variation for the trait is positively correlated with the magnitude of the change in the same trait. The results are interpreted in terms of the operation of Muller's ratchet and genetic drift as opposed to the appearance of beneficial mutations.     

Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice

Previous studies have shown that in vitro culture of human CD4+ T cells with antibodies to CD3 and CD28 immobilized on beads induced an antiviral effect to HIV-1 infection. Herein, we have used CD4+ T cells from nonhuman primates to address issues critical for use of such cells for therapy and immune reconstitution of humans and nonhuman primates infected with HIV and simian immunovirus (SIV). These studies include definition of the kinetics of the antiviral effect, the relative stability of the acquired phenotype, and whether such activated and expanded CD4+ T cells retain their immune function. Results of our studies show that antiviral effect is induced rapidly following activation with anti-CD3/CD28-coated beads. Additionally, the antiviral effect is not stable in these cells and requires continuous culture with anti-CD3/CD28 beads. Removal of CD4+ T cells from anti-CD3/CD28 stimulation renders these cells susceptible to infection, demonstrating that the resistant phenotype is not stable in these cultures. However, anti-CD3/CD28 expanded CD4+ T cells do retain immune function. Thus, although these findings imply a note of caution for therapeutic strategies aimed at providing patients with virus-resistant CD4+ T cells, the present study suggests that transfusion of such cells with retained immune function may have immune restoration capability.