Experimental osteomyelitis. IV. Therapeutic trials with rifampin alone and in combination with gentamicin, sisomicin, and cephalothin.

Levels of rifampin, gentamicin, sisomicin, and cephalothin in normal and osteomyelitic rabbit bones were measured, and the efficacy of these drugs in the treatment of osteomyelitis was evaluated. Single drug regimens, including rifampin for 14 days and gentamicin, sisomicin, and cephalothin each for 28 days, were relatively ineffective (5%-33% sterile bone cultures). Rifampin, administered for 28 days, sterilized the bones of 55% of treated animals. The combination of gentamicin and rifampin, given for either 14 or 28 days, sterilized the bones of 67% of treated animals. The combinations of rifampin plus sisomicin and of rifampin plus cephalothin, given for 28 days, were significantly more effective than these agents alone, sterilizing 90%-95% of bones. The combination of rifampin, sisomicin, and cephalothin, given for only 14 days, sterilized the bones of all treated rabbits. Staphylococci isolated from the bones of therapeutic failures that had received rifampin alone or in combination with other antibiotics were highly resistant to rifampin (minimal inhibitory concentration, greater than 250 mug/ml), whereas the organisms recovered from animals not receiving rifampin remained sensitive. Results of in vitro studies of synergy and/or bactericidal activity of antibiotic combinations correlated with in vivo results in some, but not all, instances.     

Therapeutic studies with BCG, cyclophosphamide and surgery alone and in combination on the autochthonous mammary carcinoma of the rat.

In a randomized study the effects of BCG, cyclophosphamide and surgery alone and in combination on the mammary carcinoma (induced by 7,12-dimethylbenz(a)anthracene) of the rat were investigated. Surgical excision of the tumours increased the survival time. Cyclophosphamide retarded growth of tumours and delayed the appearance of relapses compared to surgery. A single, intravenous injection of BCG (10(7) viable organisms) showed no statistically significant retardation of tumours. Immunotherapy with BCG could not increase the effectiveness of cyclophosphamide or surgery or their combination.     

Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy in metastatic breast cancer

Purpose  

Whether combination chemotherapy offers an advantage over sequential therapy in metastatic breast cancer (MBC) is still an unsettled issue. Polychemotherapy regimens containing taxanes has been shown to increase overall survival (OS), time to tumor progression (TTP), and overall response rate (ORR) when compared with regimens that did not contain a taxanes, while taxane-based doublets have a statistically significant benefit over single-agent taxane only for progression-free survival. However, the term “taxanes” generally includes both paclitaxel and docetaxel, drugs with different clinical activity. Aim of this work is to compare OS, TTP, and ORR in patients with MBC receiving docetaxel alone or in combination with chemotherapy using a formal meta-analysis.     

Fluticasone alone or in combination with salmeterol vs triamcinolone in asthma.

OBJECTIVES: To compare the efficacies of medium-dose fluticasone propionate (FP), medium-dose triamcinolone acetonide (TAA), and combined low-dose FP plus salmeterol (SL). DESIGN: Randomized, double-blind, triple-dummy, multicenter, 12-week clinical trial. SETTING: Allergy/respiratory care clinics. PATIENTS: Six hundred eighty patients with asthma previously uncontrolled with low-dose inhaled corticosteroids. INTERVENTIONS: FP, 220 microg bid; TAA, 600 microg bid; or FP, 88 microg plus SL, 42 microg bid. MEASUREMENTS AND RESULTS: Outcome measures included FEV1, peak expiratory flow (PEF), supplemental albuterol use, nighttime awakenings, asthma symptoms, and physician global assessment. Compared with TAA, 600 microg bid, treatment with FP 220, microg bid, significantly increased FEV1, morning and evening PEF, and percent symptom-free days, and significantly reduced rescue albuterol use, number of nighttime awakenings, and overall asthma symptom scores (p < or = 0.035). Improvements with low-dose FP, 88 microg, plus SL, 42 microg bid, were significantly (p < or = 0.004) greater than TAA, 600 microg bid, in all the aforementioned efficacy measures as well as percent of rescue-free days. Combined low-dose FP, 88 microg, plus SL, 42 microg bid, also significantly increased FEV1 and percent of rescue-free days, and significantly reduced albuterol use compared with medium-dose FP, 220 microg bid (p < or = 0.018). At endpoint, both FP, 220 microg bid, and FP, 88 microg, plus SL, 42 microg bid, significantly increased FEV1 by 0.48 L and 0.58 L, respectively, compared with 0.34 L with TAA, 600 microg bid. CONCLUSION: In patients who are symptomatic while taking low-dose inhaled corticosteroids, medium-dose FP (440 microg/d) and combination treatment with low-dose FP (176 microg/d) plus SL (84 microg/d) are both more effective than medium-dose TAA (1200 microg/d) in improving pulmonary function and asthma symptom control.     

Experimental klebsiella septicemia in mice: Treatment with specific antibodies from the rabbit alone and in combination with gentamicin

Summary Using a model of an experimentalKlebsiella pneumoniae septicemia in mice, we examined the therapeutic effect of passively administered specific antibacterial antibodies from rabbits. Both specific IgM and IgG antibody proved to be therapeutically effective. However, the effect of IgG was markedly superior to that of IgM with regard both to the degree of protection and the time interval allowing efficient therapy after infection. The effect of IgG was due to a marked enhancement ofin vivo phagocytosis, as demonstrated by monitoring bacterial numbers in the liver, spleen, lungs and kidneys. In mice immunocompromised with cyclophosphamide, treatment with IgG still exerted protection against low challenge inocula. When higher inocula were used, treatment with IgG ceased to influence the final mortality rates but delayed the course of the disease for several days by transient reduction of bacterial numbers in the parenchymal organs. In both normal and immunocompromised mice, concomitant treatment with gentamicin resulted in a marked synergistic enhancement of survival.

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Experimentelle Klebsiellen-Sepsis bei Mäusen: Behandlung mit spezifischen Kaninchen-Antikörpern allein und in Kombination mit Gentamicin

Zusammenfassung Am Modell einer experimentellenKlebsiella pneumoniae-Sepsis der Maus wurde der therapeutische Effekt spezifischer antibakterieller Antikörper vom Kaninchen untersucht. Sowohl IgG- als auch IgM-Antikörper erwiesen sich als therapeutisch effektiv, jedoch war der durch IgM vermittelte Schutzeffekt deutlich geringer als derjenige von IgG. Das nach der Infektion für eine effiziente Therapie zur Verfügung stehende Zeitintervall war bei Anwendung von IgM wesentlich kürzer als bei Therapie mit IgG. Wie Keimzahlbestimmungen in Leber, Milz, Lungen und Nieren zeigten, beruhte der Effekt von IgG auf einer ausgeprägten phagozytosefördernden Wirkungin vivo. Bei mit Cyclophosphamid immunsupprimierten Mäusen führte die Gabe von IgG nur dann zu einer Senkung der Letalität, wenn niedrige Infektionsdosen verabreicht wurden. Bei höheren Infektionsdosen führte die IgG-Behandlung lediglich zu einer passageren Keimzahlreduktion in den parenchymatösen Organen sowie zu einer Verzögerung des letalen Verlaufes der Sepsis um einige Tage. Die Kombinationstherapie mit IgG und Gentamicin hatte sowohl bei normalen als auch bei immunsupprimierten Mäusen einen ausgeprägten synergistischen Effekt.

     

Therapeutic studies with BCG,cyclophosphamide and surgery alone and in combination on the autochthonous mammary carcinoma of the rat

Summary In a randomized study the effects of BCG, cyclophosphamide and surgery alone and in combination on the mammary carcinoma (induced by 7,12-dimethylbenz(a)anthracene) of the rat were investigated. Surgical excision of the tumours increased the survival time. Cyclophosphamide retarded growth of tumours and delayed the appearance of relapses compared to surgery. A single, intravenous injection of BCG (10⁷ viable organisms) showed no statistically significant retardation of tumours. Immunotherapy with BCG could not increase the effectiveness of cyclophosphamide or surgery or their combination.

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Therapieversuche mit BCG, Cyclophosphamid und Operation, allein und in Kombination, am autochthonen Mammacarcinom der Ratte

Zusammenfassung In einer randomisierten Studie wurde die Wirkung von BCG, Cyclophosphamid und Operation, allein und in Kombination, auf das durch 7,12-Dimethylbenz(a)anthracen induzierte Mammacarcinom der Ratte untersucht. Die operative Entfernung der Tumoren führte zu einer Lebensverl?ngerung. Cyclophosphamid bewirkte eine Hemmung des Tumorwachstums und verz?gerte im Vergleich zur Operation das Auftreten von Rezidiven. Eine einmalige, intraven?se BCG-Injektion von 10⁷ lebenden Keimen ergab gegenüber der Kontrolle keine statistisch zu sichernde Tumorhemmung. Die Behandlung mit BCG konnte den therapeutischen Effekt von Cyclophosphamid, Operation oder deren Kombination nicht verst?rken.

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Therapeutic trials with levamisole and other agents in NZB/W mice.

The effects of levamisole, ribovirin, and cyclophosphamide in preventing the spontaneous autoimmune disease of NZB/W mice have been evaluated. These drugs all had a significant effect, both in delaying mortality, and in postponing the development of antinuclear antibodies and proteinuria. Single-stranded DNA linked to IgG was also used but had no demonstrable effect. The results of therapeutic studies in murine lupus must be interpreted with caution in relation to the human disease, but as both levamisole and ribovirin are now being used in man, our results suggest that further studies with these drugs are warranted.     

Cerebral secondary prevention--clopidogrel alone or in combination with ASS

Ohne Zusammenfassung     

Therapeutic trials on progressive muscular dystrophy.

The special medical care in the National Sanatorium prolonged the life span of the patients with progressive muscular dystrophy from 15.8 years to 20.4 years over the last 20 years. Various new drug trials for muscular dystrophy have been implemented in the last 12 years in Japan. Bestatin and Loxistatin, protease inhibitors, showed definite improvement on dystrophic mice or hamsters, animal models of muscular dystrophy. However clinical application of these drugs failed to prove the effects on patients with Duchenne muscular dystrophy. The difficulty of clinical evaluation and judgement of effects in progressive neurological diseases is discussed.     

Antimalarial activity of concanamycin A alone and in combination with pyronaridine

Concanamycin A, a macrolide antibiotic inhibitor of vacuolar H+-ATPase derived from Streptomyces sp, inhibited Plasmodium falciparum K1 growth in culture with an IC500 value of 0.2 nM. It exhibited an additive effect when tested together with the antimalarial pyronaridine.     

Effects on renal function of treatment with cefoxitin alone or in combination with furosemide.

The glomerular filtration rate measured by 51Chrome-EDTA and serum half life of cefoxitin were followed in patients with preexisting moderate renal impairment. The patients were treated with cefoxitin for two to three weeks because of chronic serious infections. The dose used in patients with an initial clearance of more than 40 mg/ml was 1 g three times daily giving a mean peak concentration of 100 microgram/ml. Seven patients were treated with cefoxitin alone and twelve with cefoxitin and furosemide (80 mg daily orally). The glomerular filtration rate did not change significantly during treatment time. There were no signs of accumulation of cefoxitin as serum half life of the drug remained unchanged both in patients treated with and without furosemide concurrently.     

Gemcitabine-based combination therapy com-pared with gemcitabine alone for advanced pancreatic cancer: a meta-analysis of nine randomized controlled trials

BACKGROUND: Pancreatic cancer is one of the most aggres-sive malignancies and chemotherapy is an effective strategy for advanced pancreatic cancer. Gemcitabine (GEM) is one of first-line agents. However, GEM-based combination therapy has shown promising efficacy in patients with advanced pancreatic cancer. This meta-analysis aimed to compare the efficacy and safety of GEM-based combination therapy versus GEM alone in the treatment of advanced pancreatic cancer.DATA SOURCES: A comprehensive search of literature was performed using PubMed, EMBASE, Web of Science and Co-chrane Central Register of Controlled Trials. A quantitative meta-analysis was performed based on the inclusion criteria from all eligible randomized controlled trials. The outcome indicators included overall survival (OS), 6-month survival, 1-year survival, progression-free survival/time-to-progression (PFS/TTP), and toxicities.RESULTS: A total of nine randomized controlled trials involv-ing 1661 patients were included in this meta-analysis. There was significant improvement in the GEM-based combination therapy with regard to the OS (HR=0.85, 95% CI: 0.76-0.95, P=0.003), PFS (HR=0.76, 95% CI: 0.65-0.90, P=0.002), 6-month survival (RR=1.09, 95% CI: 1.01-1.17, P=0.03), and the overall toxicity (RR=1.68, 95% CI: 1.52-1.86, P<0.01). However, there was no significant difference in the 1-year survival.CONCLUSIONS: GEM-based combination chemotherapy might improve the OS, 6-month survival, and PFS in advanced pan-creatic cancer. However, combined therapy also added toxicity.     

Therapeutic effects of benzoxazinorifamycin KRM-1648 administered alone or in combination with glycyrrhizin against Mycobacterium avium complex infection in mice]

We previously examined the effects of a Chinese medicine "Mao-Bushi-Saishin-To" (MBST) which has anti-inflammatory activity on the therapeutic efficacies of a benzoxazinorifamycin, KRM-1648 (KRM), against, Mycobacterium avium complex (MAC) infection induced in mice. MBST potentiated the therapeutic activity of KRM against MAC infection. In the present study, we examined the effects of another anti-inflammatory drug Glycyrrhizin, which is effective for chronic hepatitis, on the therapeutic efficacy of KRM against MAC infection induced in mice. First, KRM significantly inhibited the bacterial growth in the lungs and spleen of MAC-infected mice. Glycyrrhizin exhibited no therapeutic activity against MAC infection and did not affect the expression of the therapeutic efficacy of KRM. Secondly, treatment of murine peritoneal macrophages (M phi s) with Glycyrrhizin caused no significant changes in the M phi anti-MAC activity.