Mechanism of action of AC-1370 on phagocyte functions

The in vitro effect of three cephalosporins (cefodizime, cefotaxime, and ceftizoxime) on the growth of the following lymphocytes or their derivatives was tested: L 5178y mouse lymphoma cells, Molt-4 cells, and murine splenic lymphocytes. Within the concentration range of 0.1 to 50 ,M, the cephalosporims had no effect on L 5178y cell growth. However, Molt-4 cell growth was significantly stimulated by 0.3 to 20 ,uM cefotaxime The cephalosporin antibiotics are chemically related to the penicillins (2); both groups of agents exhibit the same mode of action on bacteria (27). Cephalosporins are therapeutically important because they are resistant to the action of penicillinase, which is the main basis for bacterial resistance to penicillin (1). Some cephalosporins have been found to cause a positive Coombs test (26), a phenomenon which has been explained by assuming either a binding of the drug to erythrocytes (24) or an interaction of the compound with thymus-dependent lymphocytes (7). Experimental studies with peripheral blood lymphocytes have indeed shown that at high concentrations (>50 ,ug/ml) of cephalosporins, the response of lymphocytes to some mitogens is suppressed (7,16). From these data, it was concluded that at least some cephalosporin derivatives display immunosuppressant effects (16 The following cephalosporins were obtained from Hoechst AG, Frankfurt, Federal Republic of Germany: cefodizime (7--[2 -(2 -aminothiazole -4 -yl)2 -syn -methoximinoacetamido]-3-(5-carboxymethyl-4-methyl-1,3-thiazole-2-ylthiomethyl)ceph-3-em-4-carbonic acid disodium salt) and cefotaxime sodium (Claforan). Ceftizoxime was a gift of Boehringer Mannheim. The cefodizime derivative was "'C-labeled at position 2 of the aminothiazolyl moiety. Its specific activity was 23.9 mCi/mmol; with respect to the number of molecules, the specific activity amounts to 1 dpm per 1.14 x 1010 molecules of cefodizime. Thin-layer chromatographical analyses on silica gel (Kieselgel 60 F254; E. Merck AG, Darmstadt) of both the unlabeled and the radioactively labeled cefodizime revealed a single spot at Rf = 0.61 with ethyl acetate-ethanol-water-formic acid (60:25:25:1) and at Rf = 0.075 with chloroform-methanol-formic acid (85:10: 10).The spots were visualized with 10o sulfuric acid (in ethanol) (heating at 1500C for 15 min).Cells and cell culture. L 5178y mouse lymphoma cells, a Thy-1,1-bearing, Fc receptor-positive T-lymphoma line (9, 11), were obtained through the courtesy of G. A. Fischer, Yale University, New Haven, Conn. The cells were grown in minimum essential medium (Spinner modification) supplemented with 10% horse serum (20

Section: Resultsmentioning

confidence: 92%

“…It was discovered that the cephalosporins cefazolin and cephalothin have no inhibiting effect on the mitogen response of human lymphocytes (8). Moreover, it was reported that cephalosporins stimulate lymphokine production in peripheral lymphocytes (14) and enhance phagocytic functions of peripheral neutrophil-rich leukocytes and macrophages (23).…”

mentioning

confidence: 99%

Differential stimulation of lymphocyte cell growth in vitro by cephalosporins

Leyhausen¹,

Seibert²,

Maidhof³

et al. 1984

“…However, the reason why DU-6859a failed to significantly eliminate the organisms from the sites of infection during the first 4 weeks is still unclear. For elucidation of the precise reason for this strange phenomenon, further detailed information concerning the pharmaceutical properties of DU-6859a is needed, including the mode of antimicrobial action against MAC organisms, pharmacokinetics, uptake and accumulation by phagocytic cells, and effects on the host immune system, as has been demonstrated for some cephalosporins (16,17).…”

Section: Resultsmentioning

confidence: 99%

In vitro and in vivo antimycobacterial activities of a new quinolone, DU-6859a

Saito

Tomioka

Sato

et al. 1994

A new fluoroquinolone, DU-6859a, was studied for its in vitro and in vivo antimycobacterial activities. MIC determination by the agar dilution method with 7H11 medium revealed that DU-6859a had MICs at which 90%o ofM. kansasii (0.78 ,ug/ml), M. marinum (1.56 ,ug/ml), M. scrofulaceum (1.56 ,g/ml), M.fortuitum (0.39 ,ug/ml), M. chelonae subsp. abscessus (6.25 ,ug/ml), and M. chelonae subsp. chelonae (1.56 ,ug/ml) were inhibited were 4 to 32 times lower than those of ofloxacin and sparfloxacin. The MICs of DU-6859a at which 90%o of M. tuberculosis (0.2 ,ug/ml) and M. avium-M. intracelulare complex (12.5 ,ug/ml each) were inhibited were comparable to those of sparfloxacin but were four-to eightfold lower than those of ofioxacin. Thus, DU-6859a possessed more potent in vitro activity than sparfloxacin and ofloxacin against most mycobacterial species.DU-6859a exerted significant efficacy against infections caused by M. intraceflulare and M. chelonae subsp. abscessus induced in mice when it was given at a dose of 1 mg per mouse (ca. 50 mg/kg of body weight) in terms of reducing the frequency of occurrence and the degree of gross pulmonary or renal lesions and bacterial loads in the lungs, spleens, or kidneys. The efficacy of DU-6859a was greater than that of ofloxacin and was more pronounced against M. chelonae infections than against M. intraceiulare infections.Since tuberculosis and Mycobacterium avium complex (MAC) infections are rapidly increasing in immunocompromised hosts, especially in AIDS patients (2, 4, 9, 35, 38), serious difficulty is frequently encountered in controlling these infections clinically. In particular, no regimen has yet been generally accepted as effective therapy for the disseminated MAC infection frequently seen in AIDS patients, although several previous clinical trials have demonstrated various combinations of antimicrobial agents have some degree of efficacy (1,2,10,15,36). Hence, the development of potent antimycobacterial drugs is urgently needed. Many studies have demonstrated that some new quinolones, including ciprofloxacin (CPFX), ofloxacin (OFLX), and sparfloxacin (SPFX), exert appreciable in vitro antimycobacterial activities (5, 7, 12, 14, 19, 22, 26, 29-31, 33, 37) and degrees of chemotherapeutic efficacy against certain types of mycobacterial infections, particularly tuberculosis and M. fortuitum infections in humans and experimental animals (8,11,19,25,28,(30)(31)(32)34). In addition, therapy with combinations that include CPFX has been reported to be efficacious against disseminated MAC infections in humans (2, 3, 13), although the contribution of the quinolone in this regimen is unclear. There also remains the problem that the antimycobacterial activities of these quinolones are limited. Furthermore, in cases of tuberculosis in AIDS patients multidrug resistance of the isolates is frequently encountered (6,24). Some new quinolones such as OFLX and CPFX may be effective against intractable pulmonary tuberculosis caused by drug-resistant tubercle bacilli (6, 34); therefore, ...

“…Cefpimizole has been reported to have greater activity in vivo than in vitro (6), to inhibit many ampicillin-resistant bacteria and have stability against hydrolysis by chromosomal ,B-lactamases (3), and to augment phagocyte function by human macrophages and neutrophils (4,5).…”

mentioning

confidence: 99%

Tolerance and disposition of cefpimizole in normal human volunteers after intramuscular administration

Novak

Lakings

Paxton

1987

Cefpimizole sodium (AC-1370, U-63196E) was administered intramuscularly in doses from 100 mg (0.5 ml) to 2,000 mg (two 3.5-ml doses) to healthy human volunteers in three double-blind placebo and positivecontrolled (cefotaxime, cephalothin) single-dose studies and in two multiple-dose studies. Mild transient pain was observed at the injection site, but no erythema, petechia, necrosis, or atrophy was noted. Creatinine phosphokinase values were increased during the study in the cefpimizole-and placebo-treated groups but began to return to normal toward the end of the study period (day 5). They were not paralleled by a similar magnitude of elevation in serum glutamic oxalacetic transaminase and lactate dehydrogenase or by pain and tenderness. There were no clinically meaningful or statistically significant changes (P > 0.5) or trends in vital signs and no other patterns of drug-related clinical abnormalities noted in any of the laboratory measurements evaluated (hematology, chemistry, urinalysis). No serious side effects occurred during or after the study. Cefpimizole was well tolerated locally and systemically by all the subjects at all administered dosage levels. Cefpimizole concentrations in serum (microbiological assay) remained above 1 ,ug/ml at 12 h after drug administration for all dose levels. The median peak concentrations in plasma for the 500-and 1,000-mg twice-daily dosages of cefpimizole were, respectively, 21.6 and 45.5 ,Ig/ml on day 1, 16.2 and 43.7 ,ug/ml on day 3, and 20.1 and 41.4,ug/ml on day 6 of the study. The apparent terminal disposition half-life throughout the study was about 2.0 h. The median amounts of cefpimizole excreted in the urine for the first 12 h of each day evaluated were 370 and 1,071 mg on day 1, 416 and 972 mg on day 3, and 370 and 975 mg on day 6 for the 500-and 1,000-mg twice-daily dosages, respectively. Dose proportionality of cefpimizole was obtained for the 500-and 1,000-mg and the 2,000-mg groups. The absorption, distribution, and elimination of cefpimizole after multiple-dose intramuscular administration were uniform, were linear in relation to dose, and did not result in drug accumulation.Cefpimizole sodium (U-63196E, AC-1370), 7-P-(D-(-)-x-(4(5)-carboxyimidazole-5(4)-carboxamido)phenylacetamido)-3-(4-,-sulfoethylpyridinium)-methyl-3-cephem-4-carboxylic acid, sodium salt, is a new cephalosporin with activity against a broad spectrum of gram-negative bacteria, including Pseudomonas aeruginosa. The drug was developed and is marketed by the Ajinomoto Company in Japan and has the chemical structure shown in Fig. 1 statistically cited variables were considered to be pertinent to the results of the study.Cefpimizole has been reported to have greater activity in vivo than in vitro (6), to inhibit many ampicillin-resistant bacteria and have stability against hydrolysis by chromosomal ,B-lactamases (3), and to augment phagocyte function by human macrophages and neutrophils (4, 5).The pharmacokinetics of cefpimizole (1) in humans receiving single-and multiple-dose intravenous inf...