Eur J Clin Pharmacol (1991) 41:503-504 European J. . . . . l of ( ~ [ ~ ( ~ t ~

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Springer-Verlag 1991

Effect of flomoxef on human platelet aggregation M. Cazzola 2, M. G. Matera 1, A. Gusmitta 3, and E Rossi 1 Institute of Pharmacology and Toxicology,1st Medical School, Federico II University and 2 Division of Pneumology and Allergy, A Cardarelli Hospital, Naples, and 3 Medical Department, ISE Trezzano sul Naviglio,Milan, Italy Received: November 15, 1990/Acceptedin revised form: March 1, 1991

Key words: Flomoxef; platelets, ADR collagen, inhibition aggregation Beta-lactam antibiotics may irreversibly inhibit adenosine diphosphate- and collagen-dependent platelet aggregation, a process that normally plays a key role in haemostasis [1]. Both carbenicillin and latamoxef have been shown markedly to prolong bleeding time in volunteers [2], a property that was related to the alpha-carboxyl side chain. However, Sunakawa et al. [3, 4] found that all the antibiotics that possess an N-methyltetrazolethiol (MTT) group in their structure, such as latamoxef, cefoperazone and cefamandole, showed inhibitory activity on platelet aggregation. Flomoxef (6315-S) is a new oxacephem antibiotic. It differs from latamoxef because it has [l-(2-hydroxyethyl)1H-tetrazol-5-yl]thiomethyl (HTT) as a side chain at the 3-position of cephem 2-group instead of (1-methyl-lH-tetrazol-5-yl)thiomethyl (MTT).

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Fig.1. Concentration-dependent effect of flomoxef on ADP- and collagen-induced platelet aggregation Mean+SEM, (n =10) /x Collagen, 2 gg/ml • ADR 3 mM © ADR 1 mM

Experiments in vitro have been done to study the direct effect of flomoxef on normal human platelets. Ten healthy subjects, 8 m and 2 f, aged from 22 to 53 y, gave their informed consent to venepuncture. No donor was receiving long-term medication before the study period. No subject took aspirin, aspirin-containing products or alcohol for i week before enrollment. Platelet aggregation was studied by the turbidimetric technique of Born [5], using ADP in the final concentration of 1 and 3 mM, and collagen in the final concentration of 2 gg/ml. Flomoxef was diluted in saline and added to PRP samples to give final concentrations of 0.01, 0.1, i and 1 0 m g . m l -~. The mixture was incubated at 37°C for 15 rain before addition of an agonist and the response was recorded for 5 min. The aggregation response in the presence or absence of flomoxef was recorded as the peak height of the aggregation wave. The percentage inhibition of platelet aggregation by the test agent was calculated as [6]: control aggregation -Test aggregation × 100 inhibition % control aggregation When compared to saline, flomoxef inhibited ADPand collagen-induced platelet aggregation (Fig. 1). The flomoxef-induced inhibition was concentration-dependent with both of the aggregating agonists (Table). However, the inhibition of aggregation was significant only at a final concentration of flomoxef of 10 rag. ml- 1with ADP (3raM) and collagen as aggregating agents, and it was not significant at concentrations of 0.1 and 1 mg. ml- ~. The aggregation rate was accelerated by flomoxef 0.01 rag. ml(Fig. 1; Table 1). The data demonstrate that flomoxef has the potential to adversely affect human platelet aggregation only at high concentrations, which are not achieved in vivo [7]. Therefore, the clinical importance of the phenomenon is negligible. Moreover, the presence of the HTT group does not appear to be responsible for the inhibitory effect onplatelet aggregation of therapeutic concentrations of flomoxef.

M. Cazzola et al.: Flomoxef and platelet aggregation

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References

2. Weitekamp MR, Caputo GM, A1-Mondhiry HR, Abet RC (1985) The effects of latamoxef, cefotaxime, and cefoperazone on platelet function and coagulation in normal volunteers. J Antimicrob Chemother 16:95-101 3. Sunakawa K, Akita H, Iwata S, Sato Y (1984) The influence of cefotaxime on intestinal flora and bleeding diatheses in infants and neonates, compared with other beta-lactams. J Antimicrob Chemother 14 [Suppl B]: 317-324 4. Sunakawa K, Akita H, Iwata S, Sato Y, Oikawa T, Ichihashi Y (1988) Effects of antibiotics on platelet aggregation. Drugs 35 [Suppl 2]: 205-207 5. Born G V R (1962) Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194:927-927 6. Fletcher C, Pearson C, Choi SC, Duma J, Evans HJ, Qureshi GD (1986) In vitro comparison of antiplatelet effects of beta-lactam penicillins. J Lab Clin Med 108:217-223 7. Hayashi I (1987) Serum and sputum concentrations and clinical results of 6315-S (Flomoxef) in respiratory tract infections. Chemotherapy (Tokyo) 35 [Suppl 1]: 593-598

1. Aber RC, Weitekamp MR (1986) Coagulation defects. In: Karchmer AW, ed. Safety of parenteral cephalosporins - a clinical review. Little Falls, New Jersey: National Infectious Diseases Information Network, 9-12

Prof. M. Cazzola Via del Parco Margherita 24 1-80121 Napoli, Italy

Table 1. Percentage inhibition of ADP- and collagen-induced platelet aggregation by flomoxef Agonist

Flomoxef

Concentration,

mg/ml

10

1

0.1

0.01

ADR 1 mM

- 10.8 (11.8)

8.6 (10.3)

14.4 (10.8)

26.2 (10.7)

ADP,3 mM

- 19.7 ( 7.7)*

-5.4 (5.1)

-2.2 (5.5)

13.4 (7.8)

Collagen, 2 gg/ml

- 24.7 ( 8.9)*

- 4.7 (5.3)

- 2.6 (2.2)

5.7 (3.9)

Mean with (SEM) * = P