Summary
In this review we analyzed the pharmacokinetic basis for high dose treatment with antibiotics of patients with cystic fibrosis. Both our results and those from other well designed pharmacokinetic studies do not support the view that low blood levels of antibacterials are a common feature of CF. We were unable to detect a decrease in absorption, nor could we find evidence for enhanced elimination of antibacterials in CF. Both these factors have been considered responsible for reducing the plasma (and tissue) levels of antibiotics. Most recent studies on kidney function are in agreement with these findings, since neither inulin nor creatinine clearance differ between CF-patients and healthy volunteers. In contrast to previous discussion, the volume of distribution (Vdss) was not elevated for any compound. The rational of weight correction of volume terms like Vdss or total clearance has never been clearly demonstrated and should therefore not be used without prior proof of relevance. Since the variability of pharmacokinetic parameters of antibiotics in CF-patients may be considerable, we suggest that a dose increase of 20–30% may be justified, but cannot agree with two to fourfold increases in dosage as previously proposed and applied in many CF-centers. Until more findings become available for non-adult CF-patients, these conclusions are only valid for adult CF-patients.
Zusammenfassung
In dieser Übersichtsarbeit wurde von uns die Grundlage der Hochdosierungstherapie von Antibiotika bei Mukoviszidose kritisch analysiert. Wir verwendeten sowohl Daten aus der Literatur als auch eigene Ergebnisse. Weder die Literaturdaten, die von uns geforderte Kriterien für Vergleichbarkeit erfüllen, noch unsere eigenen Daten haben Hinweise für generell niedrige Plasmaspiegel von Antibiotoka bei Mukoviszidose-Patienten ergeben. Wir haben außerdem nicht zeigen können, daß die Resorption verringert oder die Elimination beschleunigt ist. Beides würde die Plasma-(Gewebs-) Spiegel von Antibiotika erniedrigen. Neuere Untersuchungen zur Nierenfunktion bestätigen diese Ergebnisse, da sich weder die Inulin- noch die Kreatinin-Clearance von CF-Patienten und Gesunden unterschied. Auch die Verteilungsvolumina der Antibiotika waren nicht erhöht, wie das oft diskutiert worden war. Wir haben außerdem die Grundlagen für die oft praktizierte Gewichtskorrektur von Volumenparametern wie Cltot oder Vdss analysiert und sind zu dem Ergebnis gekommen, daß man nicht ungeprüft annehmen kann, daß eine Gewichtskorrektur dieser Volumenparameter für jede Substanz sinnvoll ist. Um die jedoch vorhandene beträchtliche Variabilität der pharmakokinetischen Parameter von Antibiotika bei Mukoviszidose-Patienten ausgleichen zu können, schlagen wir eine Dosiserhöhung um 20 bis 30% vor. Eine Dosiserhöhung um das Zwei- bis Vierfache, wie bisher vorgeschlagen und in vielen CF-Zentren durchgeführt, ist jedoch nach unserer Ansicht nicht gerechtfertigt. Bevor nicht ähnliche Untersuchungen auch bei nicht-erwachsenen CF-Patienten vorliegen, gelten die hier gemachten Dosierungsvorschläge nur für erwachsene Mukoviszidose-Patienten.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Literature
Kelly, W. H., Lovato, C. Antibiotics use in cystic fibrosis. Drug. Intell. Clin. Pharm. 18 (1984) 772–783.
Huang, N. N. Guide to drug therapy in patients with cystic fibrosis. The Cystic Fibrosis Foundation, Altanta, GA., 1974.
Høiby, N., Friis, B., Jensen, K., Koch, C., Møller, N. E., Størving, S., Szaff, M. Antimicrobial chemotherapy in cystic fibrosis patients. Acta Paediatr. Scand. suppl. 301 (1982) 75–100.
Lipow, H. J., McQuitty, J. C. Cystic Fibrosis. In:Rudolph, A. M. (ed.): Pediatrics. Appleton-Century-Crafts, Norwalk, USA, 1982, pp. 1433–1440.
Editorial. Antibiotic dosage in cystic fibrosis. Lancet I (1985) 1020–1021.
Jusko, W. J., Mosovich, L. L., Gerbracht, L. M., Mattar, M. E., Yaffe, S. J. Enhanced renal excretion of dicloxacillin in patients with cystic fibrosis. Pediatrics 56 (1975) 1038–1044.
Yaffe, S. J., Gerbracht, L. M., Mosovich, L. L., Mattar, M. E., Danish, M., Jusko, W. J. Pharmacokinetics of methicillin in patients with cystic fibrosis. J. Infect. Dis. 135 (1977) 828–831.
Park, R. W., Grand, R. J. Gastrointestinal manifestations of cystic fibrosis. A review. Gastroenterology 81 (1981) 1143–1161.
Parsons, R. L. Drug absorption in gastrointestinal disease with particular reference to malabsorption syndromes. Clin. Pharmacokinet. 2 (1977) 45–60.
Deren, J. J., Arora, B., Toskes, P. P., Hansell, J., Sibinga, S. M. Malabsorption of crystalline vitamin B12 in cystic fibrosis. N. Engl. J. Med. 288 (1973) 949–950.
Weber, A. M., Roy, C. C., Morin, L. C. Malabsorption of bile acids in children with cystic fibrosis. N. Engl. J. Med. 289 (1973) 1001–1005.
Guggenbichler, J. P., Kienel, G. Bioavailibility of oral antibiotics in cystic fibrosis. Monogr. Paediatr. 10 (1979) 34–40.
Bergan, T. Review of the pharmacokinetics of mezlocillin. J. Antimicrob. Chemother. 11, Suppl. C (1983) 1–16.
Lode, H., Niestrath, U., Koeppe, P., Langmaack, H. Azlocillin und Mezlocillin. Zwei neue semisynthetische Acylureidopenicilline. Infection 5 (1977) 163–169.
Aronoff, G. R., Sloan, R. S., Stanish, R. A., Fineberg, N. S. Mezlocillin dose dependent elimination kinetics in renal impairment. Eur. J. Clin. Pharmacol. 21 (1982) 505–509.
Strandvik, B., Malmborg, A.-S., Alfredson, H., Ericsson, A. Clinical results and pharmacokinetics of ceftazidime treatment in patients with cystic fibrosis. J. Antimicrob. Chemother. 12 (Suppl. A) (1983) 283–287.
Levy, J., Smith, A. L., Koup, J. R., Williams-Warren, J., Ramsey, B. Disposition of tobramycin in patients with cystic fibrosis: A prospective controlled study. J. Pediatr. 105 (1984) 117–124.
Vogelstein, B., Kowarski, A. A. The pharmacokinetics of amikacin in children. J. Pediatr. 91 (1977) 333–339.
Bergan, T., Michalsen, H. Pharmacokinetics of azlocillin in children with cystic fibrosis. Arzneim.-Forsch./Drug Res. 29 (II) (1979) 1955–1957.
Bosso, J. A., Saxon, B. A., Herbst, J. J., Matsen, J. M. Azlocillin pharmacokinetics in patients with cystic fibrosis. Antimicrob. Agents Chemother. 12 (1977) 286–287.
Malmborg, A. S., Alfredsson, H., Strandvik, B. Azlocillin in cystic fibrosis. Isr. J. Med. Sci. 19 (1983) 1001–1003.
Grannemann, G. R., Sennello, L. T., Sonders, R. C., Wynne, B., Thomas, E. W. Cefsulodin kinetics in healthy volunteers after intramuscular and intravenous injection. Clin. Pharmacol. Ther. 31 (1982) 95–103.
Ahrens, T., Fischer, W., Imhof, P., Füllhaas, J., Zak, O., Kradvefer, F. Human pharmacology of CGP 7174/E (SCE-129) and initial results of clinical trials in Europe. Drugs Exptl. Clin. Res. 5 (1979) 61–70.
Arvidsson, A. G., Alvan, G., Strandvik, B. Difference in renal handling of cefsulodin between patients with cystic fibrosis and normal subjects. Acta Paediatr. Scand. 72 (1983) 293–294.
Reed, M. D., Stern, R. C., Yamashita, T. S., Ackers, I., Myers, C. M., Blumer, J. L. Single dose pharmacokinetics of cefsulodin in patients with cystic fibrosis. Antimicrob. Agents Chemother. 25 (1984) 579–581.
Michalsen, H., Bergmann, T. Pharmacokinetics of netilmicin in children with and without cystic fibrosis. Antimicrob. Agents Chemother. 19 (1981) 1029–1031.
Kearns, G. L., Hilman, B. C., Wilson, J. T. Dosing implications of altered gentamicin disposition in patients with cystic fibrosis. J. Pediatr. 100 (1982) 312–318.
Gibaldi, M., Perrier, D. Pharmacokinetics. Marcel Dekker Inc., New York, Basel 1982.
Rowland, M., Tozer, T. M. Clinical Pharmacokinetics — Concepts and applications. Lea & Fibiger, Philadelphia 1980.
Benet, L. Z., Sheiner, L. B. Design and optimization of dosage regimen: pharmacokinetic data in the pharmacological basis of therapeutics. Macmillan Publ. Co., Inc., New York 1980, pp. 1675–1737.
Gibaldi, M. Biopharmaceutics and clinical pharmacokinetics. Lea & Fibiger, Philadelphia 1984.
Nahata, M. C., Lubin, A. H., Visconti, J. A. Cephalexin pharmacokinetics in patients with cystic fibrosis. Dev. Pharmacol. Ther. 7 (1984) 221–222.
Sörgel, F., Stephan, U., Wiesemann, H. G., Böwing, H. B., Geldmacher-von Mallinckrodt, M. Pharmacokinetics of cefadroxil and cefaclor in patients with cystic fibrosis (Abstract No. 120). Monatsschr. Kinderheilkd. 132 (1984) 722.
Sörgel, F., Stephan, U., Wiesemann, H. G., Dominick, H. C., Böwing, H. B. Pharmacokinetics of antibiotics in cystic fibrosis (Abstract No. 27). Eur. J. Pediatr. 143 (1985) 249.
Sörgel, F., Stephan, U., Stehr, C., Seelmann, R., Rey, M., Koch, U., Wiesemann, H. G., Dominick, H. C., Gottschalk, B. High dose treatment with antibiotics in patients with cystic fibrosis (CF)? (Abstract No. 614). 26th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology, New Orleans, LA, USA, 1986.
Kimura, T., Zamamoto, T., Ishizuka, R., Sezaki, H. Transport of cefadroxil, an aminocephalosporin antibiotic, across the small intestinal brush border membrane. Biochem. Pharmacol. 34 (1985) 81–84.
Spino, M., Chai, R. P., Isles, A. F., Thiessen, J. J., Tesoro, A., Gold, R., Mac Leod, S. M. Cloxacillin absorption and disposition in cystic fibrosis. J. Pediatr. 105 (1984) 829–835.
Dickinson, C. J., Aronoff, S. C., Stern, R. C., Reed, M. D., Blumer, J. L.: Modulation of chloramphenicol (c) bioavailability by pancreatic enzyme replacement (PER) in cystic fibrosis (CF). Ped. Res. Meeting, Abstr. 335 (1984), p. 151A.
Aladjem, M., Lotan, D., Boichis, H., Orda, S., Katznelson, D. Renal function in patients with cystic fibrosis. Nephron 34 (1983) 84–86.
Marra, G., Tirelli, S., Cavanna, G., Amoretti, M., Giunta, A., Appiani, A. C., Assael, B. M.: Renal function in cystic fibrosis (CF). Ped. Res. Meeting, Abstr. 365 (1984).
Robson, A. M., Tateishi, S., Ingelfinger, J. R., Strominger, D. B., Klahr, S. Renal function in patients with cystic fibrosis. J. Pediatr. 79 (1971) 42–50.
Spino, M., Chai, R. P., Isles, A. F., Balfe, J. W., Brown, R. G., Thiessen, J. J., Mac Leod, S. M. Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis. J. Pediatr. 107 (1985) 64–70.
MacDonald, N. E., Anas, N. G., Peterson, R. G., Schwartz, R. H., Brooks, J. G., Powell, K. R. Renal clearance of gentamicin in cystic fibrosis. J. Pediatr. 103 (1983) 985–990.
Berg, U., Kusoffsky, E., Strandvik, B. Renal function in cystic fibrosis with special reference to the renal sodium handling. Acta Paediatr. Scand. 71 (1982) 833–838.
Alvan, G., Arvidsson, A., Hedman, A., Adan-Abdi, Y., Strandvik, B. Renal elimination of cephalosporin antibiotics in patients with cystic fibrosis and normal subjects as markers for possible differences in tubular transport. Abstract in:Lawson, D. (ed.): Cystic fibrosis horizons. Proceedings of the 9th International Cystic Fibrosis Congress, June 9th–15th, 1984. John Wiley & Sons, Chichester, New York, Brisbane, Toronto, Singapore.
Sitzmann, F. C., Stephan, U. Untersuchungen zur Frage der Leberbeteiligung bei cystischer Prankreasfibrose im Kindesalter. Arch. Kinderheilk. 175 (1967) 263–270.
Di Sant'Agnese, P. A., Hubbard, V. S. The hepatobiliary system. In:Taussig, L. M. (ed.): Cystic Fibrosis. Thieme-Stratton Inc., New York 1984, pp. 296–332.
Dominick, H. C., Sutor, A. H. Liver disease in cystic fibrosis. Lancet II (1981) 1229.
Isles, A., Spino, M., Tabachnik, E., Levison, H., Thiessen, J., MacLeod, S. Theophylline disposition in cystic fibrosis. Am. Rev. Respir. Dis. 127 (1983) 417–421.
Falch, D. The influence of kidney function, body size and age on plasma concentration and urinary excretion of digoxin. Acta Med. Scand. 194 (1973) 251–256.
Bauer, L. A., Edwards, W. A. D., Dellinger, E. P., Simonowitz, D. A. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur. J. Clin. Pharmacol. 24 (1983) 643–647.
Bauer, L. A., Wareing-Tran, C., Edwards, W. A. D., Raisys, V., Ferreri, L., Jack, R., Dellinger, E. P., Simonowitz, D. Cimetidine clearance in the obese. Clin. Pharmacol. Ther. 37 (1985) 425–430.
Bauer, L. A., Blouin, R. A., Griffen, W. O., Record, K. E., Bell, R. M. Amikacin pharmacokinetics in morbidly obese patients. Am. J. Hosp. Pharm. 37 (1980) 519–522.
Reed, M. D., Stern, R. C., Myers, C. M., Yamashita, T. S., Blumer, J. L. Randomized double blind evaluation of high dose piperacillin (P) therapy in cystic fibrosis (CF) — Abstract No. 849. 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society for Microbiology. Washington, D.C., 1984.
Penketh, A., Hodson, M. E., Gaya, H., Batten, J. C. Azlocillin compared with carbenicillin in the treatment of bronchopulmonary infection due toPseudomonas aeruginosa. Thorax 39 (1984) 299–304.
Cabezudo, I., Thompson, R. L., Selden, R. F., Guenthner, S. H., Wenzel, R. P. Cefsulodin sodium therapy in cystic fibrosis patients. Antimicrob. Agents Chemother. 25 (1984) 4–6.
Bauer, L. A., Wilson, H. D., Blouin, R. A. Gentamicin and tobramicin pharmacokinetics in patients with cystic fibrosis. Clin. Pharmacy 2 (1983) 262–264.
Hendeles, L., Stillwell, P., Mangos, J. Gentamicin dosage requirements for cystic fibrosis. Drug Intell. Clin. Pharm. 15 (1981) 479 (Abstract).
Kelly, H. B., Menendez, R., Fan, L., Murphy, S. Pharmacokinetics of tobramycin in cystic fibrosis. J. Pediatr. 100 (1982) 318–321.
McCrae, W. M., Raeburn, J. A., Hanson, E. J. Tobramycin therapy of infections due toPseudomonas aeruginosa in patients with cystic fibrosis: effect of dosage and concentration of antibiotics in sputum. J. Infec. Dis. 134 (1976) 1915.
Hsu, M. C. (J.), Aguila, H. A., Schmidt, V. L., Munzenberger, P. J., Kauffmann, R. E., Polgar, G. Individualization of tobramycin dosage in patients with cystic fibrosis. Ped. Infect. Dis. 3 (1984) 526–529.
Michalsen, H., Bergan, T. Pharmacokinetics of antibiotics in children with cystic fibrosis with particular reference to netilmicin. Antimicrob. Agents Chemother. Acta. Paediatr. Scand. Suppl. 301 (1982) 101–105.
Bosso, J. A., Townsend, P. L., Herbst, J. J., Matsen, J. M. Pharmacokinetics and dosage requirements of netilmicin in cystic fibrosis patients. Antimicrob. Agents Chemother. 28 (1985) 829–831.
Jahre, J. A., Ku, F. P., Neu, H. C. Kinetics of netilmicin and gentamicin. Clin. Pharmacol. Ther. 23 (1978) 591–597.
Pechere, J. C., Dugal, R., Pechere, M. M. Kinetics of netilmicin in man. Clin. Pharmacol. Ther. 23 (1978) 677–684.
Prince, A. S., Neu, H. C. Use of piperacillin, a semisynthetic penicillin, in the therapy of acute exacerbations of pulmonary disease in patients with cystic fibrosis. J. Pediatr. 97 (1980) 148–151.
Hoogkamp-Korstanje, J. A. A., Van der Laag, J. Piperacillin and tobramycin in the treatment of pseudomonas lung infections in cystic fibrosis. J. Antimicrob. Chemother. 12 (1983) 175–183.
Stephan, U., Wiesemann, H. G., Sörgel, F. Antibiotische Therapie mit Piperacillin bei Mukoviszidose. Fortschr. Antimikr. Antineoplast. Chemother. 5–6 (1986) 1109–1111.
Wilson, C. B., Koup, J. R., Opheim, K. E., Adelman, L. A., Levy, J., Stull, T. L., Clausen, C., Smith, A. L. Piperacillin pharmacokinetics in pediatric patients. Antimicrob. Agents Chemother. 22 (1982) 442–447.
Jacobs, R. F., Trang, J. M., Kearns, G. L., Warren, R. H., Brown, A. L., Underwood, F. L., Kluza, R. B. Ticarcillin/clavulanic acid pharmacokinetics in children and young adults with cystic fibrosis. J. Pediatr. 106 (1985) 1001–1007.
Reed, M. D., Stern, R. C., O'Brien, C. A., Yamashita, T. S., Myers, C. M., Blumer, J. L. Pharmacokinetics of imipenem and cilastatin in patients with cystic fibrosis. Antimicrob. Agents Chemother. 27 (1985) 583–588.
Leeder, J. S., Spino, M., Isles, A. F., Tesoro, A. M., Gold, R., MacLeod, S. M. Ceftazidime disposition in acute and stable cystic fibrosis. Clin. Pharmacol. Ther. 36 (1984) 355–362.
Sörgel, F., Stephan, U., Dominick, H. C., Wiesemann, H. G., Böwing, H. B., Stehr, C.: Pharmacokinetics of ceftazidime in patients with cystic fibrosis. Abstract, European Workshop of Cystic Fibrosis, Jerusalem 1985.
Sörgel, F., Stephan, U., Wiesemann, H. G., Lang, E.: Pharmakokinetik von Antibiotika bei Mukoviszidose. In:Knothe, H., Adam, D., Stille, W. (eds.): Ceftazidim. FAC 4–3. Fortschr. Antimikr. Antineopl. Chemother. Futuramed Verlag München.
Kercsmar, C. M., Stern, R. C., Reed, M. D., Myers, C. M., Murdell, D., Blumer, J. L. Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response. J. Antimicrob. Chemother. 12 Suppl. A (1983) 289–295.
Padoan, R., Brienza, A., Crossignani, R. M., Lodi, G., Giunta, A., Assael, B. M., Granata, F., Passarella, E., Vallaperta, P. A., Xerri, L. Ceftazidime in treatment of acute pulmonary exacerbations in patients with cystic fibrosis. J. Pediatr. 103 (1983) 320–324.
Turner, A., Pedler, S. J., Carswell, F., Spencer, G. R., Speller, D. C. E. Serum and sputum concentrations of ceftazidime in patients with cystic fibrosis. J. Antimicrob. Chemother. 14 (1984) 521–527.
Wolfson, J. S., Hooper, D. C. The fluoroquinolones: Structures mechanisms of action and resistance, and spectra of activityin vitro. Antimicrob. Agents Chemother. 28 (1985) 581–586.
Miller, M. G., Ghoneim, A. T., Littlewood, J. M. Use of enoxacin in a patient with cystic fibrosis. Lancet I (1985) 646.
Gough, A., Barsoum, N. J., Mitchell, L., Mc Guire, E. J., de la Iglesia, F. A. Juvenile canine drug-induced arthropathy: Clinicopathological studies on articular lesions caused by oxolinic and pipemidic acids. Toxicol. Appl. Pharmacol. 51 (1979) 177–187.
Höffken, G., Lode, H., Prinzing, C., Borner, K., Koeppe, K. Pharmacokinetics of ciprofloxacin after oral and parenteral administration. Antimicrob. Agents Chemother. 28 (1985) 375–379.
Wingender, W., Graefe, K.-H., Gau, W., Förster, D., Beermann, D., Schach, P. Pharmacokinetics of ciprofloxacin after oral and intravenous administration in healthy volunteers. Eur. J. Clin. Microbiol. 3 (1984) 355–359.
Sörgel, F., Naber, K., Stephan, U., Metz, R., Jaehde, U., Gottschalk, B., Mahr, G.: Pharmakokinetik von Chinolonen — Eine Übersicht. In:Adam, D., Grobecker, H., Naber, K. (eds.): Gyrase-Hemmer II. FAC, Fortschr. Antimikr. Antineoplast. Chemother. Futuramed Verlag, München 1987 (in press).
Sörgel, F., Stephan, U., Koch, H. U., Wiesemann, H. G., Lang, E.: Absolute bioavailability and pharmacokinetics of pefloxacin in healthy volunteers. Rev. Infect. Dis. (in press).
Bender, S. W., Dalhoff, A., Shah, P. M., Strehl, R., Posselt, H. G. Ciprofloxacin pharmacokinetics in patients with cystic fibrosis. Infection 14 (1986) 23–27.
Kurz, C. C., Marget, W., Harms, K., Bertele, R.-M. Kreuzstudie Über die Wirksamkeit von Ofloxacin und Ciprofloxacin bei oraler Anwendung. Infection 14 (Suppl. 1) (1986) 82–86.
LeBel, M., Bergeron, M. G., Vallee, F., Fiset, C., Chasse, G., Bigonesse, P., Rivard, G. Pharmacokinetics and pharmacodynamics of ciprofloxacin in cystic fibrosis patients. Antimicrob. Agents Chemother. 30 (1986) 260–266.
Sörgel, F., Stephan, U., Wiesemann, H. G., Brüning, I., Dominick, H.-C., Hesseling, C.: The pharmacokinetics of ciprofloxacin in young adults with cystic fibrosis (Abstract No. 6142). 14th International Congress of Chemotherapy, Kyoto, Japan, June 23rd–28th, 1985.
Metz, R., Sörgel, F., Federspil, P., Malter, U., Koch, H. U., Stephan, U., Gottschalk, B., Manoharan, M.: Penetration of pefloxacin into saliva, sputum, sweat, tears and nasal secretions. Rev. Infect. Dis. (in press).
Sörgel, F., Stephan, U., Brüning, I., Wiesemann, H. G., Dominick, H.-C., Heidböhmer, A.: The pharmacokinetics of pefloxacin in patients with cystic fibrosis and healthy volunteers (Abstract No. 6141). 14th Congress of Chemotherapy, Kyoto, Japan, June 23rd–28th, 1985.
Bergogne-Berezin, E. Pharmacokinetics of Antibiotics in Cystic Fibrosis Patients with Particular Reference to the Bronchopulmonary Tree. Infection 15 (1987) 288–294.
Grenier, B., Autret, E., Marchand, S., Thompson, R. Kinetic Parameters of Amikacin in Cystic Fibrosis Children. Infection 15 (1987) 295–299.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sörgel, F., Stephan, U., Wiesemann, H.G. et al. High dose treatment with antibiotics in cystic fibrosis — A reappraisal with special reference to the pharmacokinetics of betalactams and new fluoroquinolones in adult CF-patients. Infection 15, 385–396 (1987). https://doi.org/10.1007/BF01647751
Issue Date:
DOI: https://doi.org/10.1007/BF01647751