A NKO-physician in the Mechelen today prescribes the following requirement:

Your assumption that ciprofloxacin strikes down is correct. After all, the pH of the Mistabron ampoules lies around 7.5 so that when mixing the two solutions a pH shift occurs and the zwitterion of Ciprofloxacin is formed. Ciprofloxacin has the following properties: pKa1 = 6.0 (attributed to the carboxyl group) and 8.8 (for the piperizinyl Group); and an instrinsitical solubility (Sz) of ciprofloxacin-zwitterion equivalent to 0.09 mg/ml. Due to the presence of two overlapping Pkas, the formula, which allows to calculate the solubility (St) in function of the pH, is slightly more complicated than normal.

St = Sz [(K1/H +) + 1 + (K2/H +)]

Above figure (click on it to enlarge) indicates the evolution of the solubility in function of the pH and allows to read which is the highest pH, which holds a certain concentration of ciprofloxacin in solution. Given the slightly alkaline pH of the Mistabron ampoules, there will most likely have to be acidified to avoid the ciprofloxacin precipitation. After all, when mixing 1 vial of Ciloxan (5 ml) with 1 ampoule of Mistabron (3 ml), the solution has a pH = 7 and after adding 5 ml of water and 117 mg NaCl (0.9%) The zwitterion strikes down. If NaCl is replaced by the corresponding amount of glucose (no salt-out effect) then also a precipitation occurs after a few minutes. This precipitate dissolves back on using 350 mg of a 3.5% citric acid solution. The pH of the solution is +/-= 4.7.

Of course, the stability of the constituents should be checked now. For Ciprofloxacin We have the following information: "The pH of Ciloxan solution should typically be between 4.4 to 4.6. Data show that ciprofloxacin does not degrade in pH 4.0 acetate buffer after 21 days at 80 Centigrade when protected from light. " So the ciprofloxacin will not create any major problems.

for Mesna (Mistabron) The stabilite data are scarce. The article "The stability of mesna in beverages and syrup for oral administration" (Cancer Chemother Pharmacol 28 298-301 (1991)) teaches us that in the presence of air Mesna ampoules after 8 days still contain only 90% of the original quantity. Ten percent has been converted to Dimesna. EDTA has a clear stabilising effect. Diluted with various soft drinks such as Coca and Pepsi Cola (sour pH), a decrease of between 2 and 4% was determined after 24 hours. With a 5-day use mine, the stability of Mesna does not seem obvious! Therefore, I suggest to leave the Mistabron ampoule out of the composition and add ex tempore when preparing the solution for the Rhinoflow. To the solution with Ciloxan we add the amount of citric acid required for the neutralization of the alkaline pH of the Mistabron ampoule.

This then gives as composition:

Ciloxan 6 Vials Dexametasone Sodium phosphate 20 mg NaCl 0.9% Citric acid solution 3.5% (M/F) 2.1 g Aqua AD 60 ml

Of this solution the patient takes 6 ml with a syringe and from the ampoule 1.5 ml (= half; the second half for the second administration) and brings both volumes into the rhinoflow. In Total, we now have 7.5 ml; Slightly less than originally prescribed.