Effective amiloride administration to

  CF-patients by powder inhalation

 

A. Krahl^*, C. Geidel^*, H. Alter^*, T.Hofmann^*, P. Bittner-Dersch^*, G. Hüls^*, J. Pabst^**, H. Lindemann^*.
^*CF-Centre Univ. of Giessen, Feulgenstr. 12, D-35385 Gießen; ^** GGU Frankfurt/Main

(12. North American CF-conference Montreal 10-14-98 to 10-18-98; Abstract: Pediatr.. Pulmonol. 1998, Suppl. 17,280)

s. auch den Überichtsartikel:
Lindemann, H.:   Amilorid und UTP.  In: Reinhardt D, Götz M, Kraemer R, Schöni MH (Hrsg). Cystische Fibrose. Springer, Berlin - Tokio 2001, S 305-307

und eine Übersicht über die wichtigsten Informationen zum Amilorid 

 

 

Introduction

Cystic fibrosis (CF) is associated with impaired   Cl^- secretion (CFTR) at the apical membrane of the respiratory epithelia. In addition, there is an elevated  Na⁺ absorption [1] which can be reduced to normal by amiloride, a sodium channel blocker. Normally, as a preventive measure aerosolized amiloride is administered by a jet nebulizer.This inhalation procedure takes a lot of time. Therefore we picked up the idea of an Australian working group to administer the amiloride by powder inhalation [2].

 

Methods

The baseline potential difference (PD) was measured using a subcutaneous reference electrode in 27 clinically stable CF-patients (age: 8 – 37 years). Then amiloride powder was administered (composition: 270mg amiloride/ 1.5 mg lactose ~ 15% amiloride) via a MAGhaler (MAG = mechanical aerosol generator) device, which enables a flow independent inhalation (Fig. 1, Fig. 2). The device is produced by the society of health and environment (GGU) [3].The main elements of the MAGhaler consist of a mechanically-wounddrive unit incorporating a grinding wheel with a face cutter. The drug, in form of a compacted solid ring tablet, is positioned inside the (exchangeable) mouthpiece on a spring-suspended tablet holder. Whenever the starter button on the drive unit is pressed, a precise amount of amiloride is released, as the face cutter revolves at a defined velocity and the ring tablet is pressed against the grinding wheel at a predetermined pressure. The size of the released particles is mainly between 0.63 and 5.4µm (95%).

Figure 1:  MAGhaler with ring tablet of highly compressed amiloride powder 
                   ( ¬  ) allowing for a largely flow independent inhalation

 

Figure 2  Principle of isostatic pressing of a ring shaped specimen of a drug

 

 

 

 

Study design: Amiloride powder was given nasally in a randomised order to four groups of patients: 1 puff of amiloride (group I), 2 puffs (group II), 3 puffs (group III), 6 puffs (group IV). Five minutes after insufflation the PD was recorded again and the decrease of PD was measured. The duration of decrease was determinated in 6 patients of the groups III and IV. It was defined by the time until the PD reached baseline values ( ± 10%).

Amiloride serum levels were measured in group IV 12 to 15 hours after powder inhalation by means of high performance liquid chromatography.

 

Results

Our data demonstrate that Na⁺ absorption is increasingly reduced by one to six puffs of amiloride powder (Tab. 1, Fig. 3).

The mean duration of PD was significantly lower in group III ( 150   ±  22.8 min) compared to group IV ( 207 ±  45 min) (Fig. 4).

Amiloride serum levels of group IV were between 1.2 and 4.7 ng/ml.

 

 

Table 1:  Influence of amiloride powder on nasal potential difference ( PD)  ( p. = puff)

Group	I ( 1 p.) n= 10	II ( 2 p.) n=10	III ( 3 p.) n=11	IV ( 6 p.) n=8
PD: basal values	- 52.6 ± 8.4	- 52.6 ± 9.5	- 55.8 ± 8.5	- 52.7 ± 7.6
PD: after inhalation	- 27.3 ± 8.2	- 22.6 ± 8.5	- 20.8 ± 5.8	- 14.8 ± 3.3
PD: % decrease	52.3 ± 15.7	57.6 ± 10.9	61.7 ± 10.2	70.9 ± 8.4

 

 

 

Figure 3:  Percentage decrease of group I to IV

 

 

Figure 4:  Duration of PD decrease in group III and IV

 

 

Conclusion

These results suggest, that administration of amiloride powder with the MAGhaler is a good, time saving application, which is a good alternative to the inhalation of amiloride solution using a jet nebulizer. The long term effect has to be proved in clinical studies. It should not be forgotten that the jet nebulizer inhalation is a useful part of physiotherapy. But especially for patients, who are short in time, on travel, at work or have a lot of drugs to inhale, the amiloride powder will be of great advantage.

 

References

[1] BOUCHER, R.C. (1994). Human airway ion transport (part two), Review. Am. J. Respir. Crit. Care Med. 150 (2), 581-93.

[2] EVERARD ML, DEVADASON SG, SUNDERLAND VB, LE SOUEF PN (1995) An alternative aerosol delivery system for amiloride. Thorax         50: 517-519

[3] RYMSA B (1998) Der MAGhaler - ein neuartiger, treibgasfreier Inhalatortyp. Atemw.-Lungenkrkh. 24:37-41