[Teaching to inhale: better utilization of powder inhalators after counseling and instruction]. / Leren inhaleren: beter gebruik van poederinhalatoren door voorlichting en instructie.

OBJECTIVE: To study the effect of instruction of patients who used an dry powder device on the correct performance of the inhalation technique and whether the effect lasts. DESIGN: Prospective. METHOD: A number of patients who used at least one drug by the dry powder devices Diskhaler or Diskus/Accuhaler were asked to demonstrate their inhalation technique in the outpatient clinic, Department of Pulmonary Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands. On a score list the receptionist recorded the correctness of every step of use of the device. Then information and instruction on the correct performance of the inhalation technique were supplied by the same receptionist until the patient mastered the inhalation technique. A simple instruction card was handed to the patient. At the next outpatient visit the effect of the instruction was measured by means of the same score list registered by the same or another receptionist. RESULTS: Data from 97 patients could be evaluated; 42 men and 55 women, with a mean age of 58 years (range: 16-84). The percentage of patients who performed all essential actions correctly increased from 12 to 62. Almost all actions were performed better at the second than at the first visit. Better inhaling technique was observed in the 53 patients who paid their second visit within 30 days as well as in the 44 who came later (mean: 96 days; range: 34-352). CONCLUSION: The performance of the inhalation technique with the Diskhaler and the Diskus/Accuhaler was poor. By means of instruction the inhalation technique improved. This improvement was also seen in the group checked after an average of 3 months.

Citalopram serum and milk levels in mother and infant during lactation.

We present a case of intensified therapeutic drug monitoring (TDM) of citalopram in mother and newborn infant after clinically observed selective serotonin reuptake inhibitor (SSRI)-associated symptoms 2 weeks until 2 months after delivery. The SSRI-associated symptoms observed in the infant (up to 3 weeks after delivery) were irregular breathing, sleep disorders, hypotonia, and hypertonia. We conclude that the SSRI-associated symptoms in the infant represent citalopram withdrawal effects rather than side effects caused by breastfeeding. This case illustrates the importance of a flexible TDM program and a multidisciplinary approach in a hospital setting to deal with cases of drug-associated adverse effects, such as SSRI withdrawal effects.

Kinetic behavior of thallium in the rat. Accelerated elimination of thallium owing to treatment with potent diuretic agents.

1. In acute experiments anesthetized rats were treated with a subthreshold dose of 204Tl+, given intravenously in order to study the elimination kinetics of Tl+. Thallium disappeared from whole blood by means of two different half-lives (5 and 196 min, respectively), whereas VDbeta amounted to 1400 ml. The same kinetic parameters were found after chronic exposure to toxic amounts of Tl+. 2. After chronic exposure to thallium (10 or 30 ppm in the drinking water), the distribution of thallium over various organs proved non-specific. However, a pronounced accumulation was found in the renal medulla. 3. In view of the importance of the renal route in the elimination of Tl+ from the body and also because of the established accumulation of the toxic metal in the kidney, the influence of potent diuretic agents like furosemide and ethacrynic acid on the excretion of Tl+ was studied. The enhanced excretion of water and ions (Na+, K+, Cl-) was accompanied by a significantly accelerated excretion of thallium ions. High doses of ethacrynic acid (25 mg/kg) proved particularly powerful in this respect. Between the enhanced excretion of thallium and potassium ions a significant correlation was obvious, thus supporting the well-known similarity in the behaviour of these ions. The marked increase in renal elimination of thallium upon intensive diuretic treatment may be useful in the management of thallotoxicosis.

Acute cardiovascular toxicity of thallium (I) ions.

The acute cardiovascular toxicity of thallium (I)-ions was studied in anesthetized rats and also in some isolated preparations. In pentobarbital-anesthetized rats, intravenously applied Tl2SO4 (range 3 to 100 mg/kg) caused a significant, dose-dependent decrease in mean arterial blood pressure and heart rate. In spontaneously beating guinea pig isolated atria, thallium (I)-ions (10(-5) to 10(-3) M) caused a concentration-dependent decrease in frequency, which was not influenced by atropine, cocaine, or by considerable changes in the potassium concentration of the medium. A direct influence of Tl+ on the sinus node is presumed. Thallium decreases contractile force probably as a result of its negative chronotropic properties, since the amplitude of contraction remained uninfluenced in electrically driven atria. Thallium (I)-ions were readily taken up by the guinea pig isolated atria. At a bath concentration of 5 times 10(-5) M Tl+ a tissue/medium ratio of approximately 45 was achieved. Probably, an exchange against cellular potassium takes place. Relaxation of vascular smooth muscle by Tl+ was demonstrated both in isolated aortic strips (rabbit) and in the isolated perfused rabbit ear preparation. Both the vascular smooth muscle relaxation and the decrease in heart rate would explain the acute hypotensive effect of thallium.

Pharmaceutical analysis of the oral iron chelator deferiprone (DMHP,L1).

The oral iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyrid-4-one, DMHP, LT or CP20) can be a useful drug in patients with transfusional hemosiderosis. From 1987 about 1000 patients in 16 countries have taken this drug on the base of clinical trials or compassionate use. Since this compound is only available as a raw substance, it is important to ascertain its purity before bringing the drug into a pharmaceutical formulation. Because deferiprone is administered chronically and in high doses, intake of potential toxic impurities can be substantial. In this article a proposal for the quality control of deferiprone is presented in the form of a pharmaceutical monograph. This includes the analytical methods required for identification, purity checking and assay. Furthermore the way we synthesized the drug to get hold of it in a pure form is described. This synthesis is also used in manufacturing the drug commercially. The monograph can be used as a guideline for standardization of the quality of deferiprone to be used for further study and treatment.

Use of clonidine for chemical submission.

CASE REPORT: An East-European prostitute in Amsterdam robbed several victims, after having sedated them with clonidine solution (available as plastic ampoules of eyedrops) added to her victims' drinks. One victim was hospitalized. His symptoms included bradycardia, hypotension, hypothermia, pallor, cyanosis, and impaired consciousness. Treatment included isoprenaline for 28 hours. The victim was released from hospital the next day. In court, the female offender confessed and was sentenced to prison for 3 1/2 years. She may have administered doses as high as 8 mg clonidine.

Methodology for the development of a drug library based upon collision-induced fragmentation for the identification of toxicologically relevant drugs in plasma samples.

The possibility of creating a robust mass spectral library with use of high-performance liquid chromatography-atmospheric pressure-electrospray ionization (HPLC-AP-ESI) for the identification of drugs misused in cases of clinical toxicology has been examined. Factors reported as influencing the fragmentation induced by "source transport region collision induced dissociation" (CID) have been tested in this study (i.e. solvent, pH, different acids or buffer salts and their concentration, different organic modifiers and the modifier concentration). The tests performed on a few "model drugs" were analysed with use of two different single quadrupole instruments. The large number of mass spectra obtained appears to be affected by the mobile phase conditions to only a minor extent. This also holds for the mass spectra obtained at two different instruments (laboratories). Subsequently breakdown curves have been measured for about 20 randomly chosen drugs by variation of the kinetic energy of their ions in the CID zone through changing the fragmenter voltage. These breakdown curves were used to optimize the fragmenter voltage for each drug. The optimized fragmenter voltages were then applied by use of a variably ramped fragmenter voltage to acquire mass spectra for the library. The chromatographic separations were run on a Zorbax Stable bond column using a 10-mM ammonium formate-acetonitrile gradient method. Spiked blank serum and patient samples with a total of 40 different drugs were extracted with use of a standard basic liquid-liquid extraction (LLE) method. A search of significant peaks in the chromatogram by application of the developed mass spectral library is shown to result in a more than 95% positive identification. reserved.

Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial.

We performed an open, nonrandomized, multicenter phase-II trial to evaluate the efficacy and toxicity of 1 year of treatment with the oral iron chelator deferiprone in 38 mainly nonthalassemic patients with transfusional iron overload. Initial serum ferritin varied between 996 and 11.644 micrograms/l. Patients were treated with 3-6 g of deferiprone daily. Mean urinary iron excretion (UIE) in 36 evaluable patients was 21.0 mg/24 h and was significantly higher in the patients with thalassemia than in those with myelodysplasia. Negative iron balance was achieved in 20 patients (56%). The median duration of treatment was 10 months; due to side effects and other causes only 20 patients completed 1 year of treatment. Mean serum ferritin levels decreased from 3563 micrograms/l at the start of the trial to 2767 micrograms/l at 6 months (26 patients, p < 0.004) and to 2186 micrograms/l at 12 months (20 patients, p < 0.005). Serum ferritin levels normalized in two patients who were no longer transfusion dependent. Deferiprone was clearly not effective in three patients (two with myelofibrosis, one with myelodysplasia). One patient with myelodysplasia developed agranulocytosis after 12 months of treatment; this was rapidly reversible after stopping deferiprone. Three patients had a mild and transient decrease in white blood cell count. Other side effects leading to withdrawal from the trial consisted mainly of nausea (3 patients), arthralgia (2), and skin rash (1). No clinical signs of zinc deficiency were seen, although zinc excretion was increased in three patients. No changes were seen in liver enzymes, creatinine, antinuclear factor, T-cell subsets, cardiac function, visual acuity, and audiogram. Although our results confirm deferiprone as an effective iron chelator in patients with thalassemia and in some patients with other forms of iron overload, there is still some concern about the safety of this drug, which therefore, at this time, should be used exclusively in well-controlled clinical trials.