Medicine shortages--a study of community pharmacies in Finland.

OBJECTIVES: To explore the frequency, the reasons behind, and the consequences of medicine shortages in Finnish community pharmacies. METHODS: During the 27-day study period in the autumn of 2013, randomly selected pharmacies reported on medicines that were in short supply from orders made to wholesalers. RESULTS: Altogether 129 (66%, n=195) pharmacies participated in the study, and the study material consisted of 3311 report forms. Of the study pharmacies, 79.8% had medicine shortages daily or almost daily. Medicines in short supply were most commonly medicines that affect the nervous system (30.8%) and the cardiovascular system (17.5%). The reason behind the shortage was reported to the pharmacies in 11.2% of the shortage cases. The medicine shortages caused problems for the pharmacies in 33.0% of the cases. In most cases (67.0%) the medicine shortages did not cause problems for the pharmacies, usually because a substitutable product was available (48.5%). CONCLUSIONS: Medicine shortages are common in Finnish community pharmacies. Medicines in short supply were commonly used medicines. The reason behind the shortage was rarely told to the pharmacies. Medicine shortages caused problems for the pharmacies in one-third of all the shortage cases. These shortages may be significant for the customers or the pharmacies, as they cause customer dissatisfaction and increase the workload of the pharmacy staff.

An international parentage and identification panel for the domestic cat (Felis catus).

Seventeen commercial and research laboratories participated in two comparison tests under the auspices of the International Society for Animal Genetics to develop an internationally tested, microsatellite-based parentage and identification panel for the domestic cat (Felis catus). Genetic marker selection was based on the polymorphism information content and allele ranges from seven random-bred populations (n = 261) from the USA, Europe and Brazil and eight breeds (n = 200) from the USA. Nineteen microsatellite markers were included in the comparison test and genotyped across the samples. Based on robustness and efficiency, nine autosomal microsatellite markers were ultimately selected as a single multiplex 'core' panel for cat identification and parentage testing. Most markers contained dinucleotide repeats. In addition to the autosomal markers, the panel included two gender-specific markers, amelogenin and zinc-finger XY, which produced genotypes for both the X and Y chromosomes. This international cat parentage and identification panel has a power of exclusion comparable to panels used in other species, ranging from 90.08% to 99.79% across breeds and 99.47% to 99.87% in random-bred cat populations.

MRI of the brain in muscle-eye-brain (MEB) disease.

Muscle-eye-brain (MEB) disease belongs to the spectrum of rare congenital syndromes with migration disorders of the brain and muscular dystrophy, along with the Walker-Warburg syndrome and Fukuyama congenital muscular dystrophy. Their features overlap, and differential diagnosis presents some difficulties. We examined the brain of 10 patients with MEB using high-field MRI and found a uniform pattern consisting of a pachygyria-type cortical migration disorder, septal and corpus callosum defects and severe hypoplasia of the pons in 7 of them.

ATP induces respiratory ciliostimulation in rat and guinea pig in vitro and in vivo.

Adenosine triphosphate (ATP) has been shown to revitalize the disturbed nasal mucociliary function in man. We investigated the effects of ATP on the ciliary beat frequency (CBF) in animals by immersing tracheal explants from rats in various concentrations of ATP, and by infusing ATP intravenously to guinea pigs. CBF was measured with a photodetector technique from the surface of the explants or from the incised trachea. ATP (from 0.01 to 1 mg/ml) in vitro increased CBF in rat tracheal explants up to 10.5% (p less than 0.05). In vivo ATP (1 mg/kg) increased the CBF by 29% (p less than 0.01) in the guinea pig trachea. As the CBF was increased by ATP, both in vitro and in vivo, it can be suggested that the improvement in mucociliary transport by exogenous ATP as shown in previous studies is caused by the ciliostimulatory effect of ATP.

Effect of codeine on rat and guinea pig tracheal ciliary beat frequency.

Codeine, the basic antitussive drug, has generally been thought to impair mucociliary function. Using the photodetection method the effect of codeine on mucociliary function was studied in rat after local and systemic administration and in guinea pig after systemic administration. In vitro rat tracheal ciliary beat frequency (CBF) was measured up to 40 min. There was 24.6 +/- 2.5% and 26.6 +/- 1.6% decrease in CBF after 1 mg/ml and after 10 mg/ml codeine solutions, respectively. In vivo codeine was administered in single i.v. doses of 10 and 15 mg/kg. No statistically significant differences were found in CBF responses, although there was a CBF decreasing tendency after the 15 mg/kg dose. The total follow-up time was 120 min. In guinea pig, 10 days s.c. codeine administration in daily doses of 3, 10 and 30 mg/kg had no effect on CBF. Although codeine was used in much higher concentrations than tissues concentrations after therapeutic doses of codeine, the effects on CBF were minimal. So it can be concluded that the generally accepted ciliostatic effect of codeine is overestimated.

The effect of ATP on the ciliary activity of normal and pathological human respiratory mucosa in vitro.

The effect of adenosine triphosphate (ATP) on the airway ciliary beating frequency (CBF) of mucosal explants excised from human maxillary sinuses was studied by measuring CBF photoelectrically before and after immersion of the explants in a solution containing ATP. In samples from 64 patients with chronic sinusitis the CBF was not significantly different from the CBF in mucosal specimens from healthy tissue of 22 patients without infection. During 15 min immersion, ATP (1 mg/ml) slightly (by 5%, p less than 0.05 in healthy tissue; by 2.7%, p less than 0.01, in tissue from sinusitis patients) increased the CBF. The effect of 10 mg/ml concentration was more pronounced (19.6%). It is concluded that the impairment in ciliary function caused by chronic sinusitis is reversible when the mucosal endothelium is cleansed of the infected mucus, and that the ciliostimulatory action of ATP seen in animals is also present in human respiratory mucosa.

The effects of vadocaine, dextromethorphan, diphenhydramine and hydroxyzine on the ciliary beat frequency in rats in vitro.

Mucociliary function is a major cleansing mechanism of the respiratory tract. Many drugs used in the treatment of respiratory diseases impair the ciliary beat frequency (CBF) of mucous membrane. Our aim was to study by means of a photoelectric technique, the effects of two antitussives--dextromethorphan and vadocaine--and two antihistamines--hydroxyzine and diphenhydramine--on the rat tracheal CBF in vitro. The CBF was measured from tracheal explants immersed in drug solutions. Dextromethorphan (1.0 mg/ml and 10.0 mg/ml) caused 16.9-20.8% decrease in the CBF during the 40 min. measurement period. Vadocaine (0.1 mg/ml and 0.5 mg/ml) decreased the CBF by 6.9%. Higher vadocaine concentrations caused a dose-dependent inhibitory effect so that mucociliary function stopped totally within 20 min. with 5.0 mg/ml vadocaine solution. Both diphenhydramine and hydroxyzine totally stopped the ciliary activity during 20 min. with concentrations of 2.5 mg/ml and 1.0 mg/ml. respectively. Locke-Ringer solution used as a control did not cause any change in the CBF. These results suggest that the antihistamines diphenhydramine and hydroxyzine are more ciliostatic than the antitussives dextromethorphan and vadocaine on the rat tracheal cilia in vitro. The results suggest further in vivo studies. The used photoelectric detection method proved to be suitable for evaluating drug effects on the CBF of respiratory mucosa.

Pharmacokinetics of ibuprofen in man: a single-dose comparison of two over-the-counter, 200 mg preparations.

The pharmacokinetic properties of two 200 mg, over-the-counter (OTC) ibuprofen preparations were compared in a randomized crossover study on ten healthy volunteers. After 2 times 200 mg single dose, one preparation produced peak plasma ibuprofen concentration 30.0 +/- 2.1 micrograms/ml at 1.6 h and the other preparation 23.2 +/- 1.9 micrograms/ml at 2.3 h (p less than 0.05). There was no statistically significant difference between the preparations in the bioavailability of ibuprofen. OTC ibuprofen preparations are mainly used for acute indications, such as fever or headache. In these cases, rapid absorption and high concentrations of active ingredient are desirable properties, especially when the amount of drug is relatively low. Therefore, the pharmacokinetic differences between these preparations may be therapeutically significant.

Pharmacokinetic comparison of a dextromethorphan-salbutamol combination tablet and a plain dextromethorphan tablet.

We compared in this double-blind crossover study the bioavailability of dextromethorphan from a dextromethorphan-salbutamol combination tablet (Redol comp) and from a plain dextromethorphan tablet (Extuson) by determining dextrorphan concentrations after single-dose oral administration in 10 healthy volunteers. The absorption of salbutamol from the combined preparation was also determined. The absorption of dextromethorphan was slightly faster from the plain dextromethorphan preparation. The peak concentration of dextrorphan was achieved at 1.5 h after Extuson and at 2 h after Redol comp (1,053.0 +/- 366.5 ng/ml and 901.5 +/- 210.9 ng/ml, NS). AUC0-12 values of dextrorphan were 4,315.6 +/- 295.0 (ng/ml)h after Extuson and 3,983.8 +/- 205.6 (ng/ml)h after Redol comp (p less than 0.05). Salbutamol was well absorbed from the combined preparation and the peak concentration was achieved at 3 h (6.57 +/- 2.95 ng/ml). Four subjects reported side-effects typical for salbutamol after the combination tablet. No side-effects were reported after the plain dextromethorphan tablet. On the basis of the present study, we conclude that the absorption of dextromethorphan from the preparations tested is almost equal and the dextromethorphan-salbutamol combination can be administered in tablet form for the treatment of cough.

Effects of intravenous ATP on tracheal ciliary activity, airway resistance and haemodynamics in rats.

The effect of the intravenous administration of ATP on the airway ciliary beating frequency (CBF) of anaesthetized rat was studied by measuring CBF photoelectrically from the inner surface of incised trachea. ATP (1 or 10 mg/kg) caused no changes in the CBF, but the decrease in CBF, which was seen after 70 min. in control rats, was abolished by ATP (10 mg/kg). ATP acutely decreased blood pressure; at 10 mg/kg, the decrease was 70 mmHg in systolic, and 60 mmHg in diastolic blood pressure. ATP also tended to increase rectal temperature and airway resistance, but these effects were not significant. ECG remained normal. Intravenous administration of ATP helps to maintain the function of tracheal cilia in anaesthetized rats at doses that, although lower blood pressure, do not cause fatal untoward effects.

Steady state pharmacokinetics of the new antitussive compound vadocaine hydrochloride.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methyl-piperidyl) propionanilide hydrochloride, OR K-242-HCl) is a novel compound, which chemically resembles amide-type local anaesthetics. Vadocaine has been proved to be an antitussive drug both in animal and in human studies. The steady state pharmacokinetic profile of vadocaine and its main metabolite in healthy volunteers after a dosage of 30 mg t.i.d. for seven days were studied. The safety of vadocaine was evaluated by ECG monitoring and by hematological and biochemical laboratory tests. Blood and urine samples were taken on the 1st, 3rd and 7th days of the study. The peak concentrations of vadocaine were on the 1st day 72.9 +/- 6.5 ng/ml at 1 h, on the 3rd day 86.4 +/- 10.3 ng/ml at 1.5 h, and on the 7th day 86.4 +/- 7.0 ng/ml at 1.5 h. AUC0-infinity values were 327.0 +/- 43.1, 449.6 +/- 81.0 and 430.5 +/- 77.1 (ng/ml)h, respectively. No side-effects or any clinically significant changes in ECG or laboratory tests were detected during the study. According to the serum concentrations and pharmacokinetic parameters the steady state level was achieved already after the third 30 mg dose of vadocaine. No cumulation of intact compound or its metabolite was seen during the study.

Effects of a gel forming dietary fiber, guar gum, on the absorption of glibenclamide and metabolic control and serum lipids in patients with non-insulin-dependent (type 2) diabetes.

Nine patients with non-insulin-dependent diabetes (NIDDM) treated with glibenclamide (3.5 mg b.i.d.) participated in this randomized double-blind placebo controlled crossover study to evaluate the effects of granulated guar gum (5 g t.i.d. with meals) on the absorption of glibenclamide and metabolic control and serum lipids. Each treatment period lasted for 4 weeks, and there was a wash-out period of one week between the treatments. The fasting blood glucose (10.5 +/- 3.4 mmol/l on guar gum vs 11.3 +/- 3.7 mmol/l on placebo, p less than 0.05) and serum total cholesterol (5.9 +/- 1.4 mmol/l on guar gum vs 6.6 +/- 1.6 mmol/l on placebo; p less than 0.05) levels were lower after the treatment with guar gum than placebo. No significant differences were observed in serum triglycerides or HDL cholesterol between guar gum and placebo treatments. The administration of guar gum together with glibenclamide did not change significantly the maximum concentration (223 +/- 196 ng/ml on guar gum vs 184 +/- 138 ng/ml on placebo; n = 7, NS) or area under the curve (AUC0-6) [729 +/- 813 (ng/ml) X h on guar gum vs 560 +/- 513 (ng/ml) X h on placebo; NS] of glibenclamide. The fasting serum glibenclamide concentrations were similar at the end of the 4-week treatment period with guar gum and placebo. In conclusion, guar gum improved the metabolic control and decreased serum lipids of patients with NIDDM. In addition, guar gum ingested with glibenclamide did not interfere with the absorption of glibenclamide.

Once-daily theophylline in the treatment of nocturnal asthma.

The efficacy and side-effects of individually adjusted doses of controlled-release theophylline given once daily in the evening (average dose 650 mg) were compared with those of standard treatment with controlled-release terbutaline 7.5 mg b.d. Thirty-six asthmatics with regular morning obstruction ("morning dipping") were studied over two treatment periods each of two weeks, according to a crossover, randomized, double blind design. Morning peak expiratory flow (PEF) was slightly but significantly higher with theophylline (363 l.min-1) than terbutaline (342 l.min-1). Feelings of dyspnoea on waking in the morning were also less pronounced with theophylline. There were no other differences between the treatment periods during the day or night, with respect to dyspnoea or any the other symptoms. Side-effects were mild and were reported with similar frequencies during both treatments. It is concluded than an individually adjusted dose of once-daily theophylline administered in the evening is at least as effective as conventional therapy with controlled-release terbutaline in preventing nocturnal and early morning asthma, when both drugs are added to regular medication with inhaled sympathomimetics and steroids.

The single dose and steady-state pharmacokinetics of a vadocaine tablet in healthy human volunteers.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methyl-piperidyl)-propionanilide hydrochloride; INN vadocaine) is a novel compound with antitussive and local anesthetic actions. In this study, the single dose and steady-state pharmacokinetics of vadocaine hydrochloride tablet were evaluated in 28 healthy volunteers. In part 1, the pharmacokinetics of a single dose of vadocaine hydrochloride tablet were compared with the pharmacokinetics of a vadocaine hydrochloride solution. The peak concentrations of vadocaine were achieved at 1 h both after the tablet and the solution and there were no statistically significant differences in serum concentrations or in pharmacokinetic parameters. In part 2, the steady-state pharmacokinetics of vadocaine tablet were studied using the dosage of 30 mg vadocaine hydrochloride t.i.d. for four days. The peak concentrations of vadocaine were achieved on the 1st day at 1 h (61.5 +/- 6.1 ng/ml) and on the 4th day at 1.5 h (64.5 +/- 7.9 ng/ml). According to the serum concentrations and pharmacokinetic parameters, no cumulation of vadocaine was observed. Also no side-effects were reported during the study. In conclusion, vadocaine used in the tablet form is suitable for multiple dosing and the pharmacokinetic profile is almost similar to vadocaine administered in aqueous solution.

Long term treatment of severe hypercholesterolaemia with guar gum.

The long term efficacy of granulated guar gum, 15-30 g per day, was studied in 23 patients with severe hypercholesterolaemia (serum cholesterol concentration between 8.0 and 14.3 mmol/l). Originally, 29 patients participated in the study. Two patients dropped out because of gastrointestinal side effects, two others were not willing to complete the study without any given reason, and two discontinued the study because of hospitalization. A 1-month placebo period preceded the guar gum treatment, and another 1-month placebo period followed after 50 weeks of active treatment. The serum total cholesterol concentration (mean +/- SEM) was reduced from 10.0 +/- 0.4 mmol/l to 8.2 +/- 0.3 mmol/l (P less than 0.001) after 8 weeks and to 9.0 +/- 0.4 mmol/l (P less than 0.001) after 50 weeks on guar gum. During the second placebo period serum cholesterol returned to the pretreatment level. After 34 weeks of active treatment the serum LDL-cholesterol concentration had fallen by 15% and that of apoprotein B by 14% from the baseline. The changes in lipid and lipoprotein levels were independent of the initial values and the type of hypercholesterolaemia. Serum triglycerides, HDL-cholesterol, body weight and blood pressure showed no significant changes during the trial. Of the study subjects, 20 reached the maximum intended dose of 30 g per day guar gum between 8 and 14 weeks and thereafter 11 subjects continued the dose of 30 g/day while 12 subjects reduced the dose to 15-25 g/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic comparison of a slow-release theophylline-hydroxyzine combination and a plain slow-release theophylline preparation.

We have compared the pharmacokinetic properties of a slow-release theophylline-hydroxyzine combination and a slow-release theophylline preparation both after a single dose administration and at steady state after the dosage of twice/day for four days in ten healthy volunteers. After a single dose, theophylline was absorbed slightly faster from the combination preparation (Retafyllin comp.) than from a plain theophylline preparation (Theo-Dur). However, in a steady state phase the pharmacokinetic profiles were quite similar. Hydroxyzine showed a slight delay in absorption from the combination preparation, but in a steady state the overall pharmacokinetic profile of hydroxyzine was similar to that of theophylline. Cumulation of either hydroxyzine or theophylline was not evident. On the basis of the present study, the slow-release combination preparation of theophylline and hydroxyzine seems suitable for twice/day dosage.

Antitussive action of the new anilide derivative vadocaine hydrochloride compared with codeine phosphate in four animal models.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel antitussive compound structurally resembling local anaesthetics. Its antitussive profile was studied in several animal models. In guinea-pigs, vadocaine reduced by about 70% the cough episodes induced by sulphur dioxide or ammonia. The effective dose was 2.5 mg/kg p.o., and codeine phosphate was less effective. In cats, vadocaine (3 mg/kg i.v.) inhibited by about 80% for 10 min the cough reflex initiated by mechanical irritation of the trachea. When vadocaine was given via the vertebral artery, it was about 10 times more active than by the intravenous route. Codeine was 3 times as active as vadocaine by both routes. This result indicates an important central component in the antitussive action of vadocaine. In another cat model, 5 mg/kg of vadocaine was somewhat weaker than 1 mg/kg of codeine in inhibiting the cough caused by electrical stimulation of the laryngeal nerve (Domenjoz' method). In dogs, both oral and intravenous doses of 6 mg/kg of vadocaine and 2 mg/kg of codeine were approximately equiactive, inhibiting by 60-80% the cough induced by electrical stimulation of the trachea. Concentrations of vadocaine in serum were around 1 microgram/ml during oral administration. By both routes, the antitussive activity (inhibition of cough by 50% or more) lasted at least 2 h. Vadocaine caused local anaesthesia in the guinea-pig wheal preparation at concentrations of 0.25% and 0.5%, and on the guinea-pig cornea at 0.5%. Duration of anaesthesia was longer than that of lidocaine. Vadocaine did not affect the guinea-pig tracheal strip preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the nonspecific central nervous system effects of the novel antitussive compound vadocaine hydrochloride.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl) propionanilide hydrochloride, OR K-242-HCl; INN: vadocaine) is a novel antitussive compound which is effective in several animal models at doses of 2.5-6 mg/kg. It has both central and peripheral local anaesthetizing properties. The present studies were aimed at exploring the specificity of the central antitussive activity of vadocaine. Vadocaine administered in doses of 25 and 50 mg/kg was not found to be effective in any of a series of experiments, although some antinociceptive activity was shown in the hotplate test and in the writhing test at a dose of 75 mg/kg. Some deteriorative activity was noted at a dose of 75 mg/kg in tests measuring motor coordination (rotarod) and spontaneous motility. This high dose of vadocaine did not affect pentobarbital sodium-induced sleeping time nor protect the animal from pentetrazole-induced convulsions. As expected, codeine phosphate was found to be a more potent antinociceptive drug than vadocaine, also enhancing spontaneous motility. Both the control anaesthetics benzonatate and lidocaine proved rather ineffective. Benzonatate (50 mg/kg) did not alter any of the results, whereas lidocaine (50 mg/kg) caused a decrease in the number of writhings. In conclusion, vadocaine can be said to initiate minor deterioration of the central nervous system only at doses about 10 times higher than those which show antitussive activity. Acute lethal doses are still 2 to 5 times higher. The central antitussive action of vadocaine can therefore be considered fairly specific.

First human studies on the safety and antitussive activity of vadocaine hydrochloride.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is a new anilide derivative which resembles lidocaine in chemical structure. The safety and antitussive effects of this new compound were studied in 6 healthy male volunteers in the first Phase I clinical trial. Vadocaine was administered in single doses of 5, 10, 15, 20, 30 and 50 mg. At these dose levels vadocaine had no effects on the cardiovascular system, the haematological variables, blood biochemistry or urinary sediment examined as safety evaluation. The antitussive properties of the compound were studied using inhaled citric acid for induction of the cough response. The antitussive properties of vadocaine were most effective at a dose of 15 mg, although no statistical significance was found. Neither was any dose-response relationship noted. However, at this dose level vadocaine is apparently safe and its antitussive properties seem promising enough for further evaluation.

Pharmacokinetics of graded single doses of the novel antitussive compound vadocaine hydrochloride in healthy male volunteers.

Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine) is an anilide derivative with antitussive and local anaesthetic properties. The pharmacokinetics of this new compound were studied in two Phase I clinical trials during safety evaluation. 6 (Part I) and 8 (Part II) healthy male volunteers participated in these studies. The pharmacokinetics were studied after single oral doses of 5, 10, 15, 20, 30 and 50 mg (Part I) and 100, 200, 300, 400 and 500 mg (Part II) of vadocaine in aqueous solution. Vadocaine was rapidly absorbed at each dose level. The AUCo----infinity value and 24-h urinary recovery of intact compound increased linearly as functions of the dose. The elimination half-life varied from 2.2 +/- 0.2 h to 3.7 +/- 1.6 h in a dose range from 5 to 50 mg, and from 2.7 +/- 0.3 h to 4.0 +/- 1.0 h in a dose range from 100 to 500 mg. The peak concentration of vadocaine after the highest dose was 2317.3 +/- 31.5 ng/ml at 1 h. When higher doses were used renal clearance did not change, although total body clearance seemed to diminish. Over 90% of vadocaine is metabolized, and the metabolic pathways may become saturated at a dose of 400 mg.