[Analgesic effect of the selective noradrenaline reuptake inhibitor reboxetine]. / Analgetische Wirkung des selektiven Noradrenalin-Wiederaufnahme-Hemmers Reboxetin. Objektive und subjektive Messung.

BACKGROUND: Reboxetine is a selective noradrenaline reuptake inhibitor (NARI). As noradrenaline plays a relevant role in antinociceptive mechanisms, the hypothesis was investigated in this study whether reboxetine has analgetic efficacy. METHODS: Twenty-four healthy volunteers were investigated in a crossover design. Reboxetine (2 x 2 mg) or placebo were given for 5 days with the "crossover" following a one-day washout in between. The primary end-points were the N1 and P2 amplitudes of laser evoked somatosensory potentials (laser SEP) of vertex EEG. In addition, visual analogue scales (VAS, 100 mm) were used. RESULTS: Reboxetine showed a higher analgesic potency than placebo, with a statistically significant superiority in capsaicinirritated skin--in the objective tests (laser SEP, P < 0.0001 for N1 and P = 0.0002 for P2) as well as in the subjective pain measurements (VAS, P < 0.0003). Besides pain, the subjective feelings of burning and itching were lower with reboxetine than with the placebo. CONCLUSIONS: The hypothesis that a selective noradrenergic substance could be of analgesic efficacy was proven the first time experimentally. Reboxetine reduced the N1 and the P2 components of the laser SEP, which speaks for central and peripheral mechanisms of action.

Playground injuries in children: a review and Pennsylvania Trauma Center experience.

ISSUES AND PURPOSE: To describe patient demographics, injury characteristics, and circumstances of playground injuries in children admitted to Pennsylvania trauma centers and to identify injury prevention strategies. DESIGN AND METHODS: Retrospective, descriptive study of 234 children ages 1 to 18 years sustaining playground-related injuries and whose hospital data were entered into the Pennsylvania Trauma Outcome Study. RESULTS: Most of the injuries occurred between April and September (77%), and noon to 6 P.M. (69%). Falls from playground equipment constituted the highest proportion of incidents (73%). Of 421 injuries (M = 1.8/patient), most were upper extremity (n = 117) and head (n = 110) injuries. PRACTICE IMPLICATIONS: Nurses can advocate for playground safety by teaching children to play safely and recommending age-appropriate equipment and protective surfacing.

Derivation and validation of a pulmonary tuberculosis prediction model.

OBJECTIVE: To describe the derivation and validation of a pulmonary tuberculosis (TB) prediction model that would enable early discontinuation of unnecessary respiratory isolation. DESIGN: Patients placed in isolation for suspected pulmonary TB were studied retrospectively (derivation cohort) and prospectively (validation cohort). Independent predictors of pulmonary TB in the derivation cohort (January 1992-March 1994) were identified by retrospective analysis. Predictors in the model were assigned weights on the basis of the results of the multivariate analysis in order to quantitate the risk of TB in an individual patient. The prospective validation consisted of application of the model to patients placed in isolation during the period April 1994 to June 1995. The predictability of the model in the derivation and validation cohorts was evaluated using receiver operating characteristics (ROC), curve analysis, and calculation of the area under the ROC curve (AUC). SETTING: A university-affiliated, urban, public hospital with a large population of prison inmates and patients with human immunodeficiency virus infection. INTERVENTIONS: Prospective application of the prediction model to patients placed in isolation during the validation period. RESULTS: Four factors were found to be independent predictors of pulmonary TB among 296 isolation episodes in the derivation cohort; positive acid-fast sputum smear (odds ratio [OR], 5.8; 95% confidence interval [CI95], 3.0-11.0; weight = 3 points), localized chest radiograph findings (OR, 2.5; CI95, 1.3-4.9; weight = 2 points), residence in a correctional facility (OR, 2.3; CI95, 1.2-4.4; weight = 2 points), and history of weight loss (OR, 1.8; CI95, 1.0-3.2; weight = 1 points). Infection control practitioners applied the model prospectively to 220 isolation episodes. The mean (+/-SE) AUCs of the ROC curve for the derivation and validation cohorts were not significantly different (.86 +/- .04 vs .86 +/- .07; P = .90). There was a significant decline in the mean duration of isolation from the onset of an automatic TB isolation policy in August 1992 to the end of the study (P = .045 by analysis of variance). CONCLUSIONS: A pulmonary TB prediction model was derived and validated prospectively in a hospital with a moderately high prevalence of TB. The model quantitated the risk of TB in an individual patient and aided infection control practitioners and primary-care physicians in their decisions to discontinue isolation during the validation period. Utilization of the model was responsible, in part, for a decrease in the mean duration of isolation during the study period. Although the model may not have general applicability due to the uniqueness of the patient population studied, this study illustrates how prediction models can be developed and used effectively to deal with a clinical problem.

Safety and efficacy of lifibrol upon four-week administration to patients with primary hypercholesterolaemia.

The efficacy and safety of lifibrol, a novel cholesterol-lowering drug, was investigated in a double-blind clinical study in 168 patients with primary hypercholesterolaemia. Placebo and four lifibrol dose groups (150, 300, 450 and 600 mg/day) were tested over a period of 4 weeks. The mean LDL-cholesterol changes were 5.7%, -11.1%, -27.7%, -34.5% and -35.0%, respectively, after 4 weeks of treatment. No major changes in HDL-cholesterol were seen after this period. With the present study design, a decrease in triglycerides (-28%) was significant in the highest dosage group only. Additionally, it was shown that further independent risk factors for coronary heart disease were favourably influenced. Fibrinogen decreased in all dosage groups with a maximal mean value of 18% and a tendency toward reduction in lipoprotein (a) was observed in patients with high baseline levels (> 30 mg.dl-1). Lifibrol was generally well tolerated in all dosage groups and no serious adverse events were reported. Laboratory parameters did not show any clinically relevant alterations.

Pharmacodynamics of nilvadipine, a new dihydropyridine-type calcium antagonist.

Nilvadipine is a new calcium antagonist of the dihydropyridine type. It reduces blood pressure by high-affinity blockade of calcium channels in arterial cells, which leads to relaxation of arterial vessels. Nilvadipine has both pharmacokinetic and pharmacodynamic advantages compared to nifedipine (the prototype of the dihydropyridines). The duration of action is longer and it has a 4- to 16-fold higher vasodilatory potency that is accompanied by less cardiodepression and adrenergic counterregulation. The higher vascular selectivity of nilvadipine is documented by its vascular/cardiac potency ratio of 251, which is 9- to 10-fold greater than that of nifedipine. When used therapeutically as an antihypertensive agent, even in patients with heart failure or concomitant beta-blockade, nilvadipine has no negative inotropic, chronotropic, or dromotropic effects. Nilvadipine has been shown to have a more potent antiatherogenic effect than that of nifedipine in vitro and in animal models.

Clinical pharmacology of the hypocholesterolemic agent K 12.148 (lifibrol) in healthy volunteers.

K 12.148 (INN:lifibrol), a new cholesterol synthesis inhibitor, was studied in healthy volunteers to evaluate tolerance/safety, the effects on lipids, and pharmacokinetics. In a sequential block design the doses of 150, 300, 600, or 900 mg, given once daily in the morning for 14 consecutive days, were examined in 40 healthy young males (8 active drug and 2 placebo per group, randomized) under well-controlled conditions. Total and LDL cholesterol serum levels decreased significantly in the 300, 600, and 900 mg groups (-13.4%, -23.8%, -25.6%, and -14.7%, -33.3%, -34.8%, respectively). whereas no significant change was seen with placebo and 150 mg. The antiatherogenic index Apo A-I/B increased in a dose-dependent manner between 300 and 900 mg. Changes in HDL cholesterol and triglycerides were not statistically significant. The study compound was tolerated well, and safety laboratory parameters did not show any relevant alterations, K 12.148 might be a very effective drug for the treatment of hypercholesterolemia.

The hypolipidemic effect of lifibrol during a long term treatment of pigs.

We investigated the hypolipidemic property of lifibrol in male and female minipigs in a long term trial over a treatment period of 6 months. Oral dosages between 12.5 mg/kg BW and 100 mg/kg BW lifibrol resulted in a strong reduction of serum cholesterol after only two weeks of treatment. The hypocholesterolemic effect was not counterbalanced and reached -76% at the end of the trial in the male pigs and -70% in the female pigs (100 mg/kg BW lifibrol). The reduction of serum cholesterol was mainly brought about by the reduction of LDL-cholesterol. Serum triglycerides seemed to be less influenced by lifibrol than serum cholesterol. The application of lifibrol had no significant influence on the weight gain of the pigs and did not alter the serum levels of AST and ALT. Lifibrol was well tolerated and the animals showed no symptoms of incompatibility.

[Clinico-pharmacologic study of a new sustained-release oral salbutamol preparation in patients with obstructive airway disease]. / Klinisch-pharmakologische Untersuchungen mit einem neuen retardierten oralen Salbutamol bei Patienten mit obstruktiver Atemwegserkrankung.

A new sustained release preparation of oral salbutamol (8 mg) was compared to salbutamol (8 mg) and placebo in 15 patients suffering from chronic obstructive airways disease in a randomized double-blind cross-over trial. Changes in airways resistance and amplitude of finger tremor as well as subjective assessment of side effects (tremors, unrest, palpitations) revealed a longer lasting effect following the sustained release preparation of salbutamol.

Hypolipemic activity of K12.148 in rats, marmosets and pigs.

The hypolipemic effect of K12.148, a new hypolipemic compound, was examined in normolipemic rats, marmosets and pigs. It could be demonstrated that this compound reduced serum lipids, and in particular serum cholesterol, very effectively in all tested animal species. The analysis of the lipids of the pig give evidence that the hypocholesterolemic effect is due to a reduction of LDL only. In vitro experiments with rat liver homogenates suggest that the hypocholesterolemic effect is brought about by the inhibition of hepatic cholesterol synthesis.

Pharmacological activities of droloxifene isomers.

Droloxifene (DROL) is a new antiestrogen which is used for the treatment of endocrine-responsive breast cancer in humans. As Droloxifene exists in a Z- and E-isomer, we investigated the main pharmacological properties of both isomers. For both compounds the following tests were conducted: affinity for the estrogen receptor (ER); effect on the growth of rat uteri; influence on the growth of the ER + human breast cancer cell line ZR-75; and isomer interconversion in vitro. DROL-(Z) had binding affinity to the cytosolic ER approximately ten times lower than that of DROL-(E). Furthermore, the estrogenic effect of DROL-(Z) in the rat uterus is weak and there is no antiestrogenic activity. The lack of antiestrogenic activity of DROL-(Z) in contrast to DROL-(E) could also be shown in the human breast cancer cells ZR-75. Thus DROL-(Z) is, as far as investigated, without antiestrogenic and estrogenic activities. Of note is the stability of both DROL-isomers. There is no interconversion or metabolism of the parent compounds DROL-(E) and DROL-(Z) in vitro.

Voltage-dependent calcium release in guinea-pig cardiac ventricular muscle as antagonized by magnesium and calcium.

An increase in extracellular potassium concentration from 4 to 16 mmol/l caused a decrease in membrane potential from -92 to -59 mV and selectively diminished the earlier of two contraction components of guinea-pig papillary muscles at 0.2 Hz stimulation frequency in the presence of noradrenaline. The influence on the early contraction component had a threshold of 8 mmol/l K+, corresponding to a membrane potential of -77 mV. However, test contractions elicited 800 ms after the 5 s stimulation interval exhibited an unimpaired early component. Since the activator calcium responsible for the early contraction component is derived, in mammalian ventricular muscle, from the junctional sarcoplasmic reticulum, it is assumed that the release site of the reticulum was filled with calcium shortly (800 ms) after a regular contraction, and lost its calcium at 16 mmol/l extracellular K+, during the 5 s stimulation interval. The potassium-induced depolarization determined the rate of calcium leakage during rest from the intracellular store. The depolarization-induced decline of the early contraction component was equally well antagonized by Mg2+ or Ca2+ without influencing the measured transmembrane potential. Both divalent cations shifted the relation between potassium concentration or membrane potential and the strength of the early contraction component to less negative membrane potentials. In order to reduce the early contraction component by 25% in the presence of 9.6 instead of 1.2 mmol/l Mg2+, the potassium concentration had to be increased from 9.6 to 22.0 mmol/l, with a respective decrease in resting membrane potential from -72.6 to -51.1 mV. The antagonistic effect of both divalent cations is though to result from the neutralization of negative charges outside the sarcolemma with a respective decrease in the outside surface potential.

Circadian variation of the hypocholesterolemic effect of K13.004 in rats.

The hypocholesterolemic effect in rats of the new lipid-lowering agent K13.004 was dependent on the time of day of its application. This dependence was shifted together with the time of peak activity of hepatic cholesterol synthesis (CS) when the feeding time of the animals was changed. This compound considerably reduced serum cholesterol only if given before the peak of hepatic CS, whereas application afterwards was ineffective. Our finding suggests that this hypolipidemic compound lowers serum cholesterol by inhibition of hepatic CS. Drugs acting in such a way should be administered prior to the maximum of hepatic sterol synthesis.

The slow phase of the staircase in guinea-pig papillary muscle, influence of agents acting on transmembrane sodium flux.

Guinea-pig papillary muscles contracting at frequencies of 0.25 to 1 Hz after rest periods long enough to be followed by a rested-state contraction showed a biphasic staircase phenomenon. An initial phase was completed within about 6 beats (fast phase of the staircase). Then a slow phase followed reaching a steady state after about 4 min only. The effect on this slow phase exerted by drugs known to influence transmembrane Na-flux was investigated. Dihydroouabain in concentrations (1.5-5 X 10(-5) mol/l), causing no increase in the rested-state contraction considerably augmented the slow phase of the staircase thereby prolonging the time from the onset to the steady state by severalfold. The fast phase, however, remained unchanged as far as the steepening slow phase did not influence it. The rest decline of force of contraction, measured by repeated interruption of stimulation, was considerably prolonged by dihydroouabain (to about sixfold the control value by 5 X 10(-5) mol/l). However, dihydroouabain did not influence the time course by which the force of contraction decreased after lowering the [Ca]0 from 3.2 to 0.8 mmol/l. Stimulation of the muscles in Ca-free medium produced a transient increase in force of contraction as visualized by test contractions after addition of Ca. This positive inotropic aftereffect which depended on the frequency of stimulation in the Ca free solution was augmented severalfold by 1.5 to 3 X 10(-5) mol/l dihydroouabain.(ABSTRACT TRUNCATED AT 250 WORDS)

No loss of estrogenic or anti-estrogenic activity after demethylation of droloxifene (3-OH-tamoxifen).

The binding affinity of 3-OH-Tamoxifen (Droloxifene or DROL) and N-demethyl-droloxifene (ND-DROL) to the cystosolic estrogen receptor of rabbit uteri was 10 times higher than that of Tamoxifen. Both compounds exhibited similar stimulation (estrogenic effect) and inhibition (anti-estrogenic effect) of uterine growth of immature female rats. 3H-Uridine incorporation into the RNA of MCF-7 and ZR-75 cells as a measure of anti-estrogenic activity was equally inhibited by concentrations of 0.05-1.0 mumol/l of both compounds. Thus, the pharmacological properties of DROL were not changed by N-demethylation.

In vivo and in vitro antiestrogenic action of 3-hydroxytamoxifen, tamoxifen and 4-hydroxytamoxifen.

This study demonstrates in vivo and in vitro properties of the non-steroidal antiestrogens tamoxifen (TAM), 4-OH-tamoxifen (4-OH-TAM) and 3-OH-tamoxifen (K 060 E). In immature rabbit uteri 4-OH-TAM and K 060 E bound to the respective estrogen receptors with a ten-fold higher affinity than TAM. Furthermore, K 060 E exhibited less agonistic (estrogenic) but higher antagonistic (antiestrogenic) activity in the immature rat uterus than TAM and 4-OH-TAM (change of uterine weight). The ratio of agonistic vs antagonistic effect of K 060 E was distinctly lower than in TAM and 4-OH-TAM. In addition, K 060 E reduced by approximately 45% the growth of the transplantable Fisher rat mammary tumor (R 3230 AC) as compared with TAM (33%). We assume that, due to the higher antitumor activity, K 060 E (3-OH-TAM) is a better antiestrogen than TAM.

[Greater oral activity of etilefrine pivalate compared to etilefrine in the cat and dog]. / Höhere orale Wirksamkeit von Etilefrinpivalat im Vergleich zu Etilefrin bei Katze und Hund.

Etilefrine pivalate (K 30 052, Ep) and etilefrine (E) were compared in regard to their effects on the circulation of cats and dogs and in regard to their effects on isolated organs (papillary muscles, atria, vena cava caudalis) of guinea pigs and rabbits. The effects of Ep and E were qualitatively equal. Ep was less effective than E on isolated organs and after intravenous injection, it was however more effective after oral or intraduodenal application. This result is in line with the hypothesis that Ep is inactivated during the first-pass to a smaller extent than E and is split after absorption to E and pivalinic acid.

Long-term effect of etilefrine pivalate on blood pressure in man.

An open and a placebo-controlled double-blind trial were carried out to measure the effect of a long-term treatment (2-6 months) with etilefrine pivalate (K 30 052, Ep) on blood pressure of 60 patients suffering from orthostatic dysregulation. Oral administration of the agent took place once daily, each dose containing 20 mg. While the acute response to a single dose was comparatively weak, long-term administration had a marked and long-lasting effect both on systolic blood pressure (+40.3 mmHg) and blood pressure amplitude (+37.5 mmHg) (p less than 0.01). Steady state values were reached only when duration of therapy was approaching 6 months. The increase in blood pressure amplitude points to an augmentation of stroke volume, whereas heart rate was virtually unaltered. Peripheral resistance appears not to be increased since diastolic pressure was unchanged. The elevation in blood pressure amplitude was fully reversible within 9 weeks of wash-out, thus hinting at functional rather than structural (sclerotic) changes in the cardiovascular system.

Comparison of the oral effectiveness of etilefrine pivalate and etilefrine in a long-term trial in man.

The influence of equimolar oral doses of etilefrine pivalate (K 30 052, Ep) and etilefrine on blood pressure of patients suffering from orthostatic dysregulation was compared. Both drugs augmented the systolic blood pressure in both, the upright and horizontal body posture. Diastolic blood pressure was not influenced. The resulting increase in blood pressure amplitude points to an augmentation of cardiac stroke volume. Ep in equimolar doses was nearly twice as active as etilefrine. This result is in line with the hypothesis that acylation of etilefrine with pivalinic acid inhibits the first-pass inactivation nearly completely.

[Double blind study of migraine therapy with etilefrine pivalate]. / Doppelblindstudie zur Migränetherapie mit Etilefrinpivalat.

In a double-blind trial of 3 months 24 hypotensive patients suffering from migraine were treated with etilefrine pivalate (K 30 052, Ep, 20 mg p.o.) or dihydroergotamine (DHE, 5 mg) or placebo. The number of attacks of migraine was significantly reduced after the 3-month treatment with Ep resp. DHE comparing with placebo. Duration of attacks, intensity and number of additional analgetic drugs were also clearly reduced after medication of Ep and DHE - in contrast to placebo medication. Effectiveness and tolerance of Ep were estimated well and occurring side-effects were only of short duration. Thus the antihypotonics Ep and DHE offer an effective therapeutic scheme for migraine in hypotensive patients. This is in accordance with the fact that hypotension plays an important role in the occurrence of migraine.