Analgesic efficacy of the serial application of a sulfurated mud bath at home.

The purpose of this randomized controlled trial was to evaluate the analgesic efficacy of a series of applications of sulfurated mud baths in outpatients suffering from back pain. Within 2 weeks 13 patients took 6 sulfurated mud baths (group A) and 12 patients 6 tap water baths (group B) at home. Before the bath and over 48 h after starting the 1st and the 6th bath, pain intensity was evaluated by the patients according to a visual analogue scale (VAS). The main outcome parameter was the weighted (for time of observation) sum of pain intensity (SPI) after the 6th bath. The mean SPI in group A was 741 mm x h (95% CI 594-864 mm x h) and in group B 1,112 mm x h (95% CI 929-1,252 mm x h) (p = 0.009), suggesting a significantly stronger analgesic effect of a series of sulfurated mud baths than of a series of tap water baths.

Oral medium-dosed metoclopramide versus placebo as highly effective antiemetic prophylaxis in in- and outpatients on noncisplatin chemotherapy.

The antiemetic effect of oral medium-dosed metoclopramide (MCL, 3.5 mg/kg b.w./cycle) and placebo for chemotherapy-induced emesis of a noncisplatin regimen was assessed for inpatients and outpatients in two double-blind placebo-controlled sequential analyses according to Bross (1952). MCL was given in 5 single doses of 0.7 mg/kg b.w. at 0 h (loading) and at 2 h (i.e. start of chemotherapy) and 6, 10 and 14 h (as maintenance doses). Both studies ended after 8 sequential pairs in favor of MCL (2 alpha = 2 beta = 0.05). Major antiemetic protection (< 2 emetic episodes per 26 h) was achieved for 8/8 of inpatients and 7/8 of outpatients (placebo 0/8 and 0/8). Side effects neither required discontinuation of the antiemetic regimen nor additional therapy. The median of MCL plasma levels ranged from 150 to 750 ng/ml and terminal half-lives from 3.9 to 8.9 h.

Minimal biliary excretion and enterohepatic recirculation of metoclopramide in patients with extrahepatic cholestasis.

The biliary excretion and apparent oral clearance of metoclopramide (MCL) were determined after oral administration of 1 mg MCL/kg body weight to 10 patients suffering from extrahepatic cholestasis with nasobiliary tube for drainage of the common bile duct. A bilioduodenal endoprosthesis was subsequently fitted in 6 of these patients, i.e. the enterohepatic circulation was restored, and the apparent oral clearance was re-determined. Biliary excretion, comprising free MCL and the products of conjugation, accounted for less than 1% of the administered dose. In accordance with this, the median areas under the plasma concentration-time-curves AUC(0-15 h) in patients with intact and interrupted enterohepatic recirculation were of similar size. The pharmacokinetic values in patients with cholestasis (median apparent oral clearance 0.5 l.kg-1.h-1; median t1/2 4.5 h) were similar to those previously reported in patients with healthy liver function. We conclude that it is not necessary to adjust single doses of MCL in patients recovering from obstructive jaundice.

Minimal biliary excretion and enterohepatic recirculation of lormetazepam in man as investigated by a new nasobiliary drainage technique.

The pharmacokinetics of lormetazepam (LMA) was studied in five patients with intact and interrupted enterohepatic recirculation (EHR) after an oral dose of 0.03 mg/kg given as solution. The disposition of lormetazepam in plasma was characterized by peak plasma levels of 14-60 ng/ml after 20-40 min. Peak plasma levels of the unchanged drug were higher (p less than 0.05) in case of interrupted EHR as compared to intact EHR. The areas and the plasma levels vs time curves of lormetazepam and its glucuronide were not statistically different and the oral clearance of lormetazepam was similar in both parts of the study (median 3.1 and 3.6 ml/min/kg). In case of interrupted EHR, 23-58% of dose was excreted as lormetazepam and its glucuronide with the urine during 24 h, in case of intact EHR, the urinary dose fraction was 9-35% (p less than 0.05). The 24 h postdose-bile fraction contained only 0.3-2.8% of the oral lormetazepam dose in form of the drug and its glucuronide. In conclusion, only negligible amounts of lormetazepam are excreted in bile. The demethylated metabolite lorazepam was not detectable in the biological samples investigated.

Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers.

Plasma levels and urinary excretion of lormetazepam (Noctamid-ampoules; 2 mg/10 ml) were studied after i.v. (0.015 mg/kg b.w.) and after p.o (0.03 mg/kg b.w.) administration of the drug to five patients with cirrhosis of the liver (C) and to five young male volunteers (N). The cirrhotic patients exhibited higher drug plasma levels (Cmax p.o.: 11-43 ng/ml [C] vs. 11-16 ng/ml [N]) and higher AUC0-24 values of the unchanged drug (i.v.: 66-102 ng.h/ml [C] vs. 54-72 ng.h/ml [N]; p.o.: 83-188 ng.h/ml [C] vs. 74-113 ng.h/ml [N]). The absolute bioavailability was increased in the C-group with 57-134% vs. 52-84% [N]. The total plasma clearance of lormetazepam was 3 ml/min/kg in the C-group and 4 ml/min/kg in the N-group and thus within the range known for elderly and young male subjects. Conversely to the parent compound, the AUC-figures of its 3-OH-glucuronide were higher in the N-group (346-434 ng.h/ml) than in the C-group (149-371 ng.h/ml). In 24 h pooled urine samples of both groups, the glucuronide of lorazepam, the N-demethylated metabolite, accounted for approximately 5-14% of the dose fraction excreted as lormetazepam glucuronide. Apart from increased levels of the unchanged drug due to porto-systemic shunt and/or disease-dependent lower glucuronidation rate, the pharmacokinetics of lormetazepam were not altered in cirrhotic patients. It can therefore be concluded that for this group of patients the drug can be administered according to the same dose regimen as that used for normal subjects.

Quantitative structure-activity studies of beta-adrenoceptor blocking drugs to decrease ventricular arrhythmias in guinea pigs.

The correlations between the physicochemical properties (n-octanol-buffer partition coefficients, P) of two series of N-alkylated and ring alkylated beta-adrenoceptor blocking phenoxypropanolamines and their antiarrhythmic activities were studied. For this purpose dose-response curves of the influence on the ventricular arrhythmia threshold (VAT) and on heart rate (HR) were determined in the anaesthetized guinea pig. The degree of N-alkylation correlated with the potency of the drugs to raise VAT and to lower HR. Intraventricular conduction was likewise depressed. Increasing ring alkylation did not consistently further increase biological activity. The combined data from series of drugs showed statistically significant parabolic correlations between hydrophobicity (log P' for pH 7.4) and the biological responses. It is concluded that the nonspecific antiarrhythmic and negative chronotropic activity of the investigated beta-adrenoceptor blocking drugs largely depend on their lipophilic properties. In addition steric and pharmacokinetic factors may be operative.

Absolute bioavailability of metoclopramide given orally or by enema in patients with normal liver function or with cirrhosis of the liver.

Single dose studies were performed with three different dosage forms of metoclopramide (0.25 mg/kg body weight) in patients with normal liver function (i.v. (Paspertin): n = 4, oral liquid preparation: n = 4, rectal micro-enema n = 4) and patients with histologically confirmed cirrhosis of the liver (i.v.: n = 6, oral liquid preparation n = 4, rectal micro-enema: n = 8). Drug plasma-concentrations were measured over 8 h by a specific gas chromatographic method. The median areas under the plasma concentration-time curves (AUC0-8) after i.v. and rectal administration were similar in both groups. In contrast, the median oral bioavailability was considerably higher in patients with cirrhosis of the liver (82%) than in patients with normal liver function (60%). It can be concluded from this study, that dosage adjustments may be necessary in oral treatment of patients with cirrhosis of the liver, especially if prolonged therapy is required.

Dose-response relationships of the objective and subjective antiemetic effects and of different side effects of metoclopramide against cisplatin induced emesis.

The graded and quantal responses of metoclopramide (MCL, Paspertin) were studied in patients (17-71 years) treated with cisplatin in combination with other cytostatics. The lowest dose of MCL was 0.125 mg/kg b.w./h i.v. over 2 h as loading infusion, then 0.0625 mg/kg/h over 24 h as the maintenance infusion, the total dose being 1.75 mg/kg per treatment cycle (n = 25). At the same schedule three different higher doses of MCL were run with total doses of 3.5 (n = 44), 7.0 (n = 120), and 14.0 (n = 161) mg/kg per cycle of cisplatin. The mean number of emetic episodes in historical control patients without MCL (n = 41) at the four different doses of cisplatin was 4.2 episodes at 25 mg/m2 of cisplatin, 6.9 episodes at 60 mg/m2, 14.9 at 90, and 21.6 episodes at 120 mg/m2 of cisplatin. The quantitative dose-response curves of the four doses of the emetic agonist cisplatin were shifted to the right by increasing doses of MCL. The following doses of cisplatin for greater than or equal to 95% antiemetic protection (i.e. only 0-2 emetic episodes as clinically sufficient protection) were obtained (at the respective mg/kg of MCL given in brackets): 13 (at 1.75 MCL), 25 (at 3.5 MCL), 42 (at 7 MCL), and 80 (at 14 MCL) mg/m2 of cisplatin, respectively. The MCL dose in order to provide greater than or equal to 95% of the patients against every mg/m2 of cisplatin was about 0.15 (range 0.13-0.18) mg/kg MCL per cycle (i.e. 6.5 mg/m2 of cisplatin are antagonized by 1 mg/kg of MCL).(ABSTRACT TRUNCATED AT 250 WORDS)

High doses of metoclopramide or droperidol in the prevention of cisplatin-induced emesis.

The antiemetic effects of the benzamide metoclopramide (MCL, Paspertin) and of the butyrophenone droperidol (DRO, Dehydrobenzperidol) were compared by two sequential analytical trials in cisplatin treated patients. In the first trial (cisplatin 60-90 mg/m2) the drugs were given as loading infusions (MCL 0.5 mg/kg, and DRO 0.05 mg/kg, each per b.w./h over 2 hr), beginning 2 hr before cisplatin administration; this was followed by the maintenance infusion at half the dose, over 24 hr (total dose of MCL 7 mg/kg, and DRO 0.7 mg/kg b.w. per cycle, resp.). During the second trial (cisplatin 90-120 mg/m2) the antiemetic dosages were doubled (total dose of 14 or 1.4 mg/kg per cycle. After 12 and 14 treatment pairs, resp., MCL was significantly (P less than 0.05) more effective than DRO. Clinically antiemetic protection (i.e. less than three vomiting episodes) were seen in 9 of 12 and 13 of 14 patients, resp., compared with only 5 of 12 and 5 of 14 patients on DRO. The incidence of major extrapyramidal side-effects was more than 2-fold higher at DRO. The benefit/risk relationships (i.e. the relation between the prevented emetic episodes and the number of extrapyramidal reactions seen) of MCL were 2.7-3.0-fold better than those of DRO. The relatively higher antiemetic efficacy of MCL may be due to its additional gastrointestinal mechanisms.

Estimation of digoxin dosage in VLBW infants using serum creatinine concentrations.

Digoxin steady state plasma concentrations (Css) and the corresponding serum creatinine concentrations were studied in 17 VLBW infants. Birth weight was in the range of 760-1 500 g (mean 1 068 g), gestational age ranged from 26 to 32 weeks (mean 28.7 weeks). Digoxin steady state plasma concentrations were found in the range of 0.5-6.5 ng/ml (mean 1.88 ng/ml) during maintenance therapy with 1.6-8.4 micrograms/kg BW/24 h (mean 4.4 micrograms/kg BW/24 h) given in two divided doses intravenously. No digoxin-like immunoreactive substance could be detected in the plasma of 18 infants (10 patients with a birth weight less than or equal to 1 500 g, 8 patients with a birth weight of 2 100-4 730 g) that were not treated with digoxin. The calculated digoxin clearance ranged from 0.38-4.03 ml/min/kg BW. Serum creatinine concentrations were found in the range of 35-274 mumol/l (0.4-3.1 mg/100 ml). A hyperbolic correlation may be derived from the digoxin clearance and the corresponding serum creatinine concentration. A linear relationship was observed between the dose normalized digoxin concentrations (y = Css/dose in 24 h) and the respective creatinine concentrations x (y = 0.52x-0.05; n = 17; s = 0.24; r = 0.86; p less than 0.01). According to this equation we suggest a dosing schedule for digoxin in VLBW infants with impaired renal function. Digoxin maintenance dose is derived from the digoxin target and the creatinine serum concentration. This dose recommendation proved reliable on four VLBW infants (birth weight 770-1 260 g) with decreased renal function.

Enhancement of the antiemetic action of metoclopramide against cisplatin-induced emesis by transdermal electrical nerve stimulation.

In a double-blind sequential trial, the influence of transdermal electrical nerve stimulation (TENS) was studied in patients who were treated with total infusions of metoclopramide 3.5 mg/kg to counter the emetic action of cisplatin 60-90 mg/m2. Transdermal electrical nerve stimulation further reduced the emetic episodes in ten of 11 treatment pairs (2 alpha = .10). This effect was blocked by naloxone. More surprisingly, TENS reduced the incidence of extrapyramidal effects of metoclopramide (i.e., akathisia and dystonia). These effects may be explained by the involvement of central nervous and peripheral TENS-induced production of opioid neuromodulators. An alternate hypothesis is the stimulation of serotonergic mechanisms via neuromodulation by opioid peptides, or by involvement of both systems.

Comparison of the antiemetic efficacy of two high-dose benzamides, metoclopramide and alizapride, against cisplatin-induced emesis.

The antiemetic effect of two benzamides, metoclopramide (MCL; Paspertin) and alizapride (AZP; Vergentan), was compared in two double-blind sequential analytical trials in cisplatin-treated patients (60-90 mg/m2). In the first trial, the drugs were given as loading infusions (0.5 mg/kg of body weight/hour over 2 hours) beginning 2 hours before cisplatin administration; the maintenance infusion (0.25 mg/kg/hour) given over 24 hours was half the dose (total dose, 7 mg/kg of body weight per treatment cycle). In the second trial, the dose of AZP was doubled. After nine and ten treatment pairs, MCL was significantly (2P less than 0.10) more effective than AZP: three of nine and four of ten patients receiving MCL remained totally free from vomiting, compared with only none of nine and one of ten patients receiving AZP. The incidence of extrapyramidal reactions was similar in all treatments. However, the administration of AZP was much more unfavorable because of moderate to severe hypotensive side effects.

[Benefit and risk of high-dose metoclopramide in comparison to high-dose haloperidol or triflupromazine in cisplatin-induced vomiting]. / Nutzen und Risiko von hochdosiertem Metoclopramid im Vergleich zu hochdosiertem Haloperidol oder Triflupromazin bei cisplatin-induziertem Erbrechen.

The antiemetic efficacy of metoclopramide (MCL, Paspertin, loading infusion 0.5 mg/kg body wt./h over 2 h, maintenance infusion 0.25 mg/kg/h over 24 h) has been compared with haloperidol (HAL, Haldol, 1/10 of MCL dosage) and with triflupromazine (TFP, Psyquil, 1/2 of MCL dosage) in two sequential analyses, against the emetic effects of cisplatin (60-90 mg/m2). After treating 14 and 8 pairs of patients respectively, MCL was significantly (alpha = 0.05) more effective than HAL or TFP. Only 1 of the 14 patients in the HAL group and 0 of 8 in the TFP group were totally protected against emesis, in contrast to 6 of 14 patients and 3 of 8 in the MCL groups. In order to quantify the benefit/risk relationship of the antiemetic drugs studied the number of prevented emetic episodes (in comparison to previous insufficient treatment) was related to the incidence of major undesired effects (i.e. dystonia and/or akathisia). This relationship was 17.8 and 12.1 for the two MCL groups; for HAL and TFP it was only 5.8 and 4.6, respectively. The high antiemetic selectivity of MCL against cisplatin-induced emesis is probably related to the still unknown action of MCL on the gastrointestinal motility. A high neuroleptic potency, with or without additional anticholinergic activity, is apparently not essential for high antiemetic protection against cisplatin.

Metoclopramide kinetics at high-dose infusion rates for prevention of cisplatin-induced emesis.

Eleven male subjects aged 24 to 58 yr received cisplatin, 90 to 120 mg/m2 iv, in combination with other cytostatic drugs such as doxorubicin HCl and bleomycin. To prevent emesis, two high-dose metoclopramide regimens were started 2 hr before cytostatic therapy. Regimen A (n = 7) consisted of a loading dose infusion of 1 mg/kg/hr over 2 hr, followed by a maintenance infusion of 0.5 mg/kg/hr over 24 hr (total dose was 14 mg/kg in each cytostatic cycle). Regimen B (n = 6) consisted of half the metoclopramide dose. The following kinetics were derived from the metoclopramide steady-state plasma levels and the t1/2 of the elimination phase 26 to 38 hr after dosing (median value and range are listed): Steady-state plasma concentration in group A and group B was 750 (480 to 1520) and 360 (300 to 480) ng/ml plasma. Drug clearance in group A and group B was 0.67 (0.3 to 1.0) and 0.70 (0.5 to 0.8) l/hr/kg. Volumes of drug distribution in group A and group B were 4.4 (1.9 to 6.5) and 4.3 (3.2 to 5.9) l/kg. Values for the t1/2 in the elimination phase in group A and group B were 4.7 (3.0 to 5.4) and 4.3 (3.7 to 5.1) hr. It appears that metoclopramide kinetics at high doses were dose linear, i.e., without evidence of cumulation. There were few side effects; vomiting was effectively suppressed by both regimens.

Improved benefit/risk ratio of higher-dose metoclopramide therapy during cisplatin-induced emesis.

Metoclopramide (Paspertin) was infused intravenously in the high doses of 1.75, 3.5, 7.0, and 14 mg/kg body wt. per treatment cycle as antiemetic therapy for cisplatin-induced emesis (363 cycles, 25-120 mg/m2). The antiemetic potency of metoclopramide increased in a log linear manner, giving from 40% to 95% protection against emesis. Gastrointestinal motility showed a similar increase, i.e. diarrhoea. In contrast, the extrapyramidal reactions, namely akathisia, rigidity and acute dystonia, did not show a dose-dependent increase in frequency and remained constant over the dose range of 3.5-14 mg/kg per cycle. The results suggest increasing benefit of metoclopramide treatment with increasing doses of the drug.

Estimation of the nonspecific cardiovascular toxicity of beta-adrenoceptor blocking drugs with different hydrophobic properties in the cat.

The structure-activity relationship between the acute nonspecific cardiovascular depressant effects of the beta-adrenoceptor blocking drugs and their hydrophobic properties was evaluated experimentally for propranolol, pindolol, practolol, and atenolol, in the anaesthetized cat after preceding beta-adrenoceptor blockade. The LD50 values (geometric mean and range in mumol/kg i.v., each drug n = 5) for the nonspecific depression of max dp/dt were: 7.5 (5.6-9.1) for propranolol, 21 (15.5-28) for pindolol, 190 (115-290) for practolol, and 230 (170-400) for atenolol. The respective partition coefficients in octanol buffer (pH 7.0) as a measure of hydrophobicity were: propranolol 5.4, pindolol 0.20, practolol 0.025, and atenolol 0.0032. These experimental data showed a good fit into the regression equation obtained previously [18]. Practolol, in contrast, had a lower toxicity than calculated because of a pronounced intrinsic sympathomimetic activity (ISA), even after catecholamine depletion. The nonspecific cardiovascular toxicity of 15 other clinically used beta-adrenoceptor blocking drugs were estimated from their respective octanol buffer partition coefficients. The fall of the diastolic blood pressure was representative of the toxicity of the compounds. It is concluded that the cardiovascular toxicity is lowest in compounds with low hydrophobicity and with distinct ISA.

Experimental observations on peritoneal transport in rabbits.

Peritoneal transfer kinetics of substances differing in molecular size and lipophilic properties were studied in anuric adult rabbits with ligated ureters. In conscious animals, the dialysate/plasma concentration ratios of creatinine (Cr) and inulin (In) rose exponentially up to 200 min of dwelling. Peritoneal CIn was 0.24 ml/min/kg, and CCr was 0.10 ml/min/kg of body wt. The transfer rate for dipropyl acetic acid (VPA) was higher than for its more lipophilic analogue dibutyl acetic acid (DBA); the apparent equilibrium of the dialysate/plasma concentration ratio for VPA was 0.3 to 0.6 and 0.15 to 0.20 for DBA. Correspondingly, the peritoneal CVPA was higher (0.08 to 0.16 ml/min/kg) than CDBA (0.04 to 0.05 ml/min/kg); peritoneal clearances were 8% vs. 1.5% of the plasma clearances. The addition of nitroglycerin, dopamine, isoprenalin, fenoterol, and nitroprusside sodium to the dialysate did not increase significantly the peritoneal CCr and CIn during 30-min cycles. In conclusion, the peritoneal transport kinetics of creatinine, inulin, and protein are qualitatively similar to clinical data, but of different magnitude. The efficiency of peritoneal dialysis depends on the lipophilic characteristics of the substance to be transferred. The vasoactive drugs studied seem not to be promising for increasing the efficiency of peritoneal transport.

Further studies of the membrane potential of the stria cells of the guinea pig in vitro.

Negative membrane potentials from the stria vascularis of the guinea pig have been recorded in vivo. Stable negative membrane potentials from the stria cells have also been recorded for as long as 2 minutes in vitro. They varied from -20 mV to -49 mV, irrespective of whether the stria vascularis was immersed in Ringer's solution for in K-Ringer's solution (approximately to the composition of an endolymph). Labelling of the inserted stria cells from which the membrane potential had been recorded demonstrated that the microelectrode tip was inside the cell. These cells will continue to show electrical activity for some time when immersed in suitable media.