摘要:

To study the transfer of drugs from plasma into human milk [milk/plasma (M/P) ratio], we developed anin vitromethod using paracetamol as the standard. The results obtained after equilibrium dialysis between milk and plasma were correlated with those obtainedin vivo.For thein vivostudy, 8 healthy postpartum women were enrolled as volunteers on the third postpartum day. After the ingestion of paracetamol 650mg, thein vivocomparison of milk and plasma area under the concentration-time curves (M/PAUCratio) yielded a ratio of 0.94.In vitrodetermination of the M/P ratios was carried out on plasma and milk taken on the third and 26th days after delivery. The M/P ratio obtained after equilibrium dialysis (0.91 ± 0.01) was in good agreement with that foundin vivo.A strong correlation was found between plasma and milk concentrations obtained by bothin vitro(r = 0.96, p < 0.0001) andin vivoprocedures (r = 0.89, p < 0.001). These results demonstrate that thein vitrodetermination of M/P ratios for drugs that transfer in milk by passive diffusion, is similar to the data obtainedin vivo.We conclude that this method can be used to avoid ethical constraints associated with thein vivodetermination of human milk and plasma relative concentrations.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

After intravenous administration of 3,6-dinicotinoylmorphine (nicomorphine) 30, 20 and 10mg to patients undergoing surgery, this agent is rapidly metabolised into the metabolites 6-mononicotinoylmorphine (6MNM) and morphine. The elimination half-lives are 1 minute for nicomorphine, 13 minutes for 6MNM and 120 minutes for morphine. Morphine is subsequently metabolised into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The half-life of these 2 glucuronide conjugates is similar, about 225 minutes. A glucuronide conjugate of 6MNM was not detected. The area under the serum concentration-time curve of nicomorphine and its metabolites is linearly related to the dose.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of vecuronium administered as a 0.1 mg/kg intravenous bolus was evaluated during both the onset of and recovery from neuromuscular block in 9 anaesthetised patients. Sigmoid Emaxmodelling of neuromuscular block versus vecuronium effect compartment concentrations indicated comparable effective concentrations at 50% block (EC50) for both onset and recovery (146 ± 12vs144 ± 13 ng/ml, respectively). However, during onset, the sigmoid was systematically steeper (gamma of 6.41 ± 0.32vs4.17 ± 0.36, respectively). Including a finite receptor concentration in the effect compartment (0.27 ± 0.04 μmol/L) led to a faster equilibration rate constant, Keo(0.097 ± 0.009vs0.058 ± 0.005 min-1) and to lower EC50(120 ± 13 ng/ml) and gamma values (3.62 ± 0.22). The neuromuscular block predicted by this model was similar to the one obtained from a separate PK-PD analysis over each phase. Therefore, to be adequate, the PK-PD modelling of non-depolarising neuromuscular blockers should involve a separate analysis of onset or recovery data, or account for the safety margin of neuromuscular transmission by adding a receptor concentration in the effect compartment.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

Several investigators have studied the drug-drug interaction that may exist when alcohol and H2-receptor antagonists (i.e. cimetidine, ranitidine, famotidine) are administered concomitantly. Results from these studies have been mixed. However, no systematic investigation of the change in blood alcohol concentrations in the social drinker versus the chronic drinker challenged by concurrent intake of alcohol and H2-receptor antagonist has been conducted.Eleven volunteers participated in this 14-day study. On day 0, study participants were administered an oral alcohol dose of 0.15 g/kg. On days 1 to 9, no medication was given. All volunteers then received cimetidine 400mg twice daily on days 10 to 13. On day 14, study participants received an oral alcohol dose of 0.15 g/kg after their morning dose of cimetidine. Blood sampling was performed on days 0 and 14 after alcohol administration.The comparative alcohol availabilities, pre- and post-cimetidine, were determined by comparing the time to peak plasma concentration (tmax), peak plasma concentration (Cmax), and the total area under the concentration-time curve (AUC). In the chronic drinkers, tmaxwas significantly shorter than in the social drinkers following cimetidine administration (p = 0.008).Chronic drinkers who drink after cimetidine administration will have higher concentrations of alcohol faster than social drinkers. Medicolegal consequences resulting from this drug-drug interaction may occur; clinicians should therefore counsel patients about the possibility of enhanced impairment resulting from concurrent administration of these 2 drugs.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

Cough is a protective mechanism and an important symptom of many respiratory diseases. When coughing is only an annoying reflex and produces no mucus clearance, inducing fatigue or exhaustion for patients and worsening their pathological condition, antitussive drugs may be indicated.In this study we evaluated the efficacy and safety of moguisteine, a new antitussive drug with a peripheral mechanism of action, in a population of 124 adult patients with persistent cough associated with various respiratory disorders. Obstructive chronic bronchitis, reported in about 50% of the study population, was the most frequent underlying diagnosis. We conducted a randomised single-blind short term treatment trial in 7 centres, comparing moguisteine (3 doses of 200mg, over 2 days) to dextromethorphan (3 doses of 30mg, over 2 days). The primary efficacy variable was the percentage reduction in the audio tape-recorded number of coughs during a 6-hour period in the morning after the last dose of the study drug versus a 6-hour recording at baseline.Patients' subjectively assessed visual analogue scale (VAS) scores of cough frequency and cough troublesomeness at night and during the morning were considered as secondary efficacy variables.Safety was assessed by means of routine clinical laboratory tests and adverse event monitoring.The postdrug percentage reduction in the number of coughs approached 30% on either drug. VAS scores of cough frequency and cough troublesomeness showed remarkable reductions in both groups, without any noteworthy difference between treatments. Possible or probable drugrelated adverse events were reported in 3 of 61 patients on moguisteine (1 heartburn, 1 gastric pain, 1 diarrhoea) and in 4 of 63 patients on dextromethorphan (1 rhinitis and slight decrease of white blood cell count, 1 syncope, 1 gastric discomfort, 1 diarrhoea). Treatment discontinuation was necessary only for 1 patient, who had a syncope after the first dose of dextromethorphan.Our results indicate that treatment with moguisteine rapidly induces substantial cough relief and that it is well tolerated and as effective as dextromethorphan.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

摘要:

Ten patients with slight to moderate renal impairment were administered 500mg of tiopronin (2-mercaptopropionylglycine, 2-MPG) orally, and the pharmacokinetics of the drug and the metabolite, 2-mercaptopropionic acid (2-MPA), were evaluated and compared with previous results from 10 healthy volunteers.Total clearance (CL/F) of tiopronin in the 10 patients was estimated at 6.8 ± 2.8 L/h compared with 10.2 ± 2.7 L/h (p < 0.05) in healthy volunteers. The corresponding values for non-proteinbound tiopronin were 19 ± 11 and 43 ± 17 L/h (p < 0.01). The peak plasma concentration (Cmax) was greater in the patients but no difference was seen in the time to peak concentration (tmax) [4.4 hours]. Renal clearance (CLR) estimated from total plasma tiopronin was 2.7 ± 1.0 and 6.5 ± 1.2 L/h in patients and healthy volunteers, respectively (p < 0.01), and the corresponding values for non-protein-bound tiopronin were 5.4 ± 2.5 and 13.3 ± 2.0 L/h, respectively.Volume of distribution (Vd/F) was reduced in patients (4.5 ± 1.8 L/kg for total tiopronin and 0.9 ± 0.4 L/kg for non-protein-bound tiopronin) and the fraction of non-protein-bound tiopronin in plasma was somewhat higher in patients but declined in a similar manner to healthy volunteers. The t½&ggr;of tiopronin was 37 hours when calculated using 48-hour data and was found to increase to 70 hours when the terminal phase (i.e. 168-hour data) was taken into account.Significant pharmacokinetic differences were found between the patients in relation to their51Cr-EDTA clearance. Thus, patients with moderate renal impairment (51Cr-EDTA clearance about 30 ml/min/1.73m2) had increased half-lives based on the &bgr;-phase (t½&bgr;) [total tiopronin] and mean residence time (t) [non-protein-bound tiopronin], decreased CL/F and CLR(total and non-protein-bound tiopronin), and decreased Vd/F (total tiopronin) when compared with patients with only slightly decreased renal function. Total urinary recovery of tiopronin in the patients (33%) was the same as in healthy volunteers, although excretion was prolonged in the patients. After 24 hours, excretion was almost complete (97%).The metabolite 2-MPA had a tmaxof about 8 to 9 hours. About 14% of tiopronin was metabolised to 2-MPA and only small amounts of 2-MPA (2%) were found in urine.It therefore appears safe to administer tiopronin to patients with slight to moderate renal impairment. However, we believe that patients with a51Cr-EDTA clearance of less than 30 ml/min/1.73m2should be closely monitored during tiopronin treatment until further investigations have been carried out.

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS

ISSN:0114-2402    

出版商:ADIS    

年代:1994

数据来源: ADIS