Jens Schou

Boric acid single dose pharmacokinetics after intravenous administration to man.

Eighth young adult male volunteers with a basic (alimentary) plasma boric acid concentration of <0.10–0.46 mg/l were given a single dose of boric acid (562–611 mg) by 20 min IV infusion. The plasma concentration curves, followed for 3 days, best fitted a three-compartment open model, although two subjects had to be left out due to inconstant basal plasma concentration values or failure to fit to the three-compartment model. The 120 h urinary excretion was 98.7±9.1% of dose, Cltot 54.6±8.0 ml/min/1.73 m2, t1/2β 21.0±4.9 h and distribution volumes V1, V2, and V3: 0.251±0.099, 0.456±0.067 and 0.340±0.128 l/kg.

Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system

AbstractObjective: The present study was performed both to investigate whether there might be a difference between the selective serotonin re-uptake inhibitors, (SSRIs) with regard to the incidence of withdrawal reactions, and to describe the associated symptoms. From the WHO database, therefore, all case reports from the year of introduction for each of the SSRIs, fluoxetine, paroxetine and sertraline, were retrieved. Sales figures were obtained from Intercontinental Medical Statistics International. The reporting rates were calculated as the number of reports per million defined daily doses (DDDs) sold per year. Results: The reporting rate of withdrawal reactions for paroxetine was found to be higher than that for sertraline and fluoxetine in each of the countries selected for detailed analyses (US, UK and Australia), as well as for all 16 countries combined. Moreover, using the WHO system of organ classification, the ratio of central nervous system to psychiatric withdrawal symptoms was 1.9 and 2.1 for paroxetine and sertraline, respectively, whereas that for fluoxetine was 0.48, indicating a possible qualitative difference between the SSRIs with respect to the nature of the withdrawal syndrome.

d-Propoxyphene kinetics after single oral and intravenous doses in man.

d‐Propoxyphene kinetics was studied in 8 healthy male subjects after single oral doses of d‐propoxyphene at 65, 130, and 190 mg and after slow intravenous infusion of 65 mg. Total urinary excretion (7 days) indicated complete oral absorption but systemic availability was reduced corresponding to first‐pass elimination of 30% to 70%. There was linearity between oral dose and the corresponding area under the plasma concentration/time curve of d‐propoxyphene and the metabolite norpropoxyphene. The kinetic measurements showed 2‐ to 3‐fold interindividual variations: oral clearance, 1.3 to 3.6 Mmin; systemic clearance, 0.6 to 1.2 l/min; apparent volume of distribution, 700 to 1,800 l; d‐propoxyphene half‐life (t½), 8 to 24 hr; and norpropoxyphene t½, 18 to 29 hr. There were pronounced intraindividual dose‐independent variations in oral clearance in some subjects. The intravenous concentration curves indicated a 3‐compartment distribution model.

Gastro-intestinal absorption and in vitro release of boric acid from water-emulsifying ointments

Boric acid taken orally by six male volunteers in a cross-over study was absorbed to equal extents from a water solution and a 3% waterless, water-emulsifying ointment, though with a slight initial delay in the latter case. Virtually complete gastro-intestinal absorption and renal excretion were indicated by the 96-hr urinary recovery, amounting to 89.1-98.3% (mean 93.9%) and 89.2-97.5% (mean 92.4%) of the dose ingested as solution and ointment, respectively, normal daily boron excretion having been taken into account. The in vitro release of boric acid, measured for 24 hr by dialysis in water at 37 degrees C, reached 95% from a purely water-based jelly but only about 5% from the water-emulsifying ointment. The low boric acid release from the ointment was not significantly influenced when the ointment was dialysed against buffer solutions of pH 2.5 and 9.6 instead of water, or when the maximum possible amount of water (26.9% w/w) was incorporated into the ointment before dialysis. The 24-hr boric acid release from a number of other oil-based ointments, either hydrophobic or water-emulsifying and containing 1-3% boric acid and 0-28.5% water, was also low (0.9-18.3% of the boric acid content). This indicates that the formulation of the ointment is an important factor in determining the extent of release of boric acid when the ointment is applied externally, but that it does not alter the absorption of boric acid should the ointment be ingested.

Dextropropoxyphene kinetics after single and repeated oral doses in man

SummaryThe kinetics of dextropropoxyphene (DP) and its main metabolite norpropoxyphene (NP) were studied in 6 healthy male subjects after a single oral dose of 195 mg DP HCl, and during and after 12 daily single oral doses of 195 mg DP HCl. The kinetics varied up to five-fold between individuals after the single dose, the apparent mean elimination half-life (t1/2) was 16 h for DP and 29 h for NP. The mean apparent overall plasma clearance (CL) for DP was 2.61/min. There was no systematic difference in DP clearance between the single and multiple doses, but the accuracy of individual predictions from single to multiple doses was poor, probably because of imprecise determinations of the AUC and t1/2 in the single dose experiments. The individual correlation between single and multiple dose kinetics was good for NP, although the predicted plasma levels during steady state were significantly higher than the observed levels (mean AUCss/AUCsd: 0.81). There was no sign of saturation kinetics on repeated administration. In fact, autoinduction, resulting in significantly lower plasma concentrations after treatment for 1 week was found for NP and was indicated for DP. On discontinuing DP after 12 days of treatment, the apparent mean t1/2 of DP was 23 h and of NP 25 h.

A Spectrophotofluorometric Micromethod for the Determination of Cortisol (Hydrocortisone) in Plasma and Tissue Obtained by Needle Biopsies

A spectrophotofluorometric micromethod which allows the quantitative determination of cortisol in 30–70 mg tissue (sampled by needle biopsies) or 100 μ1 blood plasma is described. The method is evaluated for recovery, accuracy, precision and specificity, and is found to satisfy the expectations for a micromethod. Plasma cortisol is found within the range of values from the literature obtained by ordinary macro-scale methods. The concentration of cortisol in peripheral tissue (skin plus subcutaneous tissue) varies from 0–180 ng/g wet weight. Females around menopause have a lower tissue content than younger and older females and males, with no changes in the plasma concentration.

Omeprazole and visual disorders: seeing alternatives

In the WHO data base, visual disorders reported spontaneously with omeprazole, ranitidine and cimetidine, are very rare in the context of the widespread use of these drugs. There is a maximum reporting rate of severe visual impairment possibly ascribed to i.v. omeprazole of 0.94 reports per million treatment days in one year and in one country, Germany. This gives the worst quantitative case scenario for omeprazole by a single route of administration, to be compared with the worldwide reporting rate of all severe visual disorders by all routes of administration — 0.008 reports per million treatment days. Moreover, the reported visual abnormalities have a varied pathophysiological aetiology and their number increased in Germany after the first signal was raised in that country. Thus, apart from a direct causal relationship, solicited reporting artifact is one alternate plausible explanation for the apparent excess of cases of visual disturbance to omeprazole compared with cimetidine and ranitidine. That reporting rates of clinical events on newly marketed drugs are generally higher than with older drugs is a second factor for higher reporting rates with omeprazole. Vasculitis has been suggested as an aetiological factor, but the even lower reporting rate of this reaction makes this an unlikely hypothesis without any other supporting evidence. The authors are unaware of any drug that has caused a vasculities solely affecting the eye.

D-propoxyphene kinetics in man: significance of a deep third compartment

SummaryData from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5–10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15–30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.

Spontaneous reports of drug-induced erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in Denmark 1968-1991.

Spontaneous reporting systems (SRS) have been established to monitor drug safety problems after marketing, especially rare, but serious adverse drug reactions (ADRs). Among these are the skin disorders erythema multiforme (EM), Stevens– Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The purpose of this study has been to evaluate the data on these serious skin disorders available in a SRS. All reports concerning these diseases submitted to the Danish Committee on ADRs during the period 1968 to 1991 were reviewed according to predefined criteria. Information was often scarce,and the diagnosis of the reporter had to be accepted at face value in 28% of cases. Two hundred cases of EM, 74 of SJS and 29 of TEN were identified. More than 60% of cases were hospitalized. The diseases had fatal outcome in six patients with TEN, three with SJS and a single patient suffering from EM. One hundred and twenty‐eight different drugs were reported as causal agents. Major drug groups involved were antibiotics (sulphonamides and penicillins), non‐steroidal anti‐inflammatory drugs, anti‐epileptics and analgesics. Incidence estimates based on spontaneous reports were compared to the incidence according to the literature and data from a nationwide hospital discharge diagnosis register. The reporting fraction for EM and SJS is estimated to 10– 30%, and for TEN to 25– 50%, but the validity of reports is in some cases difficult to assess owing to lack of detail.

Influence of indomethacin on the distribution of cortisol in man

SummarySimultaneous determinations of free and protein bound plasma cortisol and of the concentrations of cortisol in skin biopsies were performed after treatment with indomethacin. Neither after a single dose nor in patients on continuous treatment, were any consistent changes found in the protein binding of plasma cortisol. However, in patients treated for more than 3 weeks a significantly greater number of skin biopsies were observed with very low concentrations of cortisol. No relation between the free fraction of plasma cortisol and the tissue cortisol could be demonstrated.In vitro experiments showed no alteration of the protein binding of cortisol after the addition of indomethacin to plasma. It is concluded that indomethacin does not have antirheumatic activity because of displacement of the protein bound plasma cortisol as proposed by other workers. However, long term treatment with indomethacin does seem to influence the tissue distribution of cortisol. The possible relationship of this observation is discussed in view of reported fatalities after long continued indomethacin treatment.