Good clinical practice (GCP). / Dansk historie og engagement i international udvikling.

The wave of Good Clinical Practice (GCP) that swept Europe in the mid-eighties also hit Denmark. The influence from the USA was highly significant. However, the history of GCP in Denmark builds upon the ethical and scientific requirements for clinical trials of drugs which had developed over the preceding two decades. Furthermore, quality assurance of trials were already in progress. The Danish health authorities and the pharmaceutical industry were cooperating well in the evolution of GCP in Denmark. Parallelly, Denmark took an active part in the international harmonisation of the various GCP-guidelines within the Nordic countries, in the European Community, and world-wide through the development of the WHO- and the ICH-guidelines. In the work with these guidelines, several experts from a number of countries collaborated with Danish experts. Through this continuous interaction, Denmark profited from the tight connection with the circles and institutions where this development took place, both causing an increased awareness of GCP in Denmark, and an indisputable contribution from Danish participants to the international GCP-development. In 1987, an interdisciplinary Danish GCP Society was established. This has increased the understanding of GCP and, together with other activities, promoted the cooperation between the health authorities, the law-based ethics committee system, the sponsors, the investigators, and the Danish Data Protection Agency. The Society has arranged numerous courses and seminars, and held conferences and meetings in order to inform about GCP. The Danish GCP Society seems internationally to be rather unique in its scope and work. It is concluded that Denmark is well prepared for the coming regulations of trials on medicinal products proposed by the EU.

[Clinical drug trials. Regulation, coordination and significance of "Good Clinical Practice"]. / Klinisk laegemiddelafprøvning. Regulering, harmonisering og betydning af "Good Clinical Practice".

All major drug agencies in the world have now implemented, or have at least shown interest in, Good Clinical Practice (GCP) standards as an important part of their regulation of clinical trials. This is increasingly considered as a logical part of drug regulation in general, because the data produced in trials will later be evaluated by the government agencies, and the quality of trials and data must therefore be assured. Another significant effect of GCP will be caused by the ties between ethics, public health and scientific standard referred to in many of the requirements. This means that GCP may eventually have an impact on the entire clinical research programme, including nonregulatory projects (possibly the majority), because the same standard must apply throughout. Harmonisation is well under way internationally for both GCP and clinical trial regulation. This should also extend to the handling of scientific misconduct, the influence of GCP on health economics and the establishment of ethics committee systems. International data bases may obviously be required. Finally, the ultimate goal, the benefit for patients and society, must not be obscured by the mechanics of improving clinical trials and the harmonisation of regulations, and the investigator should maintain a key position in clinical drug development under the new regulatory conditions.

The antibacterial effect of some neuroleptics on strains isolated from patients with meningitis.

Eighty-two strains of bacteria (Neisseria meningitidis, Haemophilus influenzae, Enterobacteriaceae, Streptococcus pneumoniae, group B streptococci and Listeria monocytogenes) were examined for their in vitro susceptibility to eight drugs, seven neuroleptics (perphenazine, fluphenazine, cis(Z)-clopenthixol, haloperidol, clozapine, clebopride and SCH 23390), and the neuroleptically inactive trans(E)-clopenthixol. The phenothiazines and the thioxanthenes were, on the whole, the most active drugs when measured, the IC50(50) for each group of bacteria being 7.4 to 84 mg/l (with the exception of the activity against the enterobacteriaceae). The antibacterial potency of clozapine, which has an atypical neuroleptic profile, was between 50 and 140 mg/l. Haloperidol also showed an antibacterial activity in the concentration range 35-140 mg/l. The selective D1 antagonist, SCH 23390 and the selective D2 antagonist, clebopride, inhibited only few of the bacteria in the concentration range investigated.

Plasma, erythrocyte and urine concentrations of chlorproguanil and two metabolites in man after different doses.

Failures in the prophylactic effect of the antimalarial biguanide chlorproguanil (Lapudrine) may be caused by insufficient levels of its active metabolite chlorcycloguanil. Concentrations of chlorproguanil, chlorcycloguanil and a second metabolite, dichlorophenylbiguanide, in plasma, erythrocytes and urine, were followed in 13 volunteers, using a HPLC assay. In an initial study the basic kinetics were investigated after an oral dose of 2 mg kg-1. In the main study, the concentration-time curves were followed for 1 week after an oral dose of 20 or 80 mg chlorproguanil, respectively, after either a single dose or one weekly dose for 5 weeks. Higher concentrations of all three compounds were found in erythrocytes than in plasma. The active substance, chlorcycloguanil, was below the probably effective concentration in erythrocytes 24 h after 20 mg chlorproguanil and 72 h after 80 mg. The urinary recovery was about 45% of the dose and t1/2 31-44 h, both higher than previously reported. The apparent clearance was 0.52-0.82 l h-1 kg-1, which is lower than previously found. It is suggested that improved dose regimens, e.g. a higher dose given once a week, should be clinically tested on basis of these kinetic results.

Effect of selected neuroleptic agents and stereo-isomeric analogues on virus and eukaryotic cells.

Chlorpromazine, cis(Z)-chlorprothixene (Truxal), and the non-neuroleptic trans(E)-chlorprothixene and trans(E)-flupenthixol were studied in vitro for possible antiviral effect on Herpes simplex virus 2 and for toxic effect on human diploid fibroblasts. Based on an enzyme-linked immunosorbent assay (ELISA) antiviral activity was demonstrated for all the compounds in the concentration range 0.39 micrograms/ml-25 micrograms/ml. A cell-toxic effect was shown in the higher concentration range for all the compounds except cis(Z)-chlorprothixene. A cell-stimulatory effect was also detected at the lower concentration range (about 3.13 micrograms/ml) for all compounds. Thus both cell stimulation and antiviral effect can be found for the same agent within the same concentration range. The results point to the possibility of creating different antiviral drugs--which would also include a cell-stimulatory activity--among psychopharmacological drugs and their stereoisomeric analogues.

Topical and systemic availability of 5-aminosalicylate: comparisons of three controlled release preparations in man.

The bioavailability of three pure 5-aminosalicylic (5-ASA) preparations (Asacol, Claversal, and Pentasa) was studied in 8 ileostomy patients and 12 normal subjects after 6 days of treatment with 2000 mg 5-ASA. The local bioavailability, reflected by the 5-ASA concentration was thereby measured at two clinically relevant areas of the gut: at the entrance to, and the exit from the colon. Estimates of the systemic bioavailability were obtained from the urinary excretions and the plasma values of 5-ASA and Acetyl-5-ASA (Ac-5-ASA) during the three regimens. The three preparations studied are designed to release 5-ASA at different levels in the intestine, but there was no significant difference in the 5-ASA concentrations in the ileostomy effluents (Asacol 1.8 mmol/L, Claversal 3.4 mmol/L, Pentasa 2.0 mmol/L, median values). However, we found a smaller urinary excretion of 5-ASA and Ac-5-ASA (5.2% vs Claversal 27.9% and Pentasa 23.0%, median values of ingested daily dose) and a lower concentration of Ac-5-ASA in the ileostomy effluents after Asacol treatment (0.8 mmol/L, median value) which indicates a more distal release from this preparation compared with Claversal (2.4 mmol/L, median value) and Pentasa (5.5 mmol/L, median value). In normal subjects a higher faecal water concentration of 5-ASA was found after Asacol (9.8 mmol/L, median value) compared with Claversal (5.0 mmol/L, median value), whereas no difference between the faecal water concentrations of Ac-5-ASA was found (Asacol 21.5 mmol/L, Claversal 21.6 mmol/L, median values). This can be explained by a larger systemic absorption of 5-ASA from Claversal, and accordingly Claversal treatment resulted in the largest urinary excretion of 5-ASA and Ac-5-ASA (43.7% vs Asacol 35.6% and Pentasa 31.6%, median values of ingested daily dose). The high Ac-5-ASA concentration in the ileostomy effluents and in the faeces after Pentasa, and the low plasma values, indicate a slow 5-ASA release from this preparation throughout the small and large intestine. The results of the study indicate that Asacol is released in the distal part of the small intestine, that Pentasa is gradually released in the small and large intestine, and that Claversal shows an intermediate release pattern.

Why do we need pharmacokinetic studies?

Data on the fate of sex steroids in the human organism, such as absorption, distribution, total clearance, and elimination routes, are necessary to understand and predict drug action. However, except for a few exceptions, such data are sparsely available. It is necessary to apply several approaches (descriptive, mathematic, and analytic) to describe variability and dose-response correlations, all of which are important for individualized treatment, and therefore of therapeutic relevance. In addition, such data are now unavoidable requirements for the evaluation of safety, efficacy, and quality performed by the regulatory authorities. Therefore human kinetic information is an integral part of the knowledge that forms the basis for any treatment with sex steroids.

Therapeutic trials in general practice, an unmet need.

Clinical drug trials are not frequently carried out in general practice in spite of the fact that most drugs are used there. Reasons for this problem are most probably lack of motivation and training in drug trials among GP's. Certain areas of drug treatment are more suitable for general practice, while others are definitely not and in addition, time, financing and complex designs may be difficult to overcome. In any event the scientific quality of a project should be indisputable. The two potential roles of the GP ("the data collector" and "the project leader") are defined, and a list of questions that the GP should ask himself if approached by a sponsor is presented. Better drugs for the primary health care are badly needed, and the responsibilities for achieving this rely with the GP as well as with the medical community at large.

Trimipramine and other antipsychotics inhibit Campylobacter pylori in vitro.

A series of conventional anti-ulcer drugs, tricyclic antidepressants and neuroleptics (and some CNS non-active isomers) were tested in vitro for possible inhibition of Campylobacter pylori. These bacteria are claimed to play an etiological role in peptic ulcer disease, at least in gastritis B. While cimetidine, famotidine, ranitidine and pirenzepine were inactive, all the antipsychotic agents and their isomeric derivatives were active to various degrees with IC50 of 26-59 microM. Of special interest is trimipramine (Surmontil) that has been demonstrated to be effective against duodenal ulcers in some trials. The activity of the non-neuroleptic stereo-isomers of clopenthixol and chlorprothixene may lead to investigation in patients with peptic ulcer disease of this kind of agents. However, a firm connection between the antimicrobial activity of these compounds, their possible anti-ulcer effect and the etiological role of Campylobacter pylori in peptic ulcer disease must first be established.

Synergy between a non-neuroleptic thioxanthene stereo-isomer and penicillin in vivo.

Some neuroleptic drugs of the phenothiazine and thioxanthene groups have an antimicrobial effect in vitro. This is also true for neuroleptically inactive stereo-isomeric analogs of the thioxanthenes e.g. trans(E)-clopenthixol (t-CPT). In a murine pneumococcus peritonitis model t-CPT demonstrated a slight, but non-significant antibacterial effect in doses of 0.3-0.9 mg per mouse, while higher doses seemed to enhance the bacterial virulence. If combined with subtherapeutic doses of penicillin, a significantly higher survival rate was obtained compared with either drug given alone. In vitro studies demonstrated a similar synergistic effect. These results indicate that at least one non-neuroleptic thioxanthene stereo-isomer has an antibiotic potential also in vivo. The mechanism of action is not known.

Comparative plasma concentration profiles after i.v., i.m. and rectal administration of pethidine in children.

Plasma concentration-time curves of pethidine and norpethidine were studied in 25 children allocated after operation to three groups to receive pethidine 1 mg kg-1 i.v., i.m. or rectally. Peak concentrations occurred after 5 +/- 1, 10 +/- 2, and 60 +/- 10 min, respectively, while the maximum concentrations amounted to 2800 +/- 462, 1609 +/- 367 and 531 +/- 179 nmol litre-1, respectively. The area under the curve (0-240 min) was similarly reduced in the group with rectal administration (P less than 0.05). Compared with the i.v. data, approximately 40% systemic availability occurred after rectal application, although considerable individual variation was noted. In one child very high plasma concentrations were observed after rectal administration, possibly as a result of redistribution/recirculation phenomena. The average results are similar to those obtained when other opioids are given rectally.

Absorption of 5-aminosalicylic acid from colon and rectum.

In order to clarify the characteristics of absorption of 5-aminosalicylic acid (5-ASA) from the colon, a neutral solution was instilled into the right part of the colon and the rectum, respectively, in six volunteers. A laxative (bisacodyl) and liquid meals were given prior to each instillation. No significant difference could be demonstrated between the two parts of the large bowel, but the absorption was considerably restricted compared with previous results obtained from the jejunum. The results confirm in a direct manner earlier observations on 5-ASA released from sulphasalazine.

Comparative pharmacokinetics of ciprofloxacin and ofloxacin in cystic fibrosis patients.

The steady state pharmacokinetic properties of ciprofloxacin and ofloxacin were compared in cystic fibrosis patients. In a cross-over study eighteen adult patients with chronic Pseudomonas aeruginosa lung infection were given either oral ciprofloxacin 750 mg bid or oral ofloxacin 400 mg bid for two weeks. Three months later the alternative treatment was given. Concentrations were determined by a microbiological assay. Mean serum concentrations of ofloxacin (peak 5.9 mg/l) were higher than for ciprofloxacin (peak 4.0 mg/l). The time to reach maximal concentrations did not differ. The apparent total body clearance was significantly greater for ciprofloxacin, but renal clearances were similar. Relative to ofloxacin ciprofloxacin had a significantly shorter serum elimination half-life (3.4 vs. 6.4 h), showed less penetration into sputum (18% vs. 79%) and a lesser amount was recovered in urine (21% vs. 71% up to 12 h after dosing). No correlation was found between any pharmacokinetic parameter and change in pulmonary function.

Human pharmacokinetics of proguanil and its metabolites.

The pharmacokinetics of proguanil and its metabolites cycloguanil and p-chlorophenylbiguanide were studied in five healthy volunteers taking 200 mg orally for 14 days. A highly sensitive and specific high-performance liquid chromatographic assay was applied, clearly identifying all three compounds in plasma extracts as separate peaks. In four subjects peak plasma concentrations of proguanil (500 to 600 nmol/l) were reached after two to three hours, while cycloguanil and p-chlorophenylbiguanide showed a plateau after three and six hours, respectively. In the fifth subject peak concentrations of proguanil and cycloguanil appeared after seven hours. Trough concentrations (pre-dose in the morning) of proguanil and cycloguanil were about 200 and 100 nmol/l, respectively. Mean half-life of proguanil was estimated to approximately 20 h. The active metabolite cycloguanil constituted 30% of the total plasma drug concentration. The concentration of proguanil was higher in erythrocytes than in plasma, while that of cycloguanil was lower. Relevant clinical studies correlating plasma concentrations to the suppressive activity against malaria will be possible to perform based on the applied method and presented kinetic data.

Glucocorticoid levels and lymphocyte functions in kidney transplanted patients.

The in vitro lymphocyte response to mitogen stimulation and the in vitro lymphocyte sensitivity to glucocorticoid were examined in 72 kidney transplanted patients before and after administration of high or low doses of glucocorticoid. Administration of 10 mg of prednisone orally to 10 patients did not significantly change the mitogen responses or the lymphocyte sensitivity to methylprednisolone. Likewise, administration of 100-120 mg of methylprednisolone, intravenously to 62 patients did not significantly affect the mitogen responses, but, in contrast, the lymphocyte sensitivity to the immunosuppressive effect of methylprednisolone was clearly increased. This effect was highly significant in both cyclosporine A and azathioprine treated patients. These findings suggest that a change of the lymphocyte sensitivity to the immunosuppressive effect of methylprednisolone may occur after a high dose of glucocorticoid, anaesthesia and surgery, although no changes of the immunefunctions in vitro can be demonstrated by examining the mitogen response of the lymphocyte cultures. No relationship was found in the present study between the individual lymphocyte sensitivity to glucocorticoid and metabolic clearance rate.

Release of 5-aminosalicylic acid from Pentasa during normal and accelerated intestinal transit time.

The influence of intestinal transit time on the release of 5-aminosalicylic acid (5-ASA) from a peroral, slow-release preparation (Pentasa) was studied at steady state in seven healthy volunteers. Daily dose was 1500 mg Pentasa, normal transit time (NTT) was 24 h (16-26 h) and accelerated transit time (ATT), caused by a laxative, was 5 h (4-9 h). Median total recovery (24 h, 5-ASA + acetyl-5-ASA) was 87% (61-129%) (NTT) and 81% (56-100%) (ATT), respectively, (P greater than 0.10). The total faecal excretion of 5-ASA (per cent of dose) increased from 16%, (9-21%) (NTT) to 29%, (16-38%) (ATT) (P less than 0.02). Free 5-ASA rose from 12% (4-19%) to 17% (10-25%), the retained part (in granules) from 4% (2-5%) to 12% (4-24%). Urinary excretion decreased correspondingly from 32% (19-59%) to 21% (11-38%), predominantly as Ac-5-ASA (P less than 0.05). Mean plasma Ac-5-ASA concentration decreased from 1.42 micrograms ml-1 to 0.86 microgram ml-1 (P less than 0.05). An almost complete release of 5-ASA from Pentasa takes place during NTT. At ATT conditions about 88% is released, indicating Pentasa to be an acceptable source of 5-ASA in diarrhoeal states.

Salazosulfapyridine and metabolites in fetal and maternal body fluids with special reference to 5-aminosalicylic acid.

In 7 pregnant women, treated prophylactically with salazosulfapyridine (SASP) 3 g/day, amniotic fluid (16th week, n = 4, maternal and cord plasma (n = 5) and breast milk (n = 3) were analysed for SASP and the metabolites sulfapyridine (SP), acetyl sulfapyridine (Ac-SP), 5-aminosalicylic acid (5-ASA) and acetyl 5-aminosalicylic acid (Ac-5-ASA). Amniotic fluid contained concentrations of SASP, SP and Ac-SP and partly also Ac-5-ASA comparable to those previously found by others, whereas 5-ASA concentrations were very low. The ratios of maternal to cord plasma for all SASP metabolites were about 1:1-1:2, except for 5-ASA, cord plasma being extremely low. In breast milk, only traces of 5-ASA were detected, while Ac-5-ASA was above the plasma level. Only negligible amounts of 5-ASA are thus transferred to the fetus/newborn, which is of significance for the future use of the new non-sulfa-containing 5-ASA preparations during and after pregnancy.