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Abstract

H.-G. Eichler

Dept. of Clinical Pharmacology
Vienna University Medical School
Währinger Gürtel ¹⁸ – ²⁰
¹⁰⁹⁰ Vienna, Austria
The science of drug evaluation has changed. Those of us who trained in clinical pharmacology, pharmaceutical medicine or related fields up to the 1980s, were taught that the development and assessment of medicines was described essentially by the benefit/risk ratio. Cost of drugs received much less attention, at least within the academic community and among prescribing physicians. Since the 1990s, however, it is all too evident that the benefit/risk ratio is no longer sufficient and that a new denominator has been added to the equation describing the usefulness of medicines and influences on drug prescribing; the equation now reads: (benefit/ risk)/cost. Systematic assessment of cost-effectiveness has for long been decried by industry as a “fourth hurdle” (after quality, efficacy, and safety); nonetheless, we have to accept that the “fourth hurdle” is here, and it’s here to stay.

It is easy to see why the cost of drugs has become such a prominent concern. In the EU, average expenditure for drugs (outpatients only) per inhabitant has increased from € 63 to € 241 during the period from 1980 to 1997. When the same data are expressed as percentage of GNP, the increase is from 0.9% to 1.3%, indicating that the rise in drug costs outpaces overall economic development. Figures may be different in other countries, but the trend is universal. Again, the reasons for this increase in the drug bill are easy to pinpoint: aging populations, novel and more expensive therapeutic options, a shift from short-term to long-term treatments, and a better educated, more demanding patient population are among the cost-drivers.

An increase in drug costs is not necessarily a bad thing, if cost translates into improved health states, or if savings are achieved in other domains of the health care or social security budgets. Nonetheless, pharmaceutical industry which stands to benefit from this trend, has been slow to realize that one party’s income is another party’s cost. It is not surprising, therefore, that third party payers (government agencies, social securities, HMOs) are putting up a fight to restrain their rising drug bills. Payers have devised a variety of measures to limit the use and cost of pharmaceuticals, including prior authorization, tiered co-payment, prescribing limited to one or more specialties, delays in formulary acceptance, requirements that patient profile meet restrictive criteria, and outright exclusion of drug or class. Many of these measures are stopgap solutions, designed to “save this years budget”. Unfortunately, such short-term thinking delays rather than solves the problem of facing tough and unpopular decisions on patient entitlements. While these problems are relevant everywhere, countries in Central and Eastern Europe (CEE) and in the former Soviet Union are faced with additional burdens: in these transitional economies, health care providers are faced with the need to restructure their health care systems with budgets that are more limited than in the EU or US. At the same time, the public is demanding access to new expensive medicines. In some countries, drug budget allocation may also be weighed down by the perceived need to protect existing national, and not-so-innovative drug industries.

All of this necessitates a rethink in the allocation of drug budgets (i.e. drug re-imbursement) in CEE based on the principles of Evidence Based Medicine and sound pharmacoeconomics as well as on pre-defined national healthcare goals and policies. In spite of their considerable short-term problems, these countries, some of which may soon join the EU, currently have a unique window of opportunity to shape the future of their healthcare systems.

At this critical time, the International Journal of Clinical Pharmacology and Therapeutics wishes to stimulate the discussion on drug budget allocation in CEE. (Please refer to the “call for papers” announcement on the inside cover of this issue of the journal). It is a hope of the editors that a series of articles relevant to this topic will contribute to science-based and transparent drug reimbursement policies in these countries.

Hans-Georg Eichler, MD, MS

Dept. of Clinical Pharmacology

Vienna University Medical School

Währinger Gürtel 18 – 20

1090 Vienna, Austria

Call for papers

The International Journal of Clinical Pharmacology and Therapeutics wishes to stimulate, at this critical time, the discussion on drug budget allocation in Central and Eastern Europe (CEE). We invite authors from all sectors of the healthcare system, including industry, to submit relevant articles, commentaries or letters for publication in the journal. These articles should not be general but should describe factual examples of drug reimbursement policies or reasoned decisions as applied to individual drugs or classes in CEE.

It is a hope of the editors that this series of articles will contribute to science-based and transparent policies on drug budget allocation in these countries. (Please refer to the Editorial in this issue.)

Abstract

S. Ulrich, B. Baumann, R. Wolf, D. Lehmann, B. Peters, B. Bogerts and F.P. Meyer

¹Institute of Clinical Pharmacology, ²Psychiatric Clinic, and
³Institute of Biometry, University Hospital, Magdeburg, Germany
Objective: Therapeutic drug monitoring (TDM) of the atypical antipsychotic drug clozapine is recommended. Clinical studies have indicated a therapeutic window for clozapine serum levels in schizophrenic and schizo-affective patients during acute treatment, i.e. for patients who do not respond to treatment with typical antipsychotics. However, despite the frequent use of clozapine also in maintenance treatment, very few data are available showing the relationship between serum levels of clozapine and the prevention of relapse. Thus, the primary objective of the study was to investigate the relationship between serum levels of clozapine and relapse during maintenance treatment. Methods: A retrospective study of routine TDM-data was conducted. Samples obtained on an acute treatment ward from patients with < 4 days hospitalization (recent admissions) were regarded as samples associated with relapse. Samples which can be attributed to an intoxication were identified as described in the TDM-form. The serum level of clozapine, as well as age, gender, smoking habits, concurrent drugs, psychiatric diagnosis and dose of clozapine were evaluated. Data analysis was performed on individual samples and, alternatively, on multiple samples from a single patient which are summarized according to a typical clinical situation. Results: 404 serum levels were measured in 86 patients. After exclusion of patients receiving acute treatment, 65 relevant clinical situations were identified in 50 patients: 12 relapses, 8 intoxications (a total of 20 situations with poor outcome) and 45 situations involving patients with good maintenance outcome. Samples involving relapse had serum levels of 198 ± 211 ng/ml (10 – 624), intoxications had serum levels of 1,969 ± 705 ng/ml (900 – 2,900) and those with good outcome had serum levels of 384 ± 255 ng/ml (56 – 1,028) (mean ± SD (range)). By means of sensitivity of receiver operating characteristic curves (ROC) a lower limit of the therapeutic window can be estimated at about 50 – 250 ng/ml and an upper limit at about 745 – 1,050 ng/ml. The frequencies of good and poor outcome were significantly different within and outside these ranges, e.g. c2 = 11.8 and p < 0.001 for 250 to 745 ng/ml. Comparison of only good outcome and relapse provided a significant difference in the serum level of clozapine (Student’s t-test p = 0.024). However, 67% of relapses were predicted in a model of logistic regression only if the variables serum level and concurrent treatment with other psychotropic drugs were included simultaneously as independent variables. Neither variable was able to predict relapse if used as a single variable in separate models. Finally, it was found that serum levels of clozapine were increased in women, in aged patients and in non-smokers. Conclusions: It is tentatively concluded that serum levels of clozapine < 50 ng/ml are related to relapse irrespective of concurrent psychotropic drugs. In cases where there are no concurrent psychotropic drugs, serum levels of clozapine < 250 ng/ml are associated with relapse. The risk of relapse is low for serum levels of clozapine > 250 ng/ml irrespective of concurrent psychotropic drugs. The risk of intoxication is increased with serum levels > 750 ng/ml. The TDM of clozapine is recommended during maintenance treatment.

Abstract

R. Wanitschke¹, K.-J. Goerg² and D. Loew³

¹I. Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität, Mainz, ²Zentrum für Innere Medizin, Kliniken St. Antonius, Wuppertal und ³Wiesbaden, Germany
Constipation is a common condition occurring with increasing frequency in advanced age. As a symptom, it is not always dealt with directly by the physician, but is often left to the care of nurses. Many patients rely on self-medication. Constipation not only interferes with the quality of life, but often has the rank of a syndrome requiring competent medical intervention. This is of clinical importance, because a thorough understanding of the pathophysiology of constipation enables the clinician to identify the potential causes and, if necessary, initiate a differentiated therapy with the aid of only simple additional investigations. This review outlines a clinical approach including medical history, spectrum of causes, radiopaque pellets method to differentiate between slow transit constipation and defecation disturbances for the differential diagnosis of constipation. The mechanisms of action of laxatives (antiabsorptive, secretagogue, osmotic, filling and swelling agents) are further components and important for the individual therapy. Based on this fundamental information, a differentiated therapy is possible in each specific case such as coprostasis. Chronic symptomatic constipation reduces the quality of life and should be evaluated by physicians. If situations such as drug-induced constipation or hypothyroidism which have to be treated causally can be ruled out, laxative treatment according to the clinical picture, mode of action of drug used and side effects of the laxative can be initiated. Laxative abuse due to chronic constipation is rare and almost always associated with psychosomatic-psychiatric disorders.

Abstract

H. Sourgens, J. Schmidt and H. Derendorf

¹Independent Consultant, Munich, ²Applied Pharmacology, Dresden, Germany, and ³College of Pharmacy, University of Florida, Gainesville, FL, USA
Aims: The primary objective of this double-blind, randomized, parallel-group study was to compare the influence of the selective b₁-receptor antagonists talinolol (100 mg) and atenolol (50 mg) on the lipid metabolism in hyperlipemic patients with mild to moderate hypertension after 12 weeks of treatment. As a secondary endpoint, the influence of the drug on blood pressure, pulse rate as well as glucose metabolism were examined. Furthermore, pharmacokinetic parameters were assessed. Patients: Of the 198 patients recruited for the study, 166 were randomized to receive atenolol (n = 83) or talinolol (n = 83) for up to 12 weeks, 149 patients received the study medication for up to 48 weeks under double-blind conditions. Results: There was no difference between the antihypertensive effect of both b1-selective antagonists in patients with mild to moderate hypertension. No clinically relevant differences between the 2 drugs were observed for LDL cholesterol, HDL cholesterol, total cholesterol and triglycerides in the rather low doses given. However, there was evidence for a decrease in LDL cholesterol following treatment with talinolol, but not following treatment with atenolol, in patients with the highest initial blood pressure and in those with normalized blood pressure after 12 weeks of treatment. Parameters of glucose metabolism were not adversely affected by both drugs. Stable pharmacokinetics were observed over the 12-week administration, and steady state conditions were achieved after a 1-week treatment with both active compounds in the target population. Data indicate that once-a-day dosing can be performed with less fluctuation between peak and trough for talinolol in comparison to atenolol. Both treatments were well tolerated.

Abstract

M. Vietri, F. Vaglini, R. Cantini and G.M. Pacifici

¹Department of Neurosciences, Section of Pharmacology, Medical School, and ²Unit of Neurosurgery, University Hospital of Pisa, Italy
The first aim of this investigation was to study the sulfation of R(–)-apomorphine in human brain. The second aim was to investigate the inhibition of R(–)-apomorphine sulfation by quercetin in human brain. R(–)-apomorphine is hereafter referred to as apomorphine. Apomorphine sulfation was measured in 5 brain specimens; 3 derived from the frontal cortex and 2 derived from the temporal cortex. The rate of apomorphine sulfation was 5.6 ± 4.3 pmol/min/mg. The activities of SULT1A1 and SULT1A3, which were also measured in these samples, were 11 ± 9.1 and 2.6 ± 1.7 pmol/min/mg, respectively. The rate of apomorphine sulfation correlated with the activity of SULT1A1 (r = 0.989; p = 0.002) and SULT1A3 (r = 0.973; p = 0.005). Apomorphine sulfotransferase followed Michaelis-Menten kinetics, the Km (mean ± SD) and Vmax values (mean ± SD) of which, measured in 5 brain samples, were 32 ± 7.3 mM and 8.9 ± 7.9 pmol/min/mg, respectively. Quercetin was a potent inhibitor of apomorphine sulfation with an IC50 value, measured in 5 brain samples, of 16 ± 2.3 nM. The inhibition mechanism of quercetin using apomorphine sulfation in 5 brain samples was mixed, non-competitive with a Ki and Kies (mean ± SD) of 16 ± 4.1 and 87 ± 37 nM, respectively (p = 0.008). The intrinsic clearance value of apomorphine (mean ± SD) was 247 ± 170 ml/min/mg–1 and was decreased to 100 ± 85 ml/min/mg–1 (p < 0.01) in the presence of 25 nM quercetin. In conclusion, apomorphine is sulfated in human brain. Sulfation might reduce the level of apomorphine in human brain and be a factor limiting the effect of this drug. Quercetin is a potent inhibitor of apomorphine sulfation and may inhibit the sulfation of apomorphine in human brain in vivo.

Abstract

K.A. Jassim Al Khaja, R.P. Sequeira and V.S. Mathur

Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Bahrain
Objectives: The occurrence of aplastic anemia following topical administration of ophthalmic chloramphenicol is controversial and debated internationally. We have determined the influence of such debate on the utilization of ophthalmic chloramphenicol in Bahrain, through studying the utilization patterns of ophthalmic antimicrobial preparations by the Ministry of Health, with an emphasis on chloramphenicol, between 1993 and 2000. Cost-implications of these patterns are examined. Material and methods: Information on the annual purchase of ophthalmic antimicrobial drug preparations and their unit price was obtained from the Directorate of Materials Management, Ministry of Health, and analyzed. Results: In 1993, the 3 most commonly purchased ophthalmic antibacterial preparations were oxytetracycline 1% eye ointment (40.1%); sulfacetamide 10% and 20% eye drops (25.3%); and chloramphenicol 0.5% eye drops and 1% eye ointment (10.8%). In 2000, oxytetracycline remained the most frequently purchased preparation (33%), followed by chloramphenicol (21.2%). Between 1993 and 1999, chloramphenicol purchases fluctuated between 10% to 16.4% with a remarkable increase to 21.2%, in 2000. Chloramphenicol accounted for 8.6% and 15.1% of cost of total ophthalmic preparations purchased in 1993 and 2000, respectively. Conclusion: Despite continued concerns of potential risks of ophthalmic chloramphenicol, this preparation is extensively utilized in Bahrain. We are of the opinion that for minor infections, chloramphenicol ophthalmic preparations should be replaced by safer alternatives. Further, we recommend that their use be reserved for ocular infections that are resistant to other antimicrobials, and that ophthalmologists, at the secondary care level, should supervise such treatment.

Abstract

S.S. Joshi, S.V. Sawant, A. Shedge S.S. Joshi, S.V. Sawant, A. Shedge

¹Accutest Research Laboratories, MIDC, TTC, Navi Mumbai, India, and ²Douglas Laboratories, Pittsburgh, PA, USA
Objective: To determine the absorptive properties of 2 novel coenzyme Q10 preparations, a fast-melting tablet and an effervescent tablet, compared with currently available formulations. Materials and methods: In the first trial, the absorptive properties of 4 different coenzyme Q10 preparations (fast-melting, effervescent, soft gelatin, and powder-filled hard shell) were studied in a randomized, single-dose, crossover study. Twenty-four male subjects were given a 60 mg dose of coenzyme Q10 and plasma coenzyme Q10 was measured over the next 12 hours. Pharmacokinetic properties including area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and elimination half-life (t1/2) were measured. In a separate single-dose study, the absorptive characteristics of a different coenzyme Q10 soft gel (Q-Gel) were studied in 6 male subjects. Results: Area under the curve (mg/ml×h) for the fast-melting and effervescent formulations, while marginally greater, was not significantly different when compared to the soft gelatin and powder-filled preparations, 5.4 ± 1.04 (110%) and 5.5 ± 0.589 (112%) versus 5.0 ± 0.859 (102%) and 4.9 ± 0.812 (100%), respectively. Cmax for the 2 novel formulations was also not statistically different from the soft gelatin or powder-filled preparations, 0.87 ± 0.14 and 0.86 ± 0.074 versus 0.70 ± 0.010 and 0.81 ± 0.159 (mg/ml). Tmax however, was significantly shorter for the fast-melting and effervescent formulations compared with the soft gel and powder-filled forms, 1.3 ± 0.348 and 2.0 ± 0.552 versus 3.7 ± 0.702 and 4.1 ± 0.993 (h), respectively. The results of the second trial were similar to those of the powder-filled and soft gel formulations from the first study. Conclusions: The novel fast-melting and effervescent formulations provide a more rapid delivery of CoQ10 to the blood while exhibiting a similar AUC compared with current formulations. The potential clinical significance of this finding should be further evaluated.

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Volume 41, No. 1/2003(January)