Drug monitoring studies as a method of analyzing response criteria.

Two multicenter drug monitoring studies are presented. Some methodological problems are dealt with and the validity of such studies is discussed in terms of differential indication. In a first study (Lehmann et al., 1993) the results of a 12-week xanthinol niacinate treatment (500 to 3000 mg daily) in a cohort of 10,134 outpatients suffering from cerebrovascular insufficiencies were recorded systematically by nonreactive evaluation methods. The therapy was found to be most successful in patients with the target symptoms vertigo, tiredness, lack of concentration, affective disorder, and disturbances of vigilance and vitality. The most frequent side-effects were flush or heat sensations in 9.1% of the patients and gastrointestinal complaints in 3.3%. In a second study (Klieser et al., 1994) we systematically collected data from 219 patients with Major Depressive Disorder during five weeks of treatment with fluoxetine (20 mg daily). The results showed that depressively inhibited, anxious patients with a depression of minor severity, who showed a relatively marked improvement within the first week of treatment, profited the most from this therapy. The first study was designed to use nonreactive evaluation methods. Correlation analyses helped to identify the types of patient with a good response to treatment. The second study was organized on the model of conventional controlled pharmacological studies with the application of commonly used scales. The differential indication was to be inferred from the uni- and multivariate comparison of responders and nonresponders. In the light of these two studies, the problems of target definition, sample design, target variables, practicability, statistical analysis, and validity are discussed.

Drug monitoring study (phase IV) of xantinolnicotinate (Complamin) in general practice.

For 30 years, xantinolnicotinate has been on the market for the treatment of impaired brain function, i.e., organic brain syndromes of various etiologies. Controlled double-blind phase-III clinical trials have shown that xantinol-nicotinate is an effective drug in the treatment of dementia. Nevertheless, it is also important to assess xantinolnicotinate under routine treatment conditions in order to learn what type of patient is preferably treated, which ADRs can be observed how often, and whether the efficacy claimed by phase III studies can still be seen under routine treatment conditions. Theoretically, the more complex treatment situation in routine practice could lead to major changes in the selection of patients, the type and frequency of ADRs, or efficacy. The treatment of 10,134 patients was monitored in a treatment observation study. Results show that target illnesses are not cases of 'pure dementia', but more complex cases, in which multimorbidity plays an important role, so that the older term 'cerebrovascular insufficiency' seems more appropriate to describe this group of patients. Another interesting group is made up of younger patients suffering from a variety of psycho-organic syndromes. The assessment of therapeutic efficacy, e.g., with the SCAG, shows highly significant improvements during treatment, which are well comparable to those reported in controlled studies. The success of treatment was most expressed in the target symptoms "dizziness", "fatigue", "disturbance of concentration", "affective disorders", and "disturbance of vigilance and vitality". In 87% of these cases, no adverse drug reactions were reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of xantinolnicotinate in patients with dementia.

Activation of cerebral metabolism and improvement of microcirculation by influencing rheological parameters are claimed to be the underlying pharmacological principles responsible for the efficacy of xantinolnicotinate. This dual mechanism of action led the authors to perform a double-blind, randomized, placebo-controlled study in patients with mild to moderate dementia (DSM III), characterized by a score of 40-90 on the Sandoz Clinical Geriatric Scale (SCAG), with a separate randomization for patients with Multi-Infarct Dementia (MID) and Senile Dementia of Alzheimer Type (SDAT). It was calculated that 150 patients would have to be recruited for each group. Allocation to the respective group (MID or SDAT) was based on the Hachinski Ischemic Score and computer tomogram. Preceded by a 2-week placebo run-in period, a 12-week treatment period followed with either 3 x 1 g xantinolnicotinate (Complamin) or placebo. Prior to the study, the physician's rating of the global therapeutic effect from the clinical global impression (CGI) was designated as the primary criterion of efficacy. Secondary efficacy criteria were SCAG, the BGP nursing rating, and, as psychometric variables, tests from the Nuremberg Psychogeriatric Inventory (NAI). The improvement compared to placebo was statistically significant for the CGI in both treatment groups (p less than 0.0001) and hence independent of etiology. Concerning the nurses' rating (BGP), apart from a marginally statistically significant difference for the factor "need of help" in the SDAT group, no remarkable changes were registered during treatment. However, in the SCAG the differences between verum and placebo were significant (MID p less than 0.0002; SDAT p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Bioavailability and tolerance of xanthinol nicotinate depot preparations. Comparison of a conventional 500 mg xanthinol nicotinate depot tablet with new 500 mg and 1 g depot tablets]. / Bioverfügbarkeit und Verträglichkeit verschiedener Xantinolnicotinat-Retardformen. Vergleich einer herkömmlichen 500-mg-Xantinolnicotinant-Retardtablette mit neuen 500-mg-und 1-g-Retardtabletten.

Bioavailability (therapeutic blood levels) and tolerance of two 500-mg xanthinol nicotinate retard tablet forms and one 1-g xanthinol nicotinate retard tablet (Complamin special) were tested in 11 (12) healthy volunteers. Despite the fact that both 500-mg retard tablets had different in vitro release rates the blood levels in man were similar. These results suggest that in vitro release rates of tablets do not predict corresponding blood levels in man. The tablet with a lower release rate also showed a distinctly lower flush rate. In respect to bioavailability and tolerance the 1-g xanthinol nicotinate retard tablet was comparable with corresponding dosages of 500-mg retard tablets. The dosage given was 2 X 500 mg or 1 g xanthinol nicotinate t.i.d. over a period of 10 days each.

Xanthinol nicotinate in the management of leg ulcers associated with haemoglobinopathies.

The therapeutic role of xanthinol nicotinate, with its potent action on the peripheral circulation, in promoting healing of leg ulcers when added to conservative measures of ulcer treatment in adult beta-thalassaemia major and sickle cell thalassaemia, was evaluated in a double-blind crossover trial in 16 patients suffering from multiple leg ulcers. Conservative measures of ulcer treatment were leg raising in horizontal position for 14 hours, bed-rest, local antiseptic dressings and antibiotics. Xanthinol nicotinate or placebo was administered in a daily dose of 8 tablets (2400 mg) for 10 weeks. Comparison of the treatment results of conservative measures plus xanthinol nicotinate and those of conservative measures plus placebo revealed a statistically significant higher rate of complete ulcer healing during xanthinol nicotinate therapy (p less than 0.01). Apart from a low incidence of generalized itching and flushing at the start of the trial, xanthinol nicotinate was well tolerated in the prescribed dose.

[Changes in the oxidative glucose brain metabolism under long-term xantinol-nicotinate medication (author's transl)]. / Die Veränderung des oxidativen Glukosestoffwechsels des Gehirns unter langfristiger Xantinol-nicotinat-Medikation.

8 patients suffering from dementia were treated with xantinol-nicotinate for 4 weeks. At the beginning and at the end of the treatment cerebral blood flow and cerebral metabolic rates of oxygen, glucose and lactate were measured with the N2O-method. With regard to the initial level of each parameter CBF, CMR glucose and CMR oxygen increased significantly, if it had been decreased at the first measurement, while primarily normal or even increased parameters did not change. Seming contradictions to other authors are discussed.

[Xantinol-nicotinate in primary type-V hyperlipoproteinaemia (author's transl)]. / Xantinol-nicotinat bei primärer Typ-V-Hyperlipoproteinämie. Wirkung auf Lipide und Serumlipoproteine

The effect of xantinol-nicotinate (50 mg/kg body-weight) on serum lipids and lipoproteins was tested in 16 out-patients with primary type V hyperlipoproteinaemia. The lipids and lipoproteins were measured before treatment, during a three-week period of drug administration and ten days after it had been stopped. There were no side effects such as flushing or gastritis, and no notable reduction of weight. Each serum-lipid fraction (triglycerides, nonesterified fatty acids, phospholipids, ester-cholesterol and free cholesterol) decreased significantly, regaining the initial values ten days after the drug had been stopped. While chylomicrons and very low-density lipoproteins (VLDL) decreased, there was a significant increase in low-density lipoproteins (LDL). High-density lipoproteins were not significantly changed. The decrease in chylomicrons and the significant decrease in VLDL with xantinol-nicotinate was opposite to that seen with dietary treatment. In none of the patients did LDL increase to abnormally high levels.

Xanthinol nicotinate in peripheral vascular disease.

In a double-blind control of xanthinol nicotinate ('Complamin'; 'Complamex') in patients with severe progressive obliterative vascular disease, 25 of 33 patients who completed the trial were helped significantly by the drug, as shown by both clinical and laboratory findings. Placebo helped in 4 of 33 patients. The difference is significant (p less than 0-001). These are the results for the trial period only. The results of follow-up for 6 to 30 months are available in 18 patients: 14 of these still had appreciable help from the drug, which was continued in maintenance doses. It should be noted that 3 of 6 diabetics were no longer helped after 6 months, and that only 3 of a total of 7 patients under the age of 50 were helped; however 3 of the 4 not helped were diabetics under the age of 50. Special caution was indicated in the use of the drug in patients who have ischaemic heart disease in addition to their peripheral arterial disease. Side-effects were common, particularly a severe prolonged flush shortly after taking a dose of the drug; many patients helped by it accepted this side-effect if it occurred. Xanthinol nicotinate reduced whole-blood viscosity and cholesterol and fibrinogen in about half of the patients helped. This is a useful drug for about half the patients in whom surgery is not indicated or is contraindicated.