Patient compliance with drug therapy in schizophrenia. Economic and clinical issues

The effectiveness of drug treatment in clinical practice is considerably lower than the efficacy shown in controlled studies. The lower effectiveness in practice presumably leads to lower cost effectiveness of drug treatment in real-life situations compared with that demonstrated by studies based on results from controlled trials. Improved cost effectiveness in routine clinical practice would be a significant advantage in the treatment of schizophrenia, one of the most costly diseases in society. The aetiology of schizophrenia is unknown, and there is no cure. The main aims of therapy with antipsychotic medication include the effective relief of symptoms without the introduction of adverse effects or serious adverse events, improved quality of life, cost effectiveness and a positive long term outcome. The older classical antipsychotic drugs do not always meet these requirements because of their well-known limitations, such as a lack of response in a subgroup of individuals with schizophrenia and intolerable adverse effects. There has long been a need for new antipsychotics that can ameliorate more symptoms and have no or few adverse effects. Some of the recently introduced antipsychotics have been shown to be more effective in certain clinical situations and to have a more favourable adverse effect profile than the classical antipsychotics. A major factor contributing to the lower effectiveness of drug treatment is noncompliance, which may be very high in schizophrenia. There are several factors influencing compliance, including drug type and formulation, patient, disease status, physician, health care system, community care and family. There have been very few studies of compliance improvement strategies in schizophrenia or, indeed, in medicine in general. Current methods are relatively complex and there are differing opinions on their effectiveness. There are several ways to increase compliance in schizophrenia--the evidence is strongest for psychoeducative methods, changing to a new drug or using a depot formulation. However, considerably more research is needed in the field of compliance strategies.     

Assessment of combined oral theophylline and inhaled beta-adrenoceptor agonist bronchodilator therapy.

1. The bronchodilator effects of 500 microgram rimiterol by pressurized aerosol, 375 mg oral theophylline and both drugs in combination were compared in a randomized, placebo-controlled, double-blind trial in eight patients with chronic, partially reversible airways obstruction. 2. The four treatments were (i) oral theophylline, placebo aerosol (TP); (ii) oral placebo, rimiterol aerosol (PR); (iii) oral theophylline, rimiterol aerosol (TR) and; (iv) oral placebo, placebo aerosol (PP). The aerosol was administered 2 h after the oral treatment. 3. Significant bronchodilatation (% FEV1 change from control) compared to PP occurred with TP from 60 to 480 min and with TR from 60 to 300 min, whereas with PR only for 45 min (P less than 0.05). 4. The mean, peak % FEV1 increases from control were 51.8% at 125 min, 31.7% at 125 min, 26.1% at 210 min and 0.9% at 30 min for TR, PR, TP and PP respectively. 5. At 125 min (5 min after aerosol inhalation) the mean % FEV1 change from control with TR (51.8%) Was significantly greater than with PR (31.7%), TP (22.2%) (P less than 0.05) and PP (-2.4%) (P less than 0.01). 6. The mean, peak plasma theophylline levels were 10.19 microgram/ml at 120 min and 9.98 microgram/ml at 180 min with TR and TP respectively. Theophylline half-life ranged between 4.3 and 12.5 h (mean +/- s.e. mean, 8.0 +/- 0.8 h). 7. Additive bronchodilatation was produced when rimiterol was administered with theophylline at a time when therapeutic plasma theophylline levels were achieved.     

Pharmacist-based i.v. theophylline therapy.

With the support and guidance of the medical staff, a protocol for IV theophylline dosing and monitoring has been implemented. The patients' theophylline needs are individually determined by pharmacists using clinical criteria and historical data determined for each patient. Ongoing monitoring and dosage adjustments are provided. The protocol is described where a therapeutic range of 10-20 mcg/mL was maintained 84% of the time as verified by quality assurance audits.     

Over compliance with capecitabine oral chemotherapy

Case

A case study of a patient who over complied with adjuvant capecitabine monotherapy on several occasions is described. The patient suffered worsening side effects, predominantly palmar plantar erythrodysesthesia which resulted in dose reduction and delay. The patient had disregarded advice to stop taking the capecitabine as he perceived it as “important to fight his cancer”. The patient refused review with a psychologist.

Conclusion

There is a lack of evidence regarding the issue of over compliance. Pharmacists should consider discussing patient’s attitudes towards taking their medication and its importance to them in treating their cancer. Tools that are used to assess non-compliance could be utilised to identify patients who over comply. Further research is required to gain further understanding of the psychological factors behind patient’s decisions to over comply with treatment.     

Patient compliance with beta-blocker medication in general practice

We measured compliance with beta-blocking drugs in a group of 105 patients with uncomplicated hypertension, and without coronary heart disease or other major concomitant disease. We measured compliance with an electronic monitor (MEMS®) that records time and date of each opening of the container in which the patient's regularly prescribed beta blocker was dispensed. This measurement was compared with their physicians' estimates of their compliance with the prescribed beta blocker regimen. Patients were followed during a period of 2–6 months, for a total of 15,274 days of observation. In 820 (5.4 per cent) of observation days dosing was incorrect; in 619 days, one or more tablets were omitted, and in 201 days one or more extra doses were taken. In 64 of the 105 patients, we observed drug holidays: days without evidence of beta blocker dosing. Concordance was low between the physicians' estimates and MEMS-measured compliance, with a tendency toward physician overestimation of compliance. The study enrolled only patients long treated for uncomplicated disease, with no other serious concomitant illness; this special selection probably accounts for the relatively good compliance found.     

Pharmacodynamic interactions between infused adenosine and oral theophylline.

1. Five healthy human subjects were given, in single-blind fashion, either (a) 625 mg theophylline orally, followed 4 h later, by a 40 min infusion of adenosine (40 micrograms kg-1 min-1 for 5 min, 60 micrograms kg-1 min-1 for 5 min and 80 micrograms kg-1 min-1 for 30 min), or (b) 625 mg theophylline orally followed by 0.9% sodium chloride infusion, or (c) placebo theophylline tablets followed by adenosine infusion. 2. All five subjects experienced adverse effects during adenosine infusion, mainly at the higher infusion rates; two subjects also experienced chest pain but not during combined treatment with theophylline and adenosine. 3. Diastolic blood pressure (DBP) rose by 16.5 mmHg (P less than 0.001) following treatment with theophylline only, fell by 24.5 mmHg (P less than 0.001) during the adenosine infusion after placebo theophylline and remained unchanged during the adenosine infusion following theophylline. Pulse rate rose by 12 min-1 (P less than 0.01) during adenosine infusion following placebo, but not after theophylline alone or theophylline and adenosine combined. 4. The respiratory rate fell by 6 min-1 (P less than 0.01) during treatment with adenosine only, being lower than for the two treatments containing theophylline (P less than 0.05). 5. Plasma potassium and magnesium fell by 0.25 mmol l-1 (P less than 0.001) and 0.037 mmol l-1 (P less than 0.05), respectively, during treatment with theophylline only, but these effects were not altered by infusion of adenosine. 6. This study has demonstrated interactions between theophylline and adenosine on diastolic blood pressure and respiratory rate, but no interaction on metabolic parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Formulation approaches in enhancement of patient compliance to oral drug therapy

Introduction: Disease management of outdoor patients is mainly affected by patient compliance to the drug therapy, which in turn is governed by patient convenience. Failure to follow through with a treatment decision is one of the biggest causes of unsuccessful medical care. At present, different formulation options are available for various drugs, and hence, the decision is based on the most convenient dosage form for the patient, along with optimum therapeutic benefits.

Areas covered: This paper reviews various available formulation approaches, in the hope of improving patient convenience, compliance and the overall outcome of oral drug therapy.

Expert opinion: While parenterals are valued for their speed and efficiency of delivery, these systems generally score low on patient satisfaction surveys. The oral route is the preferred route for drug delivery, although it renders multiple obstacles to formulate a patient-convenient platform, such as unfavorable taste and swallowing difficulties. Transdermal drug delivery also provides high patient satisfaction, but is effective only for the delivery of smaller, lipophilic molecules. The increasing development of biopharmaceutical therapies renders an increasing number of challenges for formulation scientists to develop a more patient-convenient means of drug delivery.     

Formulation approaches in enhancement of patient compliance to oral drug therapy

INTRODUCTION: Disease management of outdoor patients is mainly affected by patient compliance to the drug therapy, which in turn is governed by patient convenience. Failure to follow through with a treatment decision is one of the biggest causes of unsuccessful medical care. At present, different formulation options are available for various drugs, and hence, the decision is based on the most convenient dosage form for the patient, along with optimum therapeutic benefits. AREAS COVERED: This paper reviews various available formulation approaches, in the hope of improving patient convenience, compliance and the overall outcome of oral drug therapy. EXPERT OPINION: While parenterals are valued for their speed and efficiency of delivery, these systems generally score low on patient satisfaction surveys. The oral route is the preferred route for drug delivery, although it renders multiple obstacles to formulate a patient-convenient platform, such as unfavorable taste and swallowing difficulties. Transdermal drug delivery also provides high patient satisfaction, but is effective only for the delivery of smaller, lipophilic molecules. The increasing development of biopharmaceutical therapies renders an increasing number of challenges for formulation scientists to develop a more patient-convenient means of drug delivery.     

Prediction of optimum oral theophylline dose in patients with obstructive airways disease.

The hypothesis that a logarithmic correlation exists between the plasma theophylline concentrations 6 h after a test dose C(6) and the maintenance dose calculated to achieve a desired drug concentration during chronic oral administration (DM,CALC) was tested. A nomogram based on this relationship was evaluated as a means of predicting the optimum dose of theophylline in 14 patients with obstructive airways disease (DM,PRED). Each patient was given 5 mg/kg theophylline intravenously (i.v.) and plasma theophylline concentrations were measured for 12 h thereafter including one exactly 6 h after commencing the i.v. infusion C(6). Pharmacokinetic parameters derived from the plasma concentration-time curve were used to establish DM,CALC for a concentration of 10 micrograms/ml. DM,PRED was obtained from the nomogram using both the optimum and the actual values for C(6). Subsequently oral sustained-release theophylline was administered and the dose adjusted to establish a trough concentration of approximately 10 micrograms/ml. This dose was then corrected arithmetically, assuming a linear relationship between dose and plasma level, to represent that required to achieve a plasma concentration of exactly 10 micrograms/ml (DM,ACT). The correlation between C(6) and log DM,CALC was confirmed (r = 0.97 P less than 0.001), validating the hypothesis. DM,ACT was found to correlate significantly with DM,PRED (r = 0.90, P less than 0.01) substantiating the value of the nomogram. In nine of the 14 patients, DM,ACT corresponded satisfactorily to DM,PRED. In the remaining five, for whom DM,ACT lay outside the 95% confidence limits for the predicted dose, DM,PRED in general underestimated DM,ACT, an advantage in a drug with a low therapeutic index. The predictive error for DM,PRED was lower than that for DM,CALC, and the bias using either method was not significant. The results suggest that a single plasma theophylline assay following a test dose, and the nomogram may be useful in simplifying optimal theophylline administration.     

Interference with oral theophylline absorption by continuous nasogastric feedings

Continuous enteral feedings through a nasogastric tube is the preferred route of nutritional support for malnourished patients with inadequate spontaneous oral intake. However, in patients also receiving oral medications, the use of continuous nasogastric feedings may cause malabsorption of the drugs and consequently increase the risk of an inadequate clinical response. We report a case of an elderly patient with subtherapeutic theophylline serum concentrations and recurrent bronchospasm while receiving oral theophylline and continuous enteral feedings.     

Phenotype-genotype analysis of CYP1A2 in Japanese patients receiving oral theophylline therapy

Objective To clarify the association between the cytochrome P450 (CYP) 1A2 genotype with the CYP1A2 phenotype and to search for the CYP1A2*1K haplotype, which has been shown to decrease CYP1A2 inducibility and/or other functional polymorphisms in Japanese. Methods Two polymorphisms, CYP1A2*1C and CYP1A2*1F, were genotyped in 126 patients receiving oral slow-release theophylline (TP) therapy and in 224 healthy volunteers. The CYP1A2 phenotype was assessed by the plasma [1-methyluric acid (1U) + 3-methylxanthine (3X)]/TP ratio in the patients. The volunteers were given 150 mg caffeine, and the urine [1X+1U+5-acetylamino-6-amino-3-methyluracil (AAMU)]/17U ratio was used for CYP1A2 phenotyping. CYP1A2 intron 1 and six exons (exon 2-exon 7) were sequenced in the patients whose (1U+3X)/TP ratios were below the mean−2SD of those of all patients, and intron 1 was also sequenced in an additional 20 healthy volunteers exhibiting putative low CYP1A2 activities. Results The individual (1U+3X)/TP ratios ranged from 0.007 to 0.21 (a 30-fold difference) in the patients, and the (1X+1U+AAMU)/17U ratios ranged from 1.6 to 112 (a 70-fold difference) in the healthy volunteers. The CYP1A2 activities were not significantly influenced by CYP1A2*1C or CYP1A2*1F. We found no functional polymorphisms by a sequencing analysis. Conclusion These results suggest that the CYP1A2*1C and CYP1A2*1F genotypes are not crucial factors for the variability of CYP1A2 activity and that the CYP1A2*1K haplotype is either nil or only shows a very low frequency in Japanese.