Number Of Daily Doses Research Articles

Prescription Practice for LH-RH Analogs and Androgen Receptor Antagonists in the Treatment of Advanced Prostate Cancer in Germany (1993–2003)

Introduction: Nearly 80% of the patients suffering from advanced stages of prostate cancer in Germany are treated currently with luteinizing hormone-releasing hormone (LH-RH) analogs alone or in combination with androgen receptor antagonists. The aim of this study was to assess whether the prescription practice for LH-RH analogs and direct antiandrogens between 1993 and 2003 parallels the rise in the incidence rates for prostate cancer associated with the proportional rise in daily doses. Methods: Between 1993 and 2000 a yearly randomly selected number of receipts has been evaluated from official pharmacies in Germany which have been billed to public health insurance companies. Data concerning drug use, number of daily doses, and total cost of the respective drugs have been calculated by the Research Institute of the AOK (Wissenschaftliches Institut der AOK, WIdO). These prescription data have been related to incidence and mortality rates of patients with prostate cancer. Results: Between 1993 and 2003 the age-standardized incidence rate of carcinomas of the prostate has risen by 180%, while the disease-specific mortality practically has remained nearly at the same level. The daily prescribed doses of LH-RH analogs have risen by a factor of 8.5 from 3.9 to 33.5 million daily doses during this time. In contrast, the daily doses of androgen receptor antagonists have remained unchanged between 1997 and 2001, followed by a rise of 50% between 2001 and 2003. Conclusions: The first analysis of the prescription practice of antiandrogens in the treatment of prostate cancer with respect to the incidence rates in Germany could only be facilitated by the fact that these medications are in exclusive use for this indication in Germany. The rise in prescriptions may be explained by the therapy shift from surgery to LH-RH application until the year 2000; the reasons for a further rise since 2000 remain speculative. In conclusion, only prevalence data would allow the exact calculation of medication needs among prostate cancer patients.

Year impact of highly active antiretroviral therapy on quality of life of HIV-infected Nigerians

Objective : The availability of highly active antiretroviral therapy (HAART) has resulted in a number of achievements as well as challenges. The aim of this study was to assess the influence of 48 weeks HAART of stavudine, lamivudine and nevirapine on the quality of life of HIVinfected Nigerians. Materials and Method : Quality of life indices of hemoglobin, platelet count, CD4 lymphocyte count, body weight, body mass index as well as questionnaire based outcome of adverse clinical events, general health perception and emotional effect of pill burden were assessed at baseline and compared with the 48 weeks therapy. Result : There was a HAART-dependent improvement in the hemoglobin (2.48g/dl), platelet count (55.87 x 10 9 /L), CD4 lymphocyte count (122 cells/μl) body weight (13.26kg) and body mass index (1.32) (p Conclusion : The study emphasizes the importance of HAART related quality of life survey particularly in resource poor settings in sub-Saharan Africa when there is desperate need for antiretrovirals. Efforts must be made towards simplifying the therapeutic regimen to reduce the number of daily doses and substitution with treatment combinations and strategies that minimize negative adverse effect to ensure that mortality and morbidity are minimize and quality life optimized. Highland Medical Research Journal Vol. 3(2) 2005: 62-75

Enquête sur la mise en place d’une consultation pharmaceutique pour les patients sous antirétroviraux

Highly active anti-retroviral therapies (HAART) in HIV treatment can result in complex treatment regimens. We surveyed HIV patients followed in the infectious disease department of Saint-Germain-en-Laye Hospital to assess the interest of offering patients a consultation with a pharmacist. The 3-part questionnaire enabled us to assess the medical and pharmaceutical information given to the patient, adherence, and risk factors for poor observance. The questionnaire was distributed to all patients, regardless of whether they were receiving treatment. A simple adherence score was computed as well as a score for the risk of poor adherence. Ninety patients returned analyzable questionnaires: 65 (72.2%) thought a pharmaceutical consultation would be useful. They felt it should cover in priority the following subjects: drug interactions (51%), secondary effects (49%), and what to do after forgetting a dose (44%). Treatment was perceived as positive by 82 patients (91%) and tolerated well by 57 (65%). Sixty patients (66.3%) reported that they occasionally forgot a dose, 37 (41.3%) that they regularly did. The results showed good adherence by 61.3% and poor adherence by 38.5%. Risk of non-adherence was significantly associated with three factors: the number of pills to take, the number of daily doses, and the length of the treatment. Our survey shows the interest of consultations with pharmacists as a clinical service. By reinforcing the patient's understanding, these can complete and supplement the physician's explanation and instructions on pharmaceutical topics, especially those that could not be addressed during the clinical visit. The main aim of this process is to improve adherence, which is a key element in treatment efficacy.

Interventions for improving adherence to treatment in patients with high blood pressure in ambulatory settings.

Lack of adherence to blood pressure lowering medication is a major reason for poor control of hypertension worldwide. Interventions to improve adherence to antihypertensive medication have been evaluated in randomised trials but it is unclear which interventions are effective. To determine the effectiveness of interventions aiming to increase adherence to blood pressure lowering medication in adults with high blood pressure All-language search of all articles (any year) in the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, and CINAHL in April 2002. RCTs of interventions to increase adherence to blood pressure lowering medication in adults with essential hypertension in primary care, with adherence to medication and blood pressure control as outcomes Two authors extracted data independently and in duplicate and assessed each study according to the criteria outlined by the Cochrane Collaboration Handbook. We included 38 studies testing 58 different interventions and containing data on 15519 patients. The studies were conducted in nine countries between 1975 and 2000. The duration of follow-up ranged from two to 60 months. Due to heterogeneity between studies in terms of interventions and the methods used to measure adherence, we did not pool the results. Simplifying dosing regimens increased adherence in seven out of nine studies, with a relative increase in adherence of 8 per cent to 19.6 per cent. Motivational strategies were successful in 10 out of 24 studies with generally small increases in adherence up to a maximum of 23 per cent. Complex interventions involving more than one technique increased adherence in eight out of 18 studies, ranging from 5 per cent to a maximum of 41 per cent. Patient education alone seemed largely unsuccessful. Reducing the number of daily doses appears to be effective in increasing adherence to blood pressure lowering medication and should be tried as a first line strategy, although there is less evidence of an effect on blood pressure reduction. Some motivational strategies and complex interventions appear promising, but we need more evidence on their effect through carefully designed RCTs.

Estudio multicéntrico sobre adhesión al tratamiento antibiótico en población infantil en atención primaria

To evaluate the degree of children's adherence to prescription of antibiotics and to determine factors linked to this adherence. Cross-sectional study, conducted through a telephone survey of parents of the children under study ten to fifteen days after the prescription of the antibiotic. Thirty primary care centres in 6 Spanish provinces. Parents or guardians of children from 0 to 10 who attended the primary care centres between October 1998 and January 1999 for treatment of an acute infection and who were prescribed an oral antibiotic treatment with two or more daily doses. Interventions. The measuring instrument was the Morisky-Green test. 2244 cases were studied. 1043 of them complied adequately (46.5%; 95% CI, 44.4-48.5). The factors associated with adherence were children's school situation, the age of parents or carers and the number of daily doses. Only half the children complied correctly with the treatment indicated. Pre-school children, those with parents or carers over 40 and those with a prescription of under three daily doses followed the treatment better. These factors need to be borne in mind by paediatricians when they prescribe an antibiotic.

Optimisation of Vancomycin Regimen in Neutropenic Haematological Patients with Normal Renal Function

Objective: To assess the appropriateness, on a pharmacokinetic basis, of a twice-daily regimen of vancomycin 1g in neutropenic patients with normal renal function, a regimen frequently used in the empirical treatment of this patient group. The study also used a Bayesian pharmacokinetic approach to predict vancomycin concentrations in order to determine the optimal dosage frequency of the drug (two or four daily doses) in this population. Patients and Methods: Data were collected retrospectively as part of routine therapeutic drug monitoring (TDM) of vancomycin in 16 adult neutropenic patients. TDM of vancomycin peak (Cmax) and trough (Cmin) serum concentrations was performed after twice daily administration of vancomycin lg as a 1-hour intravenous infusion for 48 hours. According to TDM results (Cmin≥7 or <7 mg/L), the vancomycin regimen was individualised (total daily dose split into two or four divided doses) by means of a Bayesian-based pharmacokinetic computer programme. TDM was then repeated on day 7. Optimal Cmin were defined as with the range of 7 to 10 mg/L. Results: On day 3 of therapy, nine patients had subtherapeutic Cmin (3.97 ± 0.59 mg/L; range 2.98 to 4.95 mg/L) according to ahigh estimated creatinine clearance (CLcr 1.79 ± 0.49 ml/kg/min; range 1.39 to 2.79 ml/kg/min), and another three patients had Cmin <7 mg/L. On day 7, higher vancomycin Cmin were achieved (8.92 ± 2.87 mg/L) in the 12 patients in whom their total daily dose was split into four (Cmin were optimal in nine and supratherapeutic in three patients), despite no major differences in the total daily dosage of vancomycin (29.77 ± 5.89 vs 30.85 ± 6.68 mg/kg; p = 0.79) and CLcr (1.63 ± 0.43 vs 1.90 ± 0.45 ml/kg/min; p = 0.19) versus day 3. Dose-normalised results suggested large interindividual pharmacokinetic variability. Conclusion: Since the volume of distribution and/or clearance of vancomycin can be increased in patients with haematological malignancies and normal renal function, increasing the number of daily doses from two to four (with the same total daily dose) may increase t > MIC, an important determinant of vancomycin efficacy. However, because of interpatient variability, TDM of vancomycin is strongly recommended to individualise therapy in this subpopulation.

Anticonvulsant drug therapy in children and adults. Practical guide for single and multiple dosage

The available scientific literature rarely addresses the important practical issue of how to establish and withdraw antiepileptic treatment. Initiation of antiepileptic therapy is mainly based on personal experience. With regard to the few data focussing on this topic and on the background of the authors' personal experience and discussions with other experienced epileptologists the authors attempt to propose a rational concept. Age-related pharmacokinetic properties of anti-epileptic drugs are discussed. Recommendations for initial starting dose, titration procedures, target dosages and number of daily doses for both standard and new antiepileptic drugs are given. Dosages for children are given on a mg/kg body weight basis. Indications and limitations for determination of drug levels are provided. Withdrawal of antiepileptic therapy has been subject of recent prospective studies in children and adults providing important prognostic factors. Etiology of the epilepsy, syndromic classification, results of neurological investigation, EEG and the personal situation of the patients have to be considered. Current knowledge is reviewed with emphasis on practical aspects of when and how to withdraw antiepileptic drugs. This review emphasizes the urgent need of further prospective studies.

Management of Community-Acquired Pneumonia

In patients with community-acquired pneumonia (CAP), it is uncommon for the causative pathogen to be identified when initial antimicrobial therapy is prescribed. Thus, an empirical approach is generally taken, based on antimicrobial therapy which covers the major pathogens of CAP. Although Streptococcus pneumoniae remains the most common pathogen in microbiologically documented CAP, atypical pathogens now account collectively for approximately 10 to 40% of episodes. Accordingly, North American guidelines recommend macrolides as one of the preferred choices in patients with mild to severe CAP, as monotherapy in those who can be treated as outpatients and as part of combination therapy for more severely ill patients. It should be noted that macrolides are not recommended when drug-resistant pneumococcal infection or aspiration is suspected. Expanded-spectrum fluoroquinolones are likely to assume an increased role in areas with high rates of drug-resistant pneumococci. Where the pathogen is known, macrolides are a reasonable choice in CAP caused by atypical pathogens and an alternative therapy for penicillin-susceptible S. pneumoniae or M. catarrhalis infection. Clarithromycin has good in vitro activity against most respiratory pathogens, including the atypical pathogens Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella spp. Clarithromycin has similar efficacy to erythromycin in adults and children with mild to moderate CAP but is better tolerated. Also, it is given in a once (delayed-release formulation) or twice daily dosage schedule, which may encourage patient compliance. As with erythromycin, clarithromycin interacts with a wide range of drugs metabolised by the CYP450 system, which limits its usefulness in patients receiving other therapies. Other newer macrolides also offer advantages over erythromycin, so all factors should be considered when selecting such an agent for treatment. Although clarithromycin, like other newer macrolides, is generally more costly than erythromycin in terms of acquisition costs, it may well be more cost effective when other factors (e.g. better tolerability, fewer daily doses) are taken into account. Conclusions: Oral clarithromycin has several features which make it an attractive treatment option for patients with mild to moderate CAP. It offers some clear advantages over erythromycin in terms of potential pharmacoeconomic benefits, reduced number of daily doses and its tolerability profile. As with other macrolides, it has a particular role in empirical use in areas without high rates of pneumococcal resistance and as targeted therapy in those with documented or suspected atypical pneumonia.

A computer model for the measurement of compliance using a dual tracer technique.

We aimed to determine whether simultaneous use of two tracer compounds with long and differing elimination half-lives may permit more precise recognition of percent compliance and discrimination among remote, intermediate, and recent patterns of daily dosing. We have derived, through computer modelling, the potential utility of digitoxin and phenobarbitone as simultaneous tracers. From kinetic data on these reliably measured compounds with long half-lives we defined the percentage error below which this pair of tracers can be expected to discern the precise, and the approximate, pattern and number of daily doses taken over a mouth. The longer the half-lives of the tracers the greater the sensitivity of our model to percentage compliance. At extremely long half-lives, relative to the period of dosing being monitored, sensitivity approaches 100% if measurement error is in the 1-2% range. The ratio of the half-lives between the two tracers that is optimal for detection of percentage compliance is 0.2 to 0.8. The detection of pattern does not depend importantly either on the tracer half-lives or on their ratio to each other. The greater the percentage compliance, the more accurately our two-tracer model determines the pattern of dosing. Precise characterization of compliance using tracers must probably await the development of compounds with half-lives measured in weeks or months. The probability of compliance of a given degree can be derived from our two-tracer technique with best-fit analysis such as we describe.

Rational prescribing of antibacterials in ambulatory children.

The rational prescribing of oral antimicrobial agents for bacterial infections in children who can be treated in an ambulatory setting is the subject of this review. First, restrictive use of antibacterials is advocated to avoid widespread development of bacterial resistance. The use of simple methods, suitable for office use, to discern viral from bacterial infections is recommended. Second, in selecting an antimicrobial agent, the physician should consider a number of distinctive features of each agent. Besides aspects of pharmacokinetics, antibacterial spectrum and tolerability, the number of daily doses and, of particular importance for children, the palatability of suspensions plays an important role in achieving patient compliance. Agents that can be administered once or twice daily and possess an agreeable taste in addition to proven efficacy, established tolerability and a reasonable price are to be preferred. Specific paediatric aspects in choosing among penicillins, cephalosporins, macrolides and other oral antibacterials are discussed. For pharmacoeconomic reasons, the optimal duration of antibacterial treatment and the role of short course therapy for various bacterial infections should be studied in more detail. Finally, rational antimicrobial treatment of common paediatric bacterial infections, such as streptococcal tonsillopharyngitis, acute otitis media, acute sinusitis, bacterial pneumonia, pertussis, Lyme borreliosis (early stage) and lower urinary tract infection is reviewed.

Use of prescription-refill records to assess patient compliance

Prescription-refill records were used to assess patient compliance, to evaluate factors previously associated with compliance, and to determine the association between selected drugs and compliance. Records were selected from a computerized database containing prescription-coverage claims, based on the following criteria: (1) the prescriptions were refilled during 1987-1989 and within two times the days' supply after the dispensing date, (2) they involved any of 12 drugs selected for study, (3) they required one to four doses per day, and (4) at least 20 records with the same regimen were available. Compliance was defined as refill within 0.2 times the days' supply after the refill-due date, and it was assessed by calculating the compliance rate and the compliance index (which describes the relationship between the refill-due date and the actual refill date). Data from 19,118 prescription-refill records were analyzed. The compliance index improved slightly as the number of concurrent medications increased, worsened as the number of doses per day increased, and improved as the immediacy of the risk of noncompliance increased. Different medications and indications were associated with different degrees of compliance. Medication compliance generally improves as the number of daily doses decreases, may improve slightly as the number of concurrent medications increases, and varies with the particular drug and indication.

Pharmacokinetics of nifedipine derived from a new retard tablet formulation

A nifedipine retard tablet formation (Glopir, 20mg) was developed to reduce the number of daily doses required in the treatment of hypertension. The plasma pharmacokinetics of this oral formulation were examined, in a single study, on 12 healthy volunteers. Single 20 mg doses of nifedipine retard tablet (Glopir, GAP & Co. Athens, Greece) were given after an overnight fast and 10 blood samples were drawn during the first 24 h after administration. Plasma concentrations of nifedipine were measured by high performance liquid chromatography. The mean peak plasma nifedipine concentration was 27.6 ng/ml at a maximum time of 24 h, after tablet ingestion. The mean apparent nifedipine elimination half-life was 16.0 +/- 7.5 h and the mean area under the plasma concentration time curve (0-24 h) 404.1 +/- 134.0 ng/ml.h. The data suggest that the tablet form has properties of a sustained-release preparation, with slow accumulation and elimination phases and can appropriately be given in a twice-daily regimen.

Controlled-Release Levodopa/Carbidopa III

Five patients with advanced Parkinson's disease and fluctuations in therapeutic response to levodopa participated in, and four completed, an open label study of the efficacy of Sinemet CR5. Reductions in the number of daily doses and "off" periods as well as the increase in interdose interval and percent "on" time versus standard Sinemet were comparable to those achieved with Sinemet CR4 in these same patients. As compared with Sinemet CR4, there was a greater delay in the occurrence of peak plasma levodopa concentrations, and relative bioavailability was reduced. Sinemet CR5 appears to offer no advantages over Sinemet CR4 in the treatment of response fluctuations in Parkinson's disease.

Controlled-release levodopa/carbidopa. II. Sinemet CR4 treatment of response fluctuations in Parkinson's disease.

Sixteen patients with Parkinson's disease and therapeutic response fluctuations entered an open-label trial of a controlled-release carbidopa/levodopa preparation, Sinemet CR4. Sinemet CR4 behaved as a slow release preparation. At the end of 6 weeks CR4 treatment, there was an increase in percent "on" time and mean interdose interval; the number of daily doses and "off" periods were diminished and a slight reduction in the variability of plasma levodopa levels was observed. Overall benefit waned over the next 6 months, despite addition of standard levodopa or Sinemet to overcome the delayed onset of antiparkinsonian effect of CR4 which resulted from prolongation in the Tmax for levodopa. The major benefits of CR4 were reduction in off time and in the number of daily off periods, with fewer levodopa doses per day and prolongation of the interdose interval.

Controlled-release levodopa/carbidopa. I. Sinemet CR3 treatment of response fluctuations in Parkinson's disease.

Eight Parkinson patients with response fluctuations completed an open-label trial of a controlled-release carbidopa/levodopa preparation (Sinemet CR3). At the end of 6 weeks, percent "on" time and mean interdose interval increased, the number of daily doses and "off" periods was decreased, and the variability of plasma levodopa levels and disability scores was reduced. However, response fluctuations continued to occur, day-to-day consistency was poor, and the bioavailability of levodopa appeared less than that of standard Sinemet. Overall benefit waned over the next 3 to 6 months. Oral controlled-release carbidopa/levodopa is capable of reducing fluctuations in plasma levodopa levels and clinical performance in Parkinson's disease. The response to this particular controlled-release formulation was suboptimal and unsustained.

Prescribed daily dose of phenoxymethylpenicillin in general practice.

Prescribed daily dose (PDD) of phenoxymethylpenicillin was estimated in a multipractice study in 1979 and in 1983. PDD increased from 2.08 mio IU in 1979 to 2.32 mio IU in 1983. PDD was independent of number of daily doses, and factors related to practice. Only slight variations with diagnosis and doctor's age was found.

Attitudes of patients with hypertension or arthritis toward the frequency of medication administration

The attitudes of patients with a nonpainful chronic illness (hypertension) and the attitudes of patients with a painful chronic illness (arthritis) toward the frequency of medication administration were compared. Hospitalized patients with rheumatoid arthritis (n = 83) and hypertension (n = 117) were interviewed by study monitors. Multiple-daily dosing was preferred by 70% of the arthritis patients and 61% of the hypertension patients for pain medications. The majority of patients in both groups preferred single-daily dosing for nonpainful conditions. The majority of patients in both groups believed that there was no difference between the dosing regimens in terms of the number of side effects. Thirty-five percent of the patients with arthritis and 19% of the patients with hypertension stated that they would consider increasing or decreasing the number of daily doses of their medication. A single daily dose might not be the optimal dosing regimen for all medications for all patients. Clinicians should consider the nature of the patient's illness and its potential influence on compliance when selecting a dosing regimen.

Effect-independent measures of tissue responses to fractionated irradiation.

Tissue repair factors measure the sparing that can be achieved from dose fractionation in the absence of proliferation. Four repair factors are analysed in these terms: FR, Frec, the ratio of linear-quadratic survival model parameters beta/alpha, and the half-time T1/2 for intracellular repair processes. A desirable feature of any repair factor is that it be independent of the level of injury induced in the tissue (or its single-dose equivalent, D1), since the comparison of tissues on the basis of the factor would not be meaningful, if they were characterized by differing D1S. Theoretically, FR and Frec are increasing functions of D1, and thus depend on level of effect. This is confirmed by analysis of skin reactions after multifractionated radiation. By contrast, beta/alpha is effect-independent as a measure of repair capacity in skin, gut, and bone marrow, tissues for which it is reasonable to assume that survival of identifiable target cells is the primary determinant of the endpoint. For a functional endpoint not clearly connected with the depletion of a specific target-cell population (late fibrotic reactions in the kidney), there was an increase in beta/alpha with increased levels of injury, but this was statistically insignificant. Effect-independence is defined for T1/2 as independence from size of dose per fraction. T1/2 is independent of fraction size in skin, gut, and spinal cord, and is longer (1.5 hours) in the late-reacting tissues (lung and spinal cord) than in those that react acutely (T1/2 less than 1 hour), with skin as the exception (T1/2 approximately 1.3 hours). Therefore, early and late-responding normal tissues may be distinguished in terms of both repair capacity and repair kinetics: repair is slower in late-responding tissues, which are also more sensitive to changes in dose fractionation. If generally true, these results imply that the potential for a therapeutic gain from hyperfractionation to spare late effects differentially would be limited by the number of daily doses that could be given, allowing sufficient time for repair between fractions in late-reacting tissues. In practice, dose fractions should be separated by 6 hours or more to permit repair to approach completion in late-responding tissues. Similar considerations lead to the conclusion that late effects would be more sensitive to changes in dose rate in low dose-rate brachytherapy.

The influence of dose frequency and agent toxicity on the cost of parenteral antibiotic therapy.

The influence of the number of daily doses on the overall cost of antibiotic therapy is examined in a general surgery patient population. Patients receiving a single first-generation cephalosporin are compared with patients receiving two or three antibiotics (including an aminoglycoside) in terms of (1) the cost of the drug and the supplies, (2) time required for nursing and pharmacy personnel to prepare and administer the doses, and (3) the influence of agent toxicity (renal function) on physician-ordered laboratory tests. On the whole, combination therapy including an aminoglycoside was four times as expensive as single-agent (first-generation cephalosporin) therapy. If future studies demonstrate that single-agent antibiotic therapy is as effective as traditional combination therapy for specific infectious diseases, the influence of the number of daily doses of drug and agent toxicity may support the cost-effective use of the newer agents.

Lithium nephrotoxicity.

Lithium-induced nephrotoxicity was first predicted in laboratory animals more than 30 years ago. Evidence in humans, however, did not begin to accumulate until the 1970s. By 1977, anecdotal information was available to suggest that lithium intoxication was not necessarily a prerequisite for the development of nephrotoxicity and that renal damage also could occur as a result of chronic lithium therapy. Since then, several factors have been identified that could influence the risk of nephrotoxicity during treatment with lithium. These include number of daily doses, type of lithium formulation, and the incidence of renal disease in patients with manic-depressive illness.