C. H. W. Koks

Drug-Drug Interactions in a Geriatric Outpatient Cohort Prevalence and Relevance

BackgroundThe prevalence of drug-drug interactions (DDIs) in a geriatric population may be high because of polypharmacy. However, wide variance in the clinical relevance of these interactions has been shown.ObjectivesTo explore whether adverse drug reactions (ADRs) as a result of DDIs can be identified by clinical evaluation, to describe the prevalence of ADRs and diminished drug effectiveness as a result of DDIs and to verify whether the top ten most frequent potential DDIs known to public pharmacies are of primary importance in geriatric outpatients in the Netherlands.MethodAll adverse events classified by the Naranjo algorithm as being a possible ADR and drug combinations resulting in diminished drug effectiveness were identified prospectively in 807 geriatric outpatients (mean age 81 years) at their first visit. The setting was a diagnostic day clinic. The Medication Appropriateness Index (MAI) and Beers criteria were used to evaluate drug use and identify possible DDIs. The ten most frequent potential interactions, according to a 1997 national database of public pharmacies (‘Top Ten’) in the Netherlands, and possible adverse events as a result of other interactions, were described. The effects of changes in medication regimen were recorded by checking the medical records.ResultsIn 300 patients (44.5% of the 674 patients taking more than one drug), 398 potential DDIs were identified. In 172 (25.5%) of patients taking more than one drug, drug combinations were identified that were responsible for at least one ADR or which possibly resulted in reduced effectiveness of therapy. Eighty-four of the 158 possible ADRs resulting from enhanced action of drugs forming combinations listed in the ‘Top Ten’ were seen in 73 patients. Only four DDIs resulting in less effective therapy that involved drug combinations in the ‘Top Ten’ were identified. Changes in drug regimens pertaining to possible interactions were proposed or put into effect in 111 of the 172 (65%) patients with possible DDIs. Sixty-one (55%) of these patients returned for follow-up. Of these, 49 (80%) were shown to have improved after changes were made to their medication regimen.ConclusionIn this study, nearly half of the geriatric outpatients attending a diagnostic day clinic who were taking more than one drug were candidates for DDIs. One-quarter of these patients were found to have possible adverse events or diminished treatment effectiveness that may have been at least partly caused by these DDIs. These potential interactions can be identified through clinical evaluation. In the majority of patients (99 of 172) the potential interactions resulting in possible ADRs or diminished effectiveness were not present in the ‘Top Ten’ interactions described by a national database of public pharmacies, a finding that emphasizes that the particular characteristics of geriatric patients (e.g. frequent psychiatric co-morbidities) need to be considered when evaluating their drug use. At least 7% of all patients taking more than one drug, and 80% of those with possible drug interactions whose drug regimen was adjusted, benefited from changes made to their drug regimens.

Clinical pharmacology of HIV protease inhibitors: focus on saquinavir, indinavir, and ritonavir

In this review the clinical pharmacology of HIV protease inhibitors, a new class of antiretroviral drugs, is discussed. After considering HIV protease function and structure, the development of inhibitors of HIV protease is presented. Three protease inhibitors are reviewed in more detail: saquinavir, indinavir, and ritonavir. Clinical trial results with these agents are evaluated. Furthermore, adverse effects, resistance, dosage and administration, clinical pharmacokinetics, pharmacokinetic-pharmacodynamic relationships, and drug interactions are discussed.

Pharmacokinetic interaction between rifampin and zidovudine.

A potential pharmacokinetic interaction between rifampin (Rimactan, Rifadin) and zidovudine (AZT, Retrovir) was investigated in the population of human immunodeficiency virus-infected patients at our hospital. The results from four patients who were on long-term (> or = 6 months) combination therapy with zidovudine and rifampin are presented. In all cases of combined use of zidovudine and rifampin, a lower area under the plasma concentration-time curve (AUC) and, consequently, a higher apparent clearance of zidovudine were found, compared with a reference population of zidovudine users. Patients had a low to normal maximum concentration of zidovudine in plasma. Elimination half-lives were normal in all but one patient. Zidovudine glucuronide concentrations were determined in three patients and three control subjects. The patients all had relatively higher peak plasma concentrations and higher AUCs of zidovudine glucuronide than the control subjects. In one patient, zidovudine and zidovudine glucuronide were also measured 2.5 months after discontinuation of rifampin. The AUC of zidovudine increased by a factor of 2. These data are in agreement with an enzyme-inducing effect of rifampin on the glucuronidation of zidovudine. They indicate that long-term combination therapy of rifampin and zidovudine leads to increased clearance of zidovudine, which may have therapeutic consequences.

Itraconazole solution: Summary of pharmacokinetic features and review of activity in the treatment of fluconazole-resistant oral candidosis in HIV-infected persons

The clinical pharmacology of itraconazole is presented in relation to its use in the treatment of fluconazole-resistant oropharyngeal candidosis. The oral solution is a new formulation of itraconazole in which itraconazole is solubilised with the use of cyclodextrin. This formulation has a higher bioavailability and leads to higher local concentrations in the oral cavity which are advantages over the solid capsule formulation. Literature, in which the use of itraconazole oral solution was described to treat fluconazole-resistant oral candidosis, is reviewed. In about 55% of the patients signs and symptoms of oral candidosis were resolved after treatment with itraconazole oral solution. Although all the reviewed studies lack data to objectively qualify all the included patients as having a fluconazole-resistant candidosis, the authors conclude, that based on the available information itraconazole oral solution 100 or 200mg twice daily can be effective for fluconazole-resistant oropharyngeal candidosis (OPC) and should be considered prior to salvage therapy with intravenous amphotericin B. The use of itraconazole, however, requires careful monitoring of the patients co-medication for potential serious drug-drug interactions.

Evaluation of clinical pharmacist interventions on drug interactions in outpatient pharmaceutical HIV‐care

Objective:  To evaluate the usefulness of intervention in drug interactions of antiretroviral drugs with coadministered agents by a clinical pharmacist in outpatient HIV‐treatment.

Etoposide phosphate, the water soluble prodrug of etoposide.

Etoposide (Vepesid) is a widely used drug in a variety of neoplasms. To improve the pharmaceutical characteristics of etoposide, etooside phosphate (Etopophos, Bristol-Myers Squibb) has been developed as a prodrug.Etoposide phosphate is the phosphate ester derivative of etoposide, in comparison to the parent compound, etoposide phosphate is highly soluble in water and can be readily formulated for intravencus uso resulting in higher ctinical application. This paper presents information on the pharmaceutical properties and the current status of etoposide phosphate in clinical triafs.

Ciprofloxacin Strongly Inhibits Clozapine Metabolism : Two Case Reports

We report on two cases of drug-drug interactions between ciprofloxacin and clozapine. The first case was a 46-year-old male patient receiving a daily dose of clozapine 900 mg. He was admitted to hospital with urosepsis and was treated with a 5-day course of ciprofloxacin and amoxicillin. Two days after completion of antibacterial therapy, the patient developed symptoms of rhabdomyolysis. Clozapine therapy was discontinued and measurement of the patient’s clozapine plasma concentration 1 day after cessation of clozapine therapy and 3 days after cessation of ciprofloxacin treatment showed that it was in excess of recommended therapeutic levels. The second patient was a 58-year-old male patient treated with a daily dose of clozapine 300 mg. He was admitted to hospital because of delirium and suspected urinary tract infection or pneumonia. Treatment with ciprofloxacin was initiated. Measurement of clozapine plasma concentrations prior to and 3 days after commencement of ciprofloxacin showed that clozapine concentrations doubled over that time period. We suggest that inhibition of cytochrome P450 (CYP) enzymes 1A2 and 3A4 by ciprofloxacin resulted in delayed clozapine metabolism and elevated clozapine plasma concentrations. This might cause severe adverse effects. We advise using another antibacterial agent or reducing the clozapine dose and monitoring clozapine levels when this antipsychotic agent is used in combination with ciprofloxacin.

Evaluation of Pharmacotherapy in Geriatric Patients after Performing Complete Geriatric Assessment at a Diagnostic Day Clinic

AbstractBackground: Elderly patients often take multiple drugs. It is known that polypharmacy, i.e. use of five or more drugs, may lead to drug interactions and adverse events. However, undertreatment of conditions or illnesses is also a concern in geriatric patients. A centralised review of both diagnoses and medication may play a key role in optimising pharmacotherapy in geriatric patients. The aims of this study were to evaluate the quality and appropriateness of medication after performing a complete geriatric assessment (CGA) and medication review at a diagnostic geriatric day clinic, to investigate reasons for drug changes, and to determine whether medication review leads to a reduction in the number of drugs used. Methods: A chart review was performed in 702 patients (mean age 82.0 years, range 57.1–104.1 years) who underwent a CGA at a diagnostic geriatric day clinic. Medication at admission, changes in medication and reasons for changes were noted. Results: Vitamins, for example folic acid and vitamin B12 (cyanocobalamin), and trimethoprim for urinary tract infections were the most frequently started medications after CGA and medication review. The number of drugs used was reduced in only a minority of patients (11.7%); reasons for discontinuation were a diagnosis that was no longer relevant (38.8%), adverse events (33.2%) and identification of better pharmacotherapeutic options (22.0%). In 69.2% of the cases a new diagnosis was the reason for starting a new medication, followed by osteoporosis prophylaxis (15.0%) and improvement in pharmacotherapy (10.6%). At admission, patients were taking a mean number of 4.6 drugs (range 0–17). A mean of 0.8 drugs (range from reduction of 5 to addition of 7) had been added per patient, resulting in a mean number of 5.4 (range 0–18) prescribed drugs at discharge. Conclusion: Evaluation of medication in patients after performing CGA at the geriatric day clinic investigated resulted in relevant medication changes. The main reason for prescribing new drugs was a new diagnosis. Absence of a relevant medical indication was the main reason for stopping drugs. CGA and medication review resulted in a mean net addition of 0.8 drugs per patient.

Treatment effects of rivastigmine on cognition, performance of daily living activities and behaviour in Alzheimer's disease in an outpatient geriatric setting

We investigated rivastigmine effectiveness in 84 Alzheimer outpatients, with a special focus on behavioural problems. Cognition, activities in daily living (ADL) and behaviour were assessed during 30 months. Changes in test results between 6 months and baseline were compared with a historical control cohort of Alzheimer patients (n = 69) by performing t‐tests and calculation of Cohens d and standardised response mean (SRM).

OCULAR COMPLICATIONS OF THE ACQUIRED IMMUNODEFICIENCY SYNDROME : FOCUS ON THE TREATMENT OF CYTOMEGALOVIRUS RETINITIS WITH GANCICLOVIR AND FOSCARNET

The most common ocular complication in patients with the acquired immunodeficiency syndrome (AIDS) is cytomegalovirus retinitis. Incidence figures vary from 20 to 76%. Patients with cytomegalovirus may suffer from mild visual impairment of one or both eyes, but as the disease progresses the retinitis will almost certainly lead to blindness. Although cytomegalovirus retinitis is not a life-threatening infection, it can largely diminish the patients quality of life. Clinical trials for the treatment of cytomegalovirus retinitis with a number of antiviral drugs have resulted in two drugs of choice, ganciclovir and foscarnet. Both drugs have an initial efficacy with induction therapy of 80–90%, but maintenance therapy is always needed to prevent a relapse. To exclude systemic side-effects of ganciclovir, intravitreal administration has been investigated with good results. Combination therapy of foscarnet and ganciclovir may be worthwhile in resistant cytomegalovirus retinitis.