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.

Traditional Chinese lipid-lowering agent red yeast rice results in significant LDL reduction but safety is uncertain - a systematic review and meta-analysis.

OBJECTIVE: To verify the safety and effectiveness of traditional Chinese red yeast rice-extract (RYR) for reduction of LDL cholesterol. METHODS: Systematic literature review and meta-analysis. Medline and EMBASE were searched until November 2014. We selected randomized studies in which RYR with a known content of the active substance monacolin K was tested against placebo or an active control group. Outcome measures were the effect of RYR on LDL cholesterol and incidence of adverse reactions with emphasis on liver and kidney injury and muscle symptoms. RESULTS: Twenty studies were analyzed. Quality of safety assessment was low in the majority of studies. RYR lowered LDL cholesterol with 1.02 mmol/L [-1.20; -0.83] compared to placebo. Effect of RYR on LDL was not different from statin therapy (0.03 mmol/L [-0.36; 0.41]). The incidence of liver and kidney injury was 0-5% and the risk was not different between treatment and control groups (risk difference -0.01 [-0.01; 0.0] and 0.0 [-0.01; 0.02]). CONCLUSIONS: RYR exerts a clinically and statistically significant reduction of 1.02 mmol/L LDL cholesterol. Only when the mild profile of adverse reactions can be affirmed in studies with adequate methodology for safety assessment, RYR might be a safe and effective treatment option for dyslipidemia and cardiovascular risk reduction in statin intolerant patients.

Penetration of zidovudine into the cerebrospinal fluid of patients infected with HIV.

OBJECTIVE: To investigate penetration of zidovudine (ZDV) into the cerebrospinal fluid (CSF) of HIV-infected patients for whom a lumbar puncture was indicated. DESIGN: A prospective study. SETTING: General 525-bed hospital with special funding for treatment and research of HIV-infected patients. PATIENTS, PARTICIPANTS: Thirty-nine patients with a medical indication for lumbar puncture who used ZDV chronically were included in this study (50 samples in total). MAIN OUTCOME MEASURE: Determination of ZDV and proteins in CSF and plasma samples. RESULTS: CSF concentrations of ZDV showed little fluctuation 1-8 h after the last ingestion of ZDV. In contrast, plasma levels displayed large variability in this period and decreased exponentially over time. As a result, the CSF/plasma ratio increased linearly over time. No significant relation between the ZDV dose, neither the medical indication for lumbar puncture nor the protein ratio (as a measure for the integrity of the blood-brain barrier), and CSF levels of ZDV was found. The CSF/plasma ratio of ZDV did not give essential information on drug distribution into CSF. CONCLUSIONS: Penetration of ZDV into the CSF appears to be independent of the dose (range, 200-1250 mg daily), which may be an explanation for the efficacy of low doses of ZDV in the prevention and treatment of HIV-related neurological diseases. ZDV levels were at steady-state during the first 6 h after ingestion. The CSF/plasma ratio of ZDV concentrations is not an appropriate marker for drug penetration into CSF.

Pharmacokinetic variability of zidovudine in HIV-infected individuals: subgroup analysis and drug interactions.

OBJECTIVE: To investigate determinants of inter- and intraindividual variability of zidovudine (ZDV) pharmacokinetics in HIV-infected patients. DESIGN: A prospective study in a general 525-bed hospital with special funding for treatment and research of HIV-infected patients. METHODS: Serial blood samples were collected from 68 HIV-infected individuals providing a total of 95 pharmacokinetic curves. ZDV was measured with high-performance liquid chromatography and radioimmunoassay. Pharmacokinetic parameters were calculated by non-compartmental analysis. Patient characteristics were investigated by multivariate analysis for an influence on ZDV pharmacokinetics. RESULTS: Apparent ZDV clearance was significantly lower in patients with a lower body weight, in women, and in patients with a more advanced stage of HIV disease. Co-administration of methadone with ZDV resulted in higher plasma concentrations of ZDV, while rifampin and ganciclovir increased apparent ZDV clearance. Age, the duration of ZDV use, CD4+ cell count, creatinine clearance, elevated serum liver enzyme levels, and the use of 11 other co-administered medications were not independently related to apparent ZDV clearance. CONCLUSIONS: The pharmacokinetic profile of ZDV in several subpopulations has been evaluated, as well as the observation of possible drug-drug interactions between ZDV and 14 different drugs or groups of drugs. These data suggest that patient-individualized antiretroviral therapy may be appropriate once pharmacokinetic-pharmacodynamic relationships have been established.

Short-term, combined use of paracetamol and zidovudine does not alter the pharmacokinetics of either drug.

OBJECTIVE: To investigate a possible pharmacokinetic interaction between zidovudine and paracetamol. METHODS: Six patients with AIDS took both zidovudine (AZT; 1000-1200 mg/day) and paracetamol (500 mg every 6 h) for 7 days. Pharmacokinetic monitoring was performed on day 0 (AZT alone) and after 7 days of combined use of paracetamol and AZT. RESULTS: Combined use of paracetamol and AZT did not result in a significant change in any of the calculated pharmacokinetic parameters of AZT or its primary metabolite AZT-glucuronide. In addition, paracetamol pharmacokinetic parameters at day 7 did not differ from those usually reported in the literature. CONCLUSION: Short-term, combined use of paracetamol and AZT does not lead to a change in the pharmacokinetics of either AZT or paracetamol. The effect of long-term use of this combination remains unknown. A recent case report of AZT-induced paracetamol hepatotoxicity [Am J Med 1992;93: 94-96] indicates that clinicians should still be aware of potential drug toxicity when prescribing both AZT and paracetamol.

Combined dapsone and clofazimine intoxication.

We report clinical findings and pharmacokinetic data regarding a combined dapsone and clofazimine intoxication in a man, who ingested 50 tablets of dapsone (100 mg) 20 capsules of clofazimine (100 mg) and two tablets of rifampicin (600 mg). Oral administration of activated charcoal (50 grams) and sodium sulphate (20 grams) after gastric lavage resulted in an elimination half-life in plasma of 11.1 and 10.8 h for dapsone and its main metabolite, monoacetyldapsone, respectively. A rapid initial decrease of the plasma concentration of clofazimine was observed after gastric lavage and administration of activated charcoal and sodium sulphate. 15 h after this treatment, clofazimine plasma levels remained relatively constant. Dapsone-induced methaemoglobinaemia (48% at admission) was treated successfully with methylene blue.

A dose-dependent delayed hypersensitivity reaction to acetaminophen after repeated acetaminophen intoxications.

We report a case of a 29-year-old woman with a borderline personality disorder who presented with intentional substantial acetaminophen (paracetamol) overdosage on nine occasions during a period of 21 months. In most cases, the patient presented at the hospital within 4 h after ingestion and was treated with gastric lavage, activated charcoal, laxatives and intravenous N-acetylcysteine. During the sixth overdosage the patient developed a rash on her chest and shoulders which was considered an anaphylactoid reaction to N-acetylcysteine. Therefore she was treated with oral methionine subsequently, but developed the rash again. The rash was then ascribed to the repeated high-doses of acetaminophen and treatment with N-acetylcysteine was reinstituted. This case shows that when an anaphylactoid reaction occurs after an acetaminophen overdose and treatment with N-acetylcysteine, acetaminophen must also be taken into account as the cause of the anaphylactoid reaction before effective therapy with N-acetylcysteine is withheld.

Identification of responders and reactive domains to rivastigmine in Alzheimer's disease.

PURPOSE: Presently, it is unclear which patients suffering from Alzheimer's Disease (AD) respond to rivastigmine and if rivastigmine acts on specific cognitive domains. The aims of this study are thus to investigate treatment effects of rivastigmine on specific cognitive domains and to find possible responsive subpopulations to rivastigmine cognitive effects. METHODS: Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG) were administered at baseline and after 6 months in 83 rivastigmine users and 96 historical controls, representing natural decline. Treatment effects on different subsections of the CAMCOG and in different subpopulations were investigated by linear regression analyses. RESULTS: Rivastigmine showed effectiveness on total CAMCOG (p < 0.001), CAMCOG non-memory subsection (p < 0.001) and subscales of language (p = 0.002), attention/calculation (p = 0.043), abstract thinking (p < 0.001) and perception (p = 0.031). In patients with baseline MMSE < or =19 rivastigmine showed significant and favourable effects compared to historical controls on total CAMCOG (p < 0.001) and both non-memory (p < 0.001) and memory subsections (p = 0.002). CONCLUSION: Rivastigmine showed primarily effectiveness on the non-memory section of the CAMCOG and patients with a baseline MMSE < or = 19 appeared to show greater responses to rivastigmine compared to patients with baseline MMSE > or = 20.

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 Cohen's d and standardised response mean (SRM). During 6 months, rivastigmine showed effect on cognition (p < 0.001, Cohen's d = 0.33, SRM = 0.78), ADL (p < 0.001, Cohen's d = -0.43, SRM = -0.54) and memory-related behaviour (p = 0.006, Cohen's d = -0.28, SRM = -0.28). Depressive behaviour worsened (p = 0.001, Cohen's d = 0.30, SRM = 0.37) and disruptive behaviour (p = 0.369, Cohen's d = -0.07, SRM = -0.09) was not effected by rivastigmine. During 30 months, a gradual decline was shown in most domains. Most RMBPC items showed stabilization during 30 months. Improvement on disruptive behaviour items and depression items was shown after 6 months of treatment in a large proportion of patients in whom behavioural problems were present at baseline. In conclusion, a huge discontinuation rate is experienced within the first half year of treatment. In the subpopulation of patients who continued rivastigmine for 6 months, it shows modest effectiveness on cognition, functionality and memory-associated behaviour compared with historical control patients. Unfortunately, disruptive behaviour is not altered by rivastigmine therapy, and depressive behaviour worsened slightly after initial treatment. During 30 months, rivastigmine showed stabilization on numerous behaviour items as measured by the RMBPC.

Pharmacokinetic aspects during continuous ambulatory peritoneal dialysis: a literature review.

Since its introduction some years ago continuous ambulatory peritoneal dialysis (CAPD) has proved to be a valuable alternative to haemodialysis in the treatment of uraemia. Factors contributing to the transport of solutes through the peritoneal membrane are discussed and the literature concerning the pharmacokinetic aspects of CAPD is reviewed.

Regional infusion of fluoropyrimidines for hepatic metastases of colorectal cancer.

Recent reports on regional chemotherapy for hepatic metastases of colorectal origin are reviewed. Because of reported side effects and lack of evidence for its superiority over conventional intravenous administration, intra-arterial administration of fluoropyrimidines cannot be advised for routine use, but should be restricted to centres participating in clinical trials on this subject.

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, etoposide 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 intravenous use, resulting in higher clinical application. This paper presents information on the pharmaceutical properties and the current status of etoposide phosphate in clinical trials.

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.

Didanosine, a new antiretroviral drug. A review.

In this article the literature about didanosine, an antiretroviral drug, is reviewed. The mechanism of action, biochemical pharmacology, pharmacokinetics, and clinical results of phase-I trials are discussed. Serious adverse effects such as pancreatitis and peripheral neuropathy have occurred in these trials. An antiretroviral effect was observed in terms of an increase in CD4+ lymphocytes and a decrease in p24 antigen levels in HIV-infected individuals. Didanosine seems to be a promising drug against HIV infection, but knowledge about its clinical efficacy is scanty.

High-performance liquid chromatographic determination of the antifungal drug fluconazole in plasma and saliva of human immunodeficiency virus-infected patients.

A high-performance liquid chromatographic (HPLC) assay has been developed for the determination of the antifungal drug fluconazole in saliva and plasma of patients infected with the human immunodeficiency virus (HIV). Samples can be heated at 60 degrees C for 30 min to inactivate the virus without loss of the analyte. The sample pretreatment involves a liquid-liquid extraction with chloroform-1-propanol (4:1, v/v). The chromatographic analysis is performed on a Lichrosorb RP-18 (5 microns) column by isocratic elution with a mobile phase of 0.01 M acetate buffer (pH 5.0)-methanol (70:30, v/v) and ultraviolet (UV) detection at 261 nm. The lower limit of is 100 ng/ml in plasma (using 500-microliters samples) and 1 microgram/ml in saliva (using 250-microliters samples) and the method is linear up to 100 micrograms/ml in plasma and saliva. At a concentration of 5 micrograms/ml the within-day and between-day precision in plasma are 7.1 and 5.7%, respectively. In saliva the within-day and between-day precision is 10.8% (at 5 micrograms/ml). The methodology is now being used in pharmacokinetic studies in HIV-infected patients in our hospital.

Preparation and stability testing of a hydrogel for topical analgesia.

With the commercial availability of a cream (EMLA) containing a eutectic mixture of local anaesthetics, 2.5% (w/w) lidocaine and 2.5% (w/w) prilocaine, effective topical anaesthesia of the intact skin is possible without the need for subcutaneous injections or exposure to high concentrations of local anaesthetics. In our hospital a topical anaesthetic product was designed for the same purpose. The home-made product contains a eutectic mixture of a local anaesthetic (5% w/w) and l-menthol (1% w/w). Prilocaine was used as the local anaesthetic because it is known for its safety and its well investigated analgesic effects. The eutectic mixture of prilocaine and l-menthol was mixed with a carbopol hydrogel (1% w/w). Preliminary testing of this anaesthetic hydrogel in our hospital has yielded satisfactory results. The anaesthetic hydrogel was found to be stable after at least 3 months' storage at ambient temperature.