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Biomedical subjects

C H Koks

Publications and source records attributed to C H Koks.

At least 19 recordsLinked to original sources
PubMed2001

The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV-1-infected individuals.

AIMS: To study the effect of fluconazole on the steady-state pharmacokinetics of the protease inhibitors ritonavir and saquinavir in HIV-1-infected patients. METHODS: Five subjects treated with saquinavir and three with ritonavir received the protease inhibitor alone (saquinavir 1200 mg three times daily, ritonavir 600 mg twice daily) on day 1, and the same protease inhibitor in combination with fluconazole (400 mg on day 2 and 200 mg on days 3 to 8). Pharmacokinetic parameters were determined on days 1 and 8. RESULTS: In the saquinavir group, the median increase in the area under the plasma concentration vs time curve was 50% from 1800 microg l(-1) h to 2700 microg l(-1) h (P = 0.04, median increase: 900 microg l(-1) h; 2.5 and 97.5 percentile: 500-1300), and 56% for the peak concentration in plasma (from 550 to 870 microg l(-1), P = 0.04; median increase: 320 microg l(-1) h, 2.5 and 97.5 percentile: 60-450 microg l(-1)). In the ritonavir group, there were no detectable changes in the pharmacokinetic parameters on addition of fluconazole. CONCLUSIONS: Because of the favourable safety profile of saquinavir, dose adjustments are probably not necessary with concomitant use of fluconazole, as is the case for ritonavir.

Administration, Oral↗
PubMed2001

Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?

The saliva/plasma concentration ratio of fluconazole was investigated in 22 HIV-1-infected individuals with an oropharyngeal Candida infection to determine whether saliva fluconazole concentrations could provide useful information for therapeutic drug monitoring in this population. Steady-state paired plasma and saliva samples were obtained after approximately 1 week of treatment with 50-or 100-mg fluconazole as capsules. A significant correlation between plasma and salivary levels of fluconazole was observed. The median saliva/plasma concentration ratio was 1.3 and was independent of the ingested dose and the plasma fluconazole concentration. The prediction of fluconazole concentrations in plasma from the concentrations in saliva was, although unbiased, not precise. From these findings, the authors conclude that although stimulated salivary fluconazole concentrations are significantly correlated with plasma concentrations, it is not possible to predict plasma fluconazole levels from the salivary concentrations with adequate precision. However, saliva fluconazole concentrations have sufficient value to test for compliance and even semiquantitative prediction of plasma concentrations.

AIDS-Related Opportunistic Infections↗
PubMed1999

P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil.

Digoxin, which has a very narrow therapeutic window, is one of the most commonly prescribed drugs in the treatment of congestive heart failure. In some cases of atrial fibrillation digoxin is used in combination with verapamil. Verapamil can increase the plasma concentration of digoxin up to 60-90%. So far the precise mechanism of this pharmacokinetic drug-drug interaction is not known. Many studies suggest that verapamil reduces the renal clearance of digoxin. The energy-dependent membrane-bound transport enzyme, P-glycoprotein, may also be involved. Reports from oncology research show that verapamil can interact with P-glycoprotein as a modulator. Also taking into account that digoxin, like many anticancer drugs, is a substrate for P-glycoprotein, it is likely that P-glycoprotein modulation accounts for the digoxin-verapamil interaction. Current knowledge suggest that the non-competitive digoxin-verapamil interaction is due to inhibition of P-glycoprotein activity by verapamil resulting in a decreased renal tubular elimination of digoxin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

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.

Acetaminophen↗
PubMed1998

Survival after massive ecstasy overdose.

INTRODUCTION: The toxicity profile of the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") is well known. This designer drug is usually taken at "house parties" and may cause severe complications, sometimes leading to death, even when taken in relatively small units (1 or 2 tablets). Up to now, only a few cases of survival after ingestion of an overdose of Ecstasy have been described. In most cases the users developed hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, and renal failure. CASE REPORT: We describe a man who, after ingesting 50 tablets of Ecstasy (in combination with oxazepam and alcohol) at home, recovered within 2 days. Presenting features were unconsciousness, apnea, and convulsions. It is suggested that in most cases severe 3,4-methylenedioxymethamphetamine toxicity results from an interaction between direct pharmacological effects of the drug and the prevailing environmental conditions (high ambient temperature, dancing in trance, little fluid intake).

Adult↗
PubMed1997

Penetration of 3'-amino-3'-deoxythymidine, a cytotoxic metabolite of zidovudine, into the cerebrospinal fluid of HIV-1-infected patients.

The penetration of 3'-amino-3'-deoxythymidine (AMT) into the cerebrospinal fluid (CSF) of HIV-1-infected patients has been investigated. In 23 patients who used zidovudine (ZDV) chronically, CSF and plasma samples were assayed for AMT and ZDV. The influences of time between ZDV oral administration and lumbar puncture, of ZDV dose, and of the medical indication for lumbar puncture based on the concentration of AMT in CSF and on the CSF-plasma concentration ratio were investigated. AMT can be detected in the CSF after oral administration of ZDV; concentrations of AMT in CSF ranged from 0.75 to 4.8 ng/ml (median, 1.7 ng/ml). The median CSF-plasma concentration ratio was 1, and equaled that for ZDV. CSF and plasma concentrations of AMT were approximately threefold higher in patients with cerebral toxoplasmosis; the CSF-plasma concentration ratio remained equal to unity in these cases. This phenomenon might be caused by a pharmacokinetic interaction between AMT and pyrimethamine, sulfadiazine, folinic acid, or a combination of these. The clinical relevance of AMT, especially the possibility of decreased efficacy of ZDV, throughout the body and in the central nervous system, and the involvement of this metabolite in ZDV-induced myelosuppression, remains to be established.

Administration, Oral↗
PubMed1997

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.

Acquired Immunodeficiency Syndrome↗
PubMed1996

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.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Pharmacokinetics of fluconazole in saliva and plasma after administration of an oral suspension and capsules.

The concentrations of fluconazole were determined at steady state in the saliva and plasma of 10 healthy volunteers after ingestion of fluconazole as capsules and after flushing the mouth for 2 min with the same dose formulated as an oral suspension and swallowing of the drug. Saliva and plasma samples were analyzed by a validated high-performance liquid chromatographic assay. Flushing and swallowing of the oral suspension resulted in a significantly (P = 0.005) higher mean area under the concentration-versus-time curve (AUC) from 0 to 24 h in saliva (89.13 +/- 23.42 mg.h/liter) than that obtained after ingestion of the same dose as capsules (69.27 +/- 12.89 mg . h/liter). The calculated mean maximum concentration in saliva just after swallowing of the suspension was 97.99 +/- 6.12 mg/liter. The peak fluconazole concentration in saliva after the ingestion of the capsules was 3.55 +/- 0.40 mg/liter. The fluconazole oral suspension and capsules resulted in comparable concentrations and AUCs in plasma. Thus, because of a higher local level of drug exposure in terms of both higher peak concentrations in saliva and a higher salivary AUC, the fluconazole oral suspension has theoretical advantages over the capsule formulation in the treatment of oropharyngeal candidiases.

Administration, Oral↗
PubMed1996

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.

Adult↗
PubMed1995

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.

Administration, Topical↗
PubMed1995

Study on didanosine concentrations in cerebrospinal fluid. Implications for the treatment and prevention of AIDS dementia complex.

It has been hypothesized that didanosine has a low efficacy in the prevention and treatment of patients with the dementia complex of acquired immunodeficiency syndrome (AIDS) because "... the drug has not been detected in the cerebrospinal fluid". We investigated didanosine concentrations in cerebrospinal fluid (CSF) and plasma of four patients with AIDS who were using didanosine chronically. Didanosine levels, 4 h after the last drug administration, averaged 0.16 (+/- 0.03) mumol/l in CSF and 0.70 (+/- 0.27) mumol/l in plasma. When compared with historical data from patients using zidovudine, didanosine concentrations in CSF appeared to be approximately half (on a molar base) those of zidovudine concentrations in the CSF. Whether this difference in CSF levels is the explanation for the presumed lower efficacy of didanosine in the prevention and treatment of AIDS dementia complex remains to be proven. However, it is clear from this study, in contrast with earlier suggestions, that didanosine is able to pass the blood-CSF barrier in human immunodeficiency virus-infected individuals.

AIDS Dementia Complex↗
PubMed1995

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.

Calibration↗
PubMed1994

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.

Acetaminophen↗
PubMed1994

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.

Adult↗
PubMed1994

Therapeutic drug monitoring of phenytoin in patients with the acquired immunodeficiency syndrome.

Serum phenytoin concentrations were investigated in 109 serum samples from 21 patients with the acquired immunodeficiency syndrome (AIDS) and in 1,231 serum samples from 557 control subjects during phenytoin therapy. Total phenytoin concentrations were significantly lower in patients with AIDS than in the reference population (8.8 +/- 0.7 mg/L (mean +/- SE) vs. 10.6 +/- 0.2 mg/L), although phenytoin doses were significantly higher in the AIDS patients. Body weight and the use of folic acid were negatively related to phenytoin concentrations, whereas use of clarithromycin resulted in higher phenytoin levels. Zidovudine did not influence phenytoin levels. Calculation of the Michaelis-Menten parameters showed that Vmax values were similar in seven human immunodeficiency virus (HIV)-infected patients as compared with 12 controls, but a nonsignificant trend of lower Km values in the HIV-positive group was observed. Measurement of free phenytoin concentrations demonstrated that the fraction of unbound drug was increased in patients with AIDS. Hypoalbuminemia was common in this population, which may complicate the interpretation of total phenytoin concentrations.

Acquired Immunodeficiency Syndrome↗