PubMed Health⌕ Search

Biomedical subjects

P L Meenhorst

Publications and source records attributed to P L Meenhorst.

At least 37 records · Page 2Linked to original sources
PubMed2000

The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals.

OBJECTIVE: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. DESIGN: Open-label, randomized, cross-over study. METHODS: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Non-compartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC[24h]), and the maximal (Cmax) and minimal plasma concentration (Cmin), the time to Cmax (t(max)), the plasma elimination half-life (t1/2), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. RESULTS: The exposure to nevirapine, as measured by the AUC[24h], was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t1/2 Cl/F and V/F were not significantly different between the two dosing regimens (P > or = 0.08). However, Cmax and Cmin were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for Cmax and Cmin as measured for the once daily and twice daily regimens were 6.69 and 5.74 microg/ml, respectively (P = 0.03), and 2.88 and 3.73 microg/ml, respectively (P < 0.01). CONCLUSION: These data show that the daily exposure to nevirapine, as measured by the plasma AUC[24h], is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, Cmax and Cmin are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established.

Adult↗
PubMed2000

Saliva as a specimen for monitoring compliance but not for predicting plasma concentrations in patients with HIV treated with indinavir.

The presence of the HIV-protease inhibitor indinavir in saliva was analyzed to investigate whether salivary indinavir concentrations are applicable to monitor compliance and/or predict plasma indinavir levels. Fourteen HIV-infected outpatients treated with indinavir and 24 healthy volunteers who ingested a single dose of indinavir were included. Paired plasma and citric-acid-stimulated saliva samples were analyzed by high-performance liquid chromatography (HPLC). Stimulated salivary indinavir concentrations showed a high correlation (r = 0.85, p < 0.01) with corresponding plasma levels. The median saliva/plasma ratio was 65% (P25 50%; P75 94%). The ratios were independent of the plasma concentration; however, a relation with time after ingestion was seen. The unbound fraction of indinavir in plasma was not significantly correlated with the saliva/plasma ratio after stimulated saliva collection, in contrast with a subset of nonstimulated saliva from healthy volunteers, where we did find a significant correlation. Although stimulated salivary indinavir concentrations are highly correlated with plasma concentrations, it is not possible to predict plasma indinavir levels by the salivary concentrations for purposes of therapeutic drug monitoring, due to large interindividual and intraindividual variation. Nevertheless, monitoring compliance by measuring the presence of indinavir in saliva is possible: ingestion of indinavir can be assessed with a sensitivity of 84.8% in the whole dosing interval or with 98.8% between 1 and 6 hours after the last dose, which is comparable with plasma.

Adolescent↗
PubMed2000

Value of different assays for detection of human cytomegalovirus (HCMV) in predicting the development of HCMV disease in human immunodeficiency virus-infected patients.

In the present prospective study, five blood tests for detection of human cytomegalovirus (HCMV), nucleic acid sequence-based amplification (NASBA) for detection of early (immediate-early antigen) and late (pp67) mRNA, PCR for detection of HCMV DNA (DNA PCR), culture, and pp65 antigenemia assay, and culture and DNA PCR of urine and throat swab specimens were compared for their abilities to predict the development of disease caused by HCMV (HCMV disease). Of 101 human immunodeficiency virus (HIV)-infected patients with </=100 CD4(+) lymphocytes per mm(3), 25 patients developed HCMV disease. The pp65 antigenemia assay (sensitivity, 50%; specificity, 89%) and DNA PCR of blood (sensitivity, 69%; specificity, 75%) were most accurate in predicting the development of HCMV disease within the next 12 months. Both blood culture and late pp67 mRNA NASBA had high specificities (91 and 90%, respectively) but low sensitivities (25 and 13%, respectively). The sensitivities of urine culture, DNA PCR, throat swab specimen culture, DNA PCR, and NASBA of blood for detection of the immediate-early antigen were 73, 87, 53, 67, and 63%, respectively, and the specificities were 58, 46, 76, 60, and 72%, respectively. The positive predictive values of all tests however, were low and did not exceed 50%. In conclusion, virological screening by these qualitative assays for detection of HCMV is of limited value for prediction of the development of HCMV disease in HIV-infected patients.

AIDS-Related Opportunistic Infections↗
PubMed1999

Quantitative pp65-antigenemia assay for the prediction of human cytomegalovirus disease in HIV-infected patients.

OBJECTIVE: To evaluate the ability of a quantified pp65-antigenemia assay to predict the development of human cytomegalovirus (HCMV) disease in patients with an advanced HIV infection. DESIGN: A prospective longitudinal study between March 1993 and December 1996. Blood samples for the pp65-antigenemia assay were drawn at 2-3 month intervals. SETTING: AIDS department of an institutional tertiary care centre. PATIENTS: A total of 101 HIV-infected patients with CD4 lymphocyte counts of 100/mm3 or less were enrolled. Ninety-seven patients were eligible for analysis. All patients gave informed consent. MAIN OUTCOME MEASURES: The development of HCMV disease. RESULTS: Of the 97 patients, 24 developed HCMV disease after a median follow-up of 10.6 months. Three months before the development of HCMV disease, an increase in the median number of pp65-antigen-positive leukocytes was observed. The highest combination of sensitivity (45%) and specificity (94%) for the development of HCMV disease within the next 3 months was found when an assay cut-off level of 48/10(5) pp65-antigen-positive leukocytes was applied, with a positive predictive value (PPV) for the development of HCMV disease of 75%. The Kaplan-Meier estimate of HCMV disease-free survival after patients reached 48/10(5) or more antigen-positive leukocytes on longitudinal follow-up was a median 3.7 months [95% confidence interval (CI), 2.5-8.5]. The hazard ratio (HR) of this threshold level for the development of HCMV disease was 9.6 (95% CI, 4.2-21.8). CONCLUSION: Longitudinal follow-up using the pp65-antigenemia assay of HIV-infected patients with a low CD4 lymphocyte count improves the identification of patients who will develop HCMV disease in the foreseeable future, and should be considered for the selection of patients who may benefit from pre-emptive HCMV treatment.

Adult↗
PubMed1999

Quantitative determination of efavirenz (DMP 266), a novel non-nucleoside reverse transcriptase inhibitor, in human plasma using isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection.

Efavirenz is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1-infected individuals. A simple and rapid high-performance liquid chromatographic method for the quantification of efavirenz in human plasma suitable for therapeutic drug monitoring in plasma is described. Sample pretreatment consists of protein precipitation with acetonitrile and subsequent evaporation of the extract to concentrate the analyte. The drug is separated from endogenous compounds by isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection at 246 nm. The method has been validated over the range of 10 to 10,000 ng/ml using a volume of 250 microl of plasma. The assay is linear over this concentration range as indicated by the F-test for lack of fit. Within- and between-day precisions are less than 4.3% for all quality control samples. The lower limit of quantitation is 10 ng/ml and the recovery of efavirenz from human plasma is 106.4% (+/- 1.8%). Frequently co-administered drugs did not interfere with the described methodology. Efavirenz is stable under various relevant storage conditions, for example when stored for 24 h at room temperature. This validated assay is suited for use in pharmacokinetic studies with efavirenz and can readily be implemented in the setting of a hospital laboratory for the monitoring of efavirenz concentrations.

Acetonitriles↗
PubMed1999

The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals.

OBJECTIVE: To explore the steady-state plasma pharmacokinetics of indinavir in twice daily dosing regimens with and without the co-administration of 100 mg ritonavir. DESIGN: Observational pharmacokinetic study. PATIENTS: HIV-1-infected individuals who use indinavir alone (1200 mg twice daily, n = 6), or the combination of 100 mg ritonavir twice daily plus either 800 mg (n = 6), or 1200 mg indinavir twice daily (n = 2). METHODS: Steady-state pharmacokinetics of indinavir and ritonavir were assessed by drawing 12 blood samples during an 8-h period after ingestion of the medication. RESULTS: Significant differences were observed for indinavir pharmacokinetics between the dosing regimens indinavir 1200 mg twice daily alone and indinavir/ ritonavir 800/100 mg twice daily with respect to the mean trough concentration (0.21 and 0.99 microg/ml, respectively, P = 0.002), the mean maximum concentration (13.79 and 8.74 microg/ml, respectively, P = 0.028), and for the mean plasma elimination half-life (1.6 and 3.2 h, respectively, P = 0.001). The combination indinavir/ritonavir 1200/100 mg twice daily led to very high exposure to indinavir and was not well tolerated. However, the combination indinavir/ritonavir 800/100 mg twice daily was well tolerated and resulted in therapeutic concentrations of indinavir with improved trough concentrations and similar maximum concentrations as observed with the licensed dosage of 800 mg three times daily. CONCLUSION: Combination of indinavir and 100 mg ritonavir in twice daily dosing regimens significantly affects the pharmacokinetic profile of indinavir. The results of this observational study provide a pharmacologic basis for the combination of indinavir (800 mg) and ritonavir (100 mg) in twice daily dosing regimens.

Adult↗
PubMed1999

Randomized trial comparing saquinavir soft gelatin capsules versus indinavir as part of triple therapy (CHEESE study).

OBJECTIVE: To compare efficacy and tolerability of saquinavir soft gelatin capsule (SQV-SGC) formulation and indinavir, both given as part of a triple drug regimen containing zidovudine and lamivudine, in HIV-1-infected individuals. DESIGN: Randomized, open label, multicentre study. PATIENTS: A total of 70 patients who were antiretroviral-naive and who had a CD4 cell count < 500 x 10(6)/I and/or > 10000 HIV RNA copies/ml plasma and/or HIV-related symptoms. Subjects were assigned randomly to zidovudine 200 mg three times per day plus lamivudine 150 mg twice per day plus either SQV-SGC 1200 mg three times per day (SQV-SGC group) or indinavir 800 mg three times per day (indinavir group). Data are presented for all patients up to week 24. RESULTS: Mean baseline CD4 cell counts (+/- SE) were 301+/-29 x 10(6) cells/l and 310 +/-43 x 10(6) cells/l in the SQV-SGC and indinavir groups, respectively. The log10 median baseline HIV RNA load was 5.00 copies/ml in the SQV-SGC group and 4.98 copies/ml in the indinavir group. No difference in antiretroviral effect between the treatment arms could be demonstrated. Intention-to-treat analysis (last observation carried forward [LOCF]) at week 24 revealed that RNA levels decreased to < 50 copies/ml in 74.3% of patients in the SQV-SGC group and in 71.4% of the patients in the indinavir group (P = 0.78). In the on-treatment analysis the proportion of patients < 50 copies/ml at week 24 was 88.0% in the SQV-SGC group and 84.6% in the indinavir group (P = 0.725). Intriguingly, the mean increase of CD4 cells in the first 24 weeks was 162+/-20 x 10(6) cells/l in the SQV-SGC group and 89+/-21 x 10(6) cells/l in the indinavir group (P = 0.01), but preliminary data indicate that this difference in CD4 cell count gain may disappear after 24 weeks of treatment. Both regimens were generally well tolerated. CONCLUSION: During the first 24 weeks of the study, we found no difference in antiviral potency between the indinavir group and the SQV-SGC group. A significantly higher CD4 response in the SQV-SGC group was observed.

Adult↗
PubMed1999

Rapid quantification of delavirdine, a novel non-nucleoside reverse transcriptase inhibitor, in human plasma using isocratic reversed-phase high-performance liquid chromatography with fluorescence detection.

Delavirdine is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1-infected patients. A simple and rapid high-performance liquid chromatographic method for the quantification of delavirdine in human plasma suitable for drug monitoring in patients is described. Sample pretreatment consists of protein precipitation with acetonitrile and subsequent evaporation of the extract to concentrate the analyte. The drug is separated from endogenous compounds by isocratic reversed-phase, high-performance liquid chromatography coupled with fluorescence detection. The optimal excitation and emission wavelengths are 300 and 425 nm, respectively. The method has been validated over the range of 50-50 000 ng/ml using only 200 microl of plasma samples. The assay is linear over this concentration range as indicated by the F-test for lack of fit. Within- and between-day precisions are less than 4.4% for all quality control samples. The lower limit of quanititation is 50 ng/ml. Recovery of delavirdine from human plasma is 93.8%. Delavirdine is stable under various conditions, for example 1 h at 60 degrees C and one week at 4 degrees C. This validated assay is suited for use in pharmacokinetic studies with delavirdine and can readily be implemented in the setting of a hospital laboratory for the monitoring of delavirdine concentrations.

Anti-HIV Agents↗
PubMed1999

Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients.

OBJECTIVE: Unusual clinical inflammatory syndromes associated with underlying previously unrecognized opportunistic infections are increasingly being noted shortly after starting highly active antiretroviral therapy (HAART). This study examined the possible relationship between such unexpected disease manifestations and in vitro parameters of microbial antigen-specific immune reactivity in patients infected with HIV-1 who had a Mycobacterium avium intracellulare or Mycobacterium xenopi infection. DESIGN: In vitro T-cell proliferation experiments were performed after specific stimulation of a patient's peripheral blood mononuclear cells (PBMC) with M. avium and M. xenopi antigen and non-specific stimulation with phytohaemagglutinin (PHA). The results were compared with appropriate controls. PATIENTS: Five patients who presented with unusual clinical syndromes associated with M. avium or M. xenopi infection within weeks of experiencing large rises in CD4+ cell counts following the initiation of antiretroviral therapy. RESULTS: In all patients except one, mycobacteria-specific lymphoproliferative responses rose significantly following HAART; this was temporally associated with elevations in CD4+ cell counts and the occurrence of clinical disease. The patient with M. xenopi infection appeared to clear his infection subsequently without antimycobacterial therapy. In three of the four patients with M. avium infection, antimycobacterial treatment could be stopped without recurrence of infection. CONCLUSION: Our findings support the hypothesis that HAART may lead to clinically relevant inflammation as a result of restoration of specific immune reactivity against microbial pathogens that are subclinically present at the time treatment is initiated. Continuation of HAART may subsequently result in protective immunity and clearance of infection.

AIDS-Related Opportunistic Infections↗
PubMed1999

Paclitaxel in the treatment of human immunodeficiency virus 1-associated Kaposi's sarcoma--drug-drug interactions with protease inhibitors and a nonnucleoside reverse transcriptase inhibitor: a case report study.

PURPOSE: To describe the pharmacokinetics of paclitaxel and to investigate the interaction potential with protease inhibitors (indinavir, ritonavir, saquinavir) and the nonnucleoside reverse transcriptase inhibitor nevirapine, for which strong theoretical indications for clinically relevant drug interactions exist. METHODS: The 24-h plasma pharmacokinetics of paclitaxel (Taxol, given at 100 mg/m2 by 3-h intravenous infusion) and concomitantly infused antiretroviral drugs were determined in a human immunodeficiency virus 1 (HIV-1)-infected male patient with refractory Kaposi's sarcoma (KS) during high-activity antiretroviral therapy and after discontinuation of this regimen. The plasma pharmacokinetics of paclitaxel, indinavir, ritonavir, saquinavir, and nevirapine were closely monitored. Since all these drugs are extensively metabolized via the cytochrome P450 enzyme system and are substrates for the multidrug transporter P-glycoprotein, investigation of drug-drug interactions was considered important. RESULTS: In this case report study the pharmacokinetics of paclitaxel given concomitantly with various antiretroviral drugs were comparable with those of historical controls who had been treated with single-agent paclitaxel. The pharmacokinetics of indinavir, ritonavir, saquinavir, and nevirapine were also not statistically significantly different from those recorded for historical controls. Paclitaxel was well tolerated and resulted in a significant clinical response in this patient. CONCLUSION: Dose adjustments of paclitaxel, indinavir, ritonavir, saquinavir, or nevirapine are apparently not needed if HIV-1-associated KS is treated with paclitaxel at a dose of 100 mg/m2 as shown in the present case. It is stressed, however, that controlled studies are necessary to substantiate these preliminary case report findings.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults.

Today's antiretroviral combination regimens can induce significant and sustained decreases in human immunodeficiency virus (HIV)-RNA levels, allowing the immune system to recover. To what extent immune reconstitution is possible and what factors determine the outcome have thus far not been resolved. We studied 19 subjects, treated for 2 years with protease inhibitor-containing triple therapy, who had a strong suppression of HIV-RNA levels. CD4+ T-cell numbers increased from medians of 170 to 420x106 cells/L, but in a number of subjects T-cell numbers did not further increase after week 72, without having reached normal values. Long-term CD4+ T-cell change was mainly caused by a slow but continuous increase in naive CD4+ T cells (CD45RA+CD62L+) and was predicted by the baseline number of these cells. Our data indicate that long-term immunological recovery is gradual, even during strong suppression of viral replication, not always complete, and dependent on the preexisting level of naive CD4+ T cells.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Monitoring of epstein-barr virus DNA load in peripheral blood by quantitative competitive PCR.

A competitive quantitative PCR (Q-PCR) assay combined with simple silica-based DNA extraction was developed for monitoring of Epstein-Barr virus (EBV) DNA load in unfractionated peripheral blood. The Q-PCR is based on competitive coamplification of a highly conserved 213-bp region of the EBNA-1 open reading frame with an internal standard (IS), added in a known concentration. The IS has the same amplicon length and base composition as the wild-type (WT) EBNA-1 amplicon but differs in 23 internally randomized bases. Competitive coamplification yields two PCR products that are quantified by enzyme immunoassay or by electrochemiluminescence detection, with probes specific for the 23 differing internal nucleotides. The Q-PCR has a sensitivity of 10 copies of either WT or IS plasmid DNA. The Q-PCR was validated by quantification of known amounts of plasmid containing the WT EBNA-1 target. Furthermore, we determined EBV genome copy numbers in different cell lines. For EBV quantification in clinical samples, DNA was isolated from lysed whole blood by silica-affinity purification. Forty-six percent of healthy donor peripheral blood samples were positive by Q-PCR. In most of these samples, viral load was less than 2,000 EBV copies/ml of blood. In peripheral blood samples from two AIDS-related non-Hodgkin's lymphoma patients, elevated EBV loads (up to 120,000 copies/ml) were observed, which decreased upon therapy. In Burkitt's lymphoma patients, up to 4,592,000 EBV genome copies/ml of blood were detected. In conclusion, the EBNA-1-based Q-PCR assay provides a reproducible, accurate, and easy method for studying the relationship between EBV load and clinical parameters.

Burkitt Lymphoma↗
PubMed1998

Comparison of the plasma pharmacokinetics and renal clearance of didanosine during once and twice daily dosing in HIV-1 infected individuals.

OBJECTIVE: To compare the plasma pharmacokinetics of didanosine during once daily (qd) and twice daily (bid) dosing. DESIGN: Open-label, randomized, cross-over study. METHODS: HIV-1 infected patients who used didanosine were randomized to either a qd or a bid dosing regimen of didanosine. The total daily dose of didanosine was identical in both regimens. Seven days after the start of the study, the pharmacokinetic profile of didanosine in plasma and urine was assessed during an 8-h period. The next day, the patient was switched to the opposite dosing regimen, and after another 7 days, the study was concluded by again assessing the plasma and urine pharmacokinetics of didanosine during 8 h. RESULTS: A total of 19 patients completed the study. The pharmacokinetics of didanosine in plasma (with maximum plasma concentration adjusted for dose) and urine were not significantly different in the qd and bid dosing regimen (P > 0.28 for all parameters). CONCLUSION: We conclude that qd dosing of didanosine leads to a similar exposure in plasma as bid dosing (using the same total daily dose). Since qd dosing may lead to improved compliance of patients to regimens containing didanosine, these results provide a rationale for prescribing didanosine in a qd regimen, and is reassuring when we realize that the drug is being administered in a qd dosing regimen on a large scale in clinical practice.

Adult↗
PubMed1998

Simultaneous quantitative determination of the HIV protease inhibitors amprenavir, indinavir, nelfinavir, ritonavir and saquinavir in human plasma by ion-pair high-performance liquid chromatography with ultraviolet detection.

A reversed-phase high-performance liquid chromatographic assay for the simultaneous quantitative determination of five HIV protease inhibitors (i.e. amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) in human plasma is described. Sample pretreatment consisted of solid-phase extraction prior to ion-pair, reversed-phase high-performance liquid chromatography with ultraviolet detection at 210 nm (amprenavir, indinavir and nelfinavir) and 239 nm (saquinavir and ritonavir). For amprenavir, indinavir and saquinavir the method has been validated over the range of 25 ng/ml to 25 microg/ml using a 0.6 ml sample volume. For nelfinavir and ritonavir the method has been validated over the range of 50 ng/ml to 25 microg/ml. The method proved to be accurate, with an average accuracy at four concentrations ranging from 90.6 to 109.2%, and precise, with the within-day and between-day precision ranging from 1.8 to 6.7%, and 0.7 to 7.6%, respectively. The protease inhibitors which can be quantified by using this assay proved to be stable under various conditions. This assay can readily be used in a hospital laboratory for the routine monitoring of plasma concentrations of these protease inhibitors.

Anti-HIV Agents↗
PubMed1998

Rapid determination of nevirapine in human plasma by ion-pair reversed-phase high-performance liquid chromatography with ultraviolet detection.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1-infected patients. A simple and rapid high-performance liquid chromatographic method for the quantification of nevirapine in human plasma is described. Sample pretreatment consists of protein precipitation with acetonitrile. The analyte is separated from endogenous compounds by isocratic reversed-phase, ion-pair, high-performance liquid chromatography with ultraviolet detection at 282 nm. The method has been validated over the range of 52-10400 ng/ml using 250 microl of plasma. The assay was linear over this concentration range. Within- and between-day precisions were less than 4.5% for all quality control samples. The lower limit of quantitation was 52 ng/ml. Recovery of nevirapine from human plasma was 94.5%. This validated assay is suited for use in pharmacokinetic studies with nevirapine and can readily be used in a hospital laboratory for the monitoring of nevirapine concentrations.

Anti-HIV Agents↗
PubMed1998

High-performance liquid chromatographic determination of ritonavir in human plasma, cerebrospinal fluid and saliva.

A simple, ion-pair high-performance liquid chromatographic method has been developed and validated for the quantitative determination of the HIV protease inhibitor ritonavir in human plasma, cerebrospinal fluid and saliva. Sample pretreatment consisted of precipitation of proteins with acetonitrile prior to high-performance liquid chromatography with ultraviolet detection at 239 nm. The method has been validated over the range of 50 ng/ml to 50 microg/ml with use of 100-microl volumes of sample. The currently described assay has been used successfully for the analysis of ritonavir in plasma, cerebrospinal fluid and saliva in HIV-1 infected patients.

Acquired Immunodeficiency Syndrome↗