Influence of Local Properties on the Perception of Global Object Orientation.

In previous studies, the effect on perception of individual features such as curvature and edges have been studied with specifically designed stimuli. However, the effect of local properties on the perception of the global object has so far received little attention. In this study, cylinders with an elliptical cross section and rectangular blocks were used to investigate the effect and relative importance of curvature, change in curvature and edges, as local properties, on the ability of subjects to determine the orientation of the stimuli, which is a global property. We found that when curvature was present the threshold to determine the orientation was 43 percent lower than when curvature was absent. When, in addition, the change in curvature could be felt, the threshold was 37 percent lower than when only curvature could be felt. Finally, when edges were felt during exploration, the threshold increased by 46 percent compared to when the subjects were instructed to avoid the edges in the blocks. We conclude that the perception of curvature and change in curvature improve the performance of humans in perception of the whole shape, whereas edges, when not directly contributing to the task, disrupt performance.

PRK vs LASEK vs Epi-LASIK: a comparison of corneal haze, postoperative pain and visual recovery in moderate to high myopia.

INTRODUCTION: The field of refractive surgery continues to evolve amid continued concerns as to which surgical technique minimizes the risk of inducing ectasia. PURPOSE: To compare clinical outcomes between PRK, LASEK and Epi-LASIK in moderately to highly myopic eyes (-4.00 D to -8.00 D). MATERIALS AND METHODS: A retrospective chart review of 100 PRK eyes, 100 LASEK eyes (with alcohol) and 97 Epi-LASIK eyes was performed. Post-operative pain, uncorrected visual acuity, and corneal haze data was recorded and analyzed at post-op days 1, 4 and 7 and at post-op months 1, 3, 6 and 12. RESULTS: In all groups surgical corrections ranged from -4.00 D to -8.00 D. There was less pain associated with the epi-LASIK procedure especially early (post-op days 1 and 4). Visual recovery was superior within the PRK group during the first post-operative week but by post-op week 4 all three were equal. Haze scores were similar but a trend for less haze was demonstrated with epi-LASIK at 6 and 12 months. CONCLUSION: Epi-LASIK has a slight advantage over PRK and LASEK early on in the post-op course with regards to pain. Visual recovery is similar by 4 weeks and is better with PRK early. In addition, epi-LASIK trends toward less significant haze.

Pharmacologic study of paclitaxel administered with or without the cytoprotective agent amifostine, and given as a single agent or in combination with epirubicin and cisplatin in patients with advanced solid tumors.

The main purpose of this study was to investigate whether the coadministration of amifostine alters the pharmacokinetic behavior of paclitaxel. Eight patients were included in the study: six received paclitaxel in combination with epirubicin and cisplatin, and two received paclitaxel as a single agent. Doses of paclitaxel in these protocols were 135, 150, 175, and 200 mg/m(2) and two patients were treated at each dose level. Pharmacokinetic sampling for paclitaxel analysis was performed in each patient during two consecutive cycles, one with and one without amifostine (750 mg/m(2) as a 15-minute intravenous infusion 30 minutes before paclitaxel administration). At each dose level, the pharmacokinetic data of paclitaxel were compared per patient for a cycle without amifostine versus a cycle with amifostine. Amifostine did not seem to interact pharmacokinetically with paclitaxel, given either alone or in combination chemotherapy. This is in line with the clinical findings that amifostine has no negative effects on the antitumor activity of various antineoplastic agents. Also, amifostine may reduce toxic effects of combination chemotherapy regimens that include paclitaxel.

Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients.

The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (CI=37.8-134 ml/h/m2; t 1/2=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (Vss=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.

A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel.

PURPOSE: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. METHODS: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. RESULTS: The following single-point model was selected as optimal: AUC carboplatin (min mg(-1) ml(-1)) = 418. c(2.5 h)(mg/ml) + 0.43 (min mg(-1) ml(-1)), where c(2.5 h) is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 +/- 1.6%) and precise (root mean square error = 10.1 +/- 1.5%). CONCLUSIONS: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualize treatment.

Metal chelators/antioxidants: approaches to protect erythrocytic oxidative stress injury during Plasmodium berghei infection in Mastomys coucha.

Desferal, N-acetyl penicillamine (metal chelators) and propylgallate, catechin, and reduced glutathione (antioxidants) suppressed the erythrocytic oxidative damage generated during Plasmodium berghei infection in Mastomys coucha. Superoxide anion and lipid peroxide levels were increased and on the contrary, superoxide dismutase activity was noticeably decreased in the infected erythrocytes. Metal chelators/antioxidant treatment to infected animals resulted in restoration of O(2)(-), LPO and SOD to near normal levels. Furthermore, treatment of the above mentioned agents displayed a controlled mortality/survival time and parasitaemia. In conclusion, metal chelators/antioxidants were found to be effective against oxidative stress injury and parasite growth resulting in prolonged survival time of the host during experimental malaria.

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients.

The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175-3 h = 42.8+/-24.9 ml h(-1) m(-2); CI175-24 h = 79.7+/-24.3; P = 0.035 and Cl135-3 h = 44.1+/-21.8 ml h(-1) m(-1); Cl140-96 h = 211.8+/-32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics-pharmacodynamics relationships.

Pharmacokinetics of paclitaxel administered in combination with cisplatin, etoposide and bleomycin in patients with advanced solid tumours.

PURPOSE: To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours. METHODS: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m(2)) were administered in combination with etoposide 100 or 120 mg/m(2), and fixed dose of cisplatin 20 mg/m(2) and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II-V. RESULTS: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m(2) dose level (II) was 7.0 +/- 3.6 h micromol(-1) l(-1), for the 175-mg/m(2) dose level (III) 10.6 +/- 2. 8 h micromol(-1) l(-1), for the 200-mg/m(2) dose level (IV) it was 16.0 +/- 5.0 h micromol(-1) l(-1), and for the 175-mg/m(2) dose level (V) it was 12.5 +/- 6.1 h micromol(-1) l(-1). The mean peak plasma concentration (C(max)) values for dose levels II-V were 1.9 +/- 1.1 micromol/l, 3.4 +/- 1.2 micromol/l, 4.3 +/- 1.0 micromol/l and 3.8 +/- 1.2 h micromol/l, respectively. CONCLUSION: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C(max) and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-micromol/l threshold concentration (t > 0.1 microM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded.

Pharmacokinetics of paclitaxel administered as a 3-hour or 96-hour infusion.

AIM: To investigate the pharmacokinetics of paclitaxel (Paxene) administered to patients with advanced breast or ovarian cancer and to document safety and anti-tumour activity in this study population. PATIENTS AND METHODS: Patients with advanced breast or ovarian cancer were accrued to two clinical studies. Paclitaxel (Paxene) was administered as a 3-h 175 mg m-2 or as a 96-h 140 mg m-2(105 mg m-2 in the presence of liver metastases) infusion. Patients not responding to the 3-h schedule were permitted to cross-over to the 96-h schedule. The data were compared to those of five patients who were previously treated with paclitaxel administered as Taxol (140 mg m-296-h infusion) at our Institute. RESULTS: Fourteen patients with breast cancer and five ovarian cancer patients were entered into this study. Seven patients received the 3-h regimen, and 12 were assigned to the 96-h schedule. Five patients originally treated with the 3-h schedule, crossed over to the 96-h arm. For the 3-h 175 mg m-2 dose, the area under the plasma concentration vs time curve (AUC) was (mean+/-SD) 16.9+/-4.8 h x micromol x l-1, whereas the AUCs were 5.5+/-1.2 and 4.3+/-0.9 h x micromol x l-1 for the 96-h 140 mg m-2 and 105 mg m-2 doses, respectively. The clearance of paclitaxel was independent of the dose in the 96-h group, indicating linear pharmacokinetics. Pharmacokinetics of Paxene (96-h 140 mg m-2) were not significantly different from the kinetics after Taxol (96-h 140 mg m-2) administration.

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.

A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen.

PURPOSE: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. METHODS: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model). in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin-thiotepa-cyclophosphamide combination). RESULTS: The measured mean AUC in our population was 4.1 min x mg/ml (median 3.9, range 1.9 6.3, SD 1.0 min x mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min x mg/ml (median 4.2, range 2.4-8.4, SD 1.2 min x mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. CONCLUSION: Although easy and attractive to use, the Ghazal-Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations.

Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer.

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 microg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Phase I and pharmacologic study of weekly doxorubicin and 1 h infusional paclitaxel in patients with advanced breast cancer.

Doxorubicin and paclitaxel both display strong antitumor activity in the treatment of breast cancer. The optimal schedule of this combination, however, remains undefined. In this phase I and pharmacologic study, we administered weekly 12 mg/m2 doxorubicin as a bolus infusion immediately followed by a 1 h 80 mg/m2 paclitaxel infusion to patients with metastatic breast cancer. A total of 119 weekly courses were delivered to seven patients. Grade IV neutropenia was observed in two patients at the first dose level, thus already defining the maximum tolerated dose. Pronounced non-hematologic toxicities were mild neuropathy (grade I: 39%) and stomatitis (grade I: 19%, grade II: 8%). No signs of cardiac toxicity were observed with this dose schedule. Three partial responses were achieved in this group of heavily pretreated patients. The pharmacokinetics of paclitaxel, doxorubicin and Cremophor EL with this schedule were analyzed. Overall, the schedule was well tolerated and combined with its preliminary response rate justifies further evaluation in phase II studies.

Pharmacologic study of 3-hour 135 mg M-2 paclitaxel in platinum pretreated patients with advanced ovarian cancer.

Paclitaxel (Taxol(R)) is an active agent in platinum-refractory ovarian cancer. Since the available pharmacokinetic data of 135 mg m-2 paclitaxel administered by 3-h infusion are scarce and fragmented, we now describe a comprehensive pharmacologic study in a group of 13 patients who were pretreated with platinum for advanced ovarian cancer. The mean paclitaxel AUC was 10.3+/-2.4 h micromol l-1 (range 6.8-13.9 h micromol l-1). Quantification of the two major paclitaxel metabolites, 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel yielded AUCs of 0.44+/-0.30 h micromol l-1 and 0.31+/-0.20 h micromol l-1, respectively. The AUC of 3'-p-hydroxypaclitaxel was significantly different from that of patients with an altered hepatic function. The administration of 135 mg m-2 single-paclitaxel was safe, and the toxicities observed at higher doses in earlier studies were absent in this study. This is important, because the schedule and paclitaxel dose of 135 mg m-2 given by a 3-h infusion is expected to be used more frequently in combination with other cytotoxic agents with the aim of improving efficacy.

Carboplatin dosage formulae can generate inaccurate predictions of Carboplatin exposure in carboplatin/paclitaxel combination regimens.

Carboplatin is a frequently used antitumour agent recommended to be administered according to the Calvert formula: dose = AUC x (GFR+25), where GFR is the glomerular filtration rate as measured by (51)Cr-EDTA clearance and AUC is the targeted area under the carboplatin concentration versus time curve. In several modified Calvert formulae, the GFR is estimated on the basis of serum creatinine levels. We compared AUCs of carboplatin that were predicted by modified Calvert formulae with actual measured AUCs in 75 courses in patients with non-small cell lung cancer or ovarian cancer who were treated with the combination of carboplatin-paclitaxel. Predictions were made using two modified Calvert formulae, in which the GFR was calculated by serum creatinine level-based equations, according to Jelliffe (Eq. 1) and Cockroft-Gault (Eq. 2). We also studied the performance of a formula for the clearance of carboplatin, as proposed by Chatelut (Eq. 3). The actual measured mean AUC was 4.6 mg/ml.min (range 1.9 to 10.4 mg/ml.min, SD 1.7). Equation 1 overestimated the AUC by 32.9% with an imprecision of 43.0%, and equation 2 overestimated the AUC by 27.6% with an imprecision of 33.4%. For equation 3, an AUC overestimation of only 10.2%, but with an imprecision of 25.3%, was observed. In conclusion, all three equations overestimated the carboplatin AUCs and had poor precisions. We concluded that the real carboplatin AUCs were lower than calculated, using the three tested formulae. This may have important consequences for ongoing and future phase II and III studies with carboplatin-paclitaxel combinations, utilising these formulae to calculate the carboplatin dose. Thus far, the original Calvert dosage formula remains the 'golden standard'.

Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been demonstrated to be an active anticancer agent, including in platinum-refractory ovarian cancer. The pharmacokinetics of paclitaxel have been extensively described. It displays nonlinear pharmacokinetics in humans, especially when administered in shorter infusion times and at higher doses. Several relationships have been established between pharmacokinetics and pharmacodynamics. In both animal and human studies, hepatic metabolism and biliary excretion have been identified as the main elimination pathways of paclitaxel. It thus can be expected that hepatic dysfunction will have a major impact on the pharmacokinetics of paclitaxel and its main metabolite 6alpha-hydroxypaclitaxel and, thus, on pharmacodynamic outcome (toxicities and responses). Because patients with an altered hepatic function were excluded from most phase I and II studies conducted thus far, little is known about the pharmacokinetics and pharmacodynamics in this group of patients. This report summarizes paclitaxel's metabolism and clinical observations concerning its pharmacokinetics and pharmacodynamics in patients with altered hepatic function. It has been shown that hepatic impairment has a great influence on the systemic exposure of paclitaxel and metabolites with pharmacodynamic consequences. A decrease of biliary elimination is probably the major mechanistic effect that influences paclitaxel metabolism and elimination. Specific dosing guidelines in the treatment of patients with altered hepatic function are required.

Evidence for selection of virulent sub-populations of Entamoeba histolytica by cholesterol.

Quantitatively much higher Concanavalin A (Con. A) agglutinability, haemolytic potency, and activities of acid hydrolases, namely phosphatase (EC 3.1.3.2), ribonuclease (EC 2.7.7.16), deoxyribonuclease (EC 3.1.4.5) and proteinase--were observed in a virulent strain of Entamoeba histolytica (IP-106), as compared to attenuated and avirulent strains (200-NIH) and DKB respectively. In addition, significant differences in these parameters were observed among clonal cultures derived from the latter two cultures by cultivation of single amoebic cells picked out by micromanipulation. Repeated sub-culturing of parent cultures of both these strains in cholesterol-enriched medium resulted in marked enhancement of all the above activities, but no such change occurred in the derived clonal cultures following similar cholesterol treatment. The implication of these findings in relation to enhancement of the virulence of E. histolytica by cholesterol is discussed.

A geochemical basis for endomyocardial fibrosis.

In a search for geochemical factors that could play a role in the pathogenesis of tropical endomyocardial fibrosis, endomyocardial tissue samples obtained from patients at necropsy or operation were analysed for major elements present in laterite and monazite, which are important soil constituents of Kerala State of India. Atomic absorption spectrophotometry was used for detecting iron, silicon, aluminium, zinc, magnesium, calcium, sodium, potassium, and manganese and neutron activation analysis for thorium. Compared with control samples from victims of fatal accidents, an excess of thorium, sodium, and calcium and a deficiency of magnesium were present in samples from patients. It has been shown earlier that the staple diets of people in Kerala have high concentrations of thorium, and these data show that thorium can become concentrated in cardiac tissues. It is speculated that thorium excess in conjunction with magnesium deficiency may play a role in the causation of tropical endomyocardial fibrosis.