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At least 1,117 records · Page 62Linked to original sources
PubMed1991

Two phase I studies of carboplatin dose escalation in chemotherapy-naive ovarian cancer patients supported with granulocyte-macrophage colony-stimulating factor.

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) may reduce myelosuppression and, thus, allow dose escalation of certain chemotherapeutic agents. We conducted two sequential phase I trials of escalating doses of carboplatin and a fixed dose and schedule of rHuGM-CSF in ovarian cancer patients who had not previously had chemotherapy, i.e., chemotherapy-naive patients. In the first trial, patients were assigned to regimens of increasing dose levels of carboplatin (starting at 400 mg/m2) and fixed doses and schedules of cyclophosphamide (600 mg/m2) and rHuGM-CSF (10 micrograms/kg given subcutaneously once daily on days 2-11). Chemotherapy was given every 3 weeks (regimen A). In the subsequent trial, the design was the same except that cyclophosphamide was omitted (regimen B). Fifteen patients received regimen A, and seven patients received regimen B. In regimen A, all three patients treated at the first dose level tolerated five cycles at full doses. Hematologic toxicity was dose limiting at the 600-mg/m2 dose level. When 500 mg/m2 carboplatin was given, six of eight patients tolerated three or four cycles at full doses before requiring dose reductions or treatment delays. In regimen B, doses could not be escalated above the first dose level (600 mg/m2) because of severe hematological toxicity. Nonhematological toxicity was tolerable and managed with acetaminophen, antihistamines, and/or nonsteroidal, anti-inflammatory medication. Compliance was excellent. We conclude that (a) rHuGM-CSF can be given safely and reliably to chemotherapy-naive ovarian cancer patients receiving these treatment regimens, (b) early and severe thrombocytopenia was a major problem with or without cyclophosphamide with doses of carboplatin at or above 600 mg/m2, and (c) 500 mg/m2 carboplatin administered every 3 weeks is the highest dose in regimen A that can be given safely in the outpatient setting.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Assessment of the aversion coefficient in nuclear safety in Hungary.

The key elements of the optimization practice as applied to radiation protection are the monetary value of the averted person-sievert and the aversion coefficient. Determination of the monetary value of the unit averted person-sievert (as alpha(base)-parameter) in Hungary was presented in a previous paper. The estimation of this parameter was carried out by the willingness-to-pay (WTP) method associated with averted occupational exposure (at the NPP Paks/Hungary). The aversion coefficient predicts the importance of dose reduction based on the magnitude of the dose. The assessment of the aversion coefficient occurred also by means of the WTP method in the spring of 2000. Its value has been estimated on the basis of individual preferences concerning the distribution of individual exposure in nuclear safety. The results achieved by the WTP among the radiation specialists from the NPP Paks, Hungary, assessed a value for the aversion coefficient of 1.86 over the whole range of individual exposure levels. This value is a bit greater than the value obtained in France (1.7) and the higher coefficient expresses a higher priority to reduce the highest individual exposures.

Humans↗
PubMed1995

Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer.

BACKGROUND: Combination chemotherapy for metastatic breast cancer will palliate symptoms in the majority of patients but only a small percentage will have prolonged survival. Higher doses of doxorubicin lead to increased response rates in breast cancer and early studies have shown that epirubicin could be tolerated in higher doses with less relative toxicity than doxorubicin. AIMS: This study was initiated to assess the dose of epirubicin that could be tolerated by escalating its dose while maintaining a fixed dose of cyclophosphamide. Simultaneously tumour response rate, spectrum of toxicities, duration of response and overall survival in patients with metastatic breast cancer were assessed. METHODS: Patients with metastatic breast cancer commenced chemotherapy with a starting dose of epirubicin of 120 milligram per metre squared (mg/m2) and cyclophosphamide 600 mg/m2. The dose of epirubicin was to be escalated or reduced depending on toxicity. RESULTS: Forty female patients were entered into this study and three patients withdrew because of toxicity. Overall tumour response rate was 75% with 27.5% of patients obtaining a complete response. Median time to progressive disease was 35 weeks and median overall survival was 48 weeks, with median survival for complete responders being 103 weeks. Thirty-one (77%) patients completed five or more courses of treatment. Haematological toxicity was the main side effect and 70% of patients required a dose reduction. No patients were eligible for a dose escalation. One patient died as a consequence of neutropenic sepsis. Four (10%) patients had treatment ceased because of decrease in left ventricular ejection fraction and one patient died as a consequence of heart failure. Four patients remain alive. CONCLUSIONS: High dose epirubicin combined with cyclophosphamide is an effective treatment regimen for metastatic breast cancer obtaining higher overall response rates with increased percentage complete responses compared to conventional dose chemotherapy. Although toxicity was increased, high dose chemotherapy was well tolerated and mortality associated with treatment was not increased. No dose escalations of epirubicin were possible and a dose of 90 mg/m2 of epirubicin would be the maximum dose when used in combination with cyclophosphamide. Further trials are required to determine the influence of this high dose therapy on survival duration and whether comparable benefits can be achieved with shorter durations of therapy.

Adenocarcinoma↗
PubMed1981

Trigeminal neuralgia: time course of pain in relation to carbamazepine dosing.

Eight in-patients with idiopathic trigeminal neuralgia (TN) were studied while receiving carbamazepine (CBZ) treatment. The aim was to study diurnal pain distribution, its relation to CBZ dosing and plasma concentration and the effect of decreasing the dose. All pain attacks were registered by the patients at three-hour intervals. CBZ was given b.i.d. in a single blind manner with the patient unaware of dose and dose changes. Plasma concentrations of CBZ were followed every fourth hour during a period of altogether sixteen dosage intervals. The diurnal pain distribution revealed marked intra-individual similarities with pain-free nights and a significant drop in pain during mid-day hours. The latter coincided in time with the peak plasma concentration of CBZ, thus indicating an effect of plasma concentration fluctuations on pain relief. Shorter dosage intervals might therefore be beneficial in problem cases. A significant increase in pain was detected within six to nine hours after a dose reduction, whereas the full effect of the dose change seemed to be established only after one day.

Aged↗
PubMed1995

Panoramic and restrictive intraoral radiography in comprehensive oral radiographic diagnosis.

It has been suggested that information from the panoramic radiograph makes it possible to appropriately select supplementary intraoral radiographs to achieve a comprehensive examination of teeth and surrounding bone with less patient dose but no significant information loss. Number of intraoral radiographs selected, information loss and monetary costs with such a procedure was evaluated in 40 patients. Results show that, on average, 5.1 intraoral radiographs were selected to supplement the panoramic radiograph. Of these, 3.1 contained information different from that in the panoramic radiograph but 2.0 did not. An additional 3.4 ought to have been taken to reach the result of the 'gold standard' achieved from a simultaneous evaluation by two expert observers of panoramic radiographs and full mouth surveys with intraoral radiographs. Sensitivity for the combined use of panoramic and supplementary intraoral radiographs was high (80-96%, depending on type of teeth) as regards periapical lesions and marginal bone loss but low for caries (42-96%). Specificity was high for periapical lesions and caries (95-97%) but low for marginal bone loss (50-92%). In Sweden, patient costs become almost the same for a combination of panoramic radiography and 8.5 intraoral radiographs as for a full mouth survey comprising 20 intraoral radiographs. The radiation dose reduction is 40-50% considering that the dose from a panoramic radiograph approximately corresponds to 2-4 intraoral radiographs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2001

Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults.

Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.

Adenine↗
PubMed1994

Targeted pharmacotherapy in depression management: comparative pharmacokinetics of fluoxetine, paroxetine and sertraline.

In contrast to tricyclic antidepressants (TCAs), the selective serotonin reuptake inhibitors (SSRIs) have a high affinity for the serotonin uptake site with little or no affinity for alpha-adrenergic, cholinergic or histaminic receptors. SSRIs, again in contrast to TCAs, do not slow intracardiac conduction. These differences between TCAs and SSRIs are important in terms of both discomforting and more serious adverse effects. Despite their more focused effects, the SSRIs are as effective as TCAs in treating major depression. The SSRIs have similar properties in terms of their pharmacodynamics, but important differences in terms of pharmacokinetics and their effects on hepatic function. Sertraline, and the starting dose of paroxetine have an elimination half-life (t1/2) of approximately 24 h. However, the half-life of paroxetine, but not of sertraline, becomes longer at higher doses due to paroxetine's inhibition of its own clearance. At t1/2 of 24 h makes once-daily dosing feasible and allows for new steady-state concentrations and wash-out within a reasonable time after dose adjustment. Fluoxetine has a t1/2 of 2-4 days and has an active metabolite with a t1/2 of 7-15 days. Such a half-life makes dose titration more difficult, and can result in prolonged effects even after dose reduction or drug discontinuation. Sertraline has dose-proportional changes in plasma concentrations, in contrast to fluoxetine and paroxetine. Thus, dose increases with fluoxetine and paroxetine produce greater than expected changes in plasma drug concentration, and hence, in concentration-dependent effects.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Naphthylamine↗
PubMedDate not supplied

AAPM/RSNA Physics Tutorial for Residents: Topics in CT. Radiation dose in CT.

This article describes basic radiation dose concepts as well as those specifically developed to describe the radiation dose from computed tomography (CT). Basic concepts of radiation dose are reviewed, including exposure, absorbed dose, and effective dose. Radiation dose from CT demonstrates variations within the scan plane and along the z axis because of its unique geometry and usage. Several CT-specific dose descriptors have been developed: the Multiple Scan Average Dose descriptor, the Computed Tomography Dose Index (CTDI) and its variations (CTDI(100), CTDI(w), CTDI(vol)), and the dose-length product. Factors that affect radiation dose from CT include the beam energy, tube current-time product, pitch, collimation, patient size, and dose reduction options. Methods of reducing the radiation dose to a patient from CT include reducing the milliampere-seconds value, increasing the pitch, varying the milliampere-seconds value according to patient size, and reducing the beam energy. The effective dose from CT can be estimated by using Monte Carlo methods to simulate CT of a mathematical patient model, by estimating the energy imparted to the body region being scanned, or by using conversion factors for general anatomic regions. Issues related to radiation dose from CT are being addressed by the Society for Pediatric Radiology, the American Association of Physicists in Medicine, the American College of Radiology, and the Center for Devices and Radiological Health of the Food and Drug Administration.

Humans↗
PubMed1996

Controlled trial with chloroquine diphosphate in systemic lupus erythematosus.

INTRODUCTION: Antimalarials have been recognized as effective drugs for the treatment of articular and cutaneous manifestations of systemic lupus erythematosus (SLE), but its potential in the management of systemic features of the disease has not yet been thoroughly evaluated. OBJECTIVES: This study intended to evaluate the efficacy of chloroquine diphosphate (CDP) in preventing flares and in reducing the maintenance corticosteroid dose in patients with SLE without life-threatening manifestations. MATERIALS AND METHODS: Twenty-four SLE patients with no life-threatening manifestation were enrolled in a 12-month double blind placebo-controlled trial with CDP (250 mg/day). Patients were subjected each month to clinical examination by a rheumatologist and to SLE-relevant laboratory tests. At each visit, prednisone dose could be adjusted according to the clinical status. Ophthalmologic examination was performed every six months. Outcome measures included SLEDAI score and the required prednisone dose. SLE flare was defined as an increase in SLEDAI score of at least three points. Prednisone dose reduction was defined as a minimum 50% dose decrease with no concomitant disease flare. RESULTS: Twenty-three patients completed the study. One patient in the placebo (PL) group dropped out due to severe dyspepsia. No major side-effect was observed in the remaining patients. PL and CDP groups showed no significant difference at the beginning of the study with regard to sex, age, ethnic classification, disease duration, SLEDAI and prednisone dose. Along the trial the prednisone dose became progressively lower in CDP group as compared to PL group and the difference reached statistical significance at 4, 6 and 12 months. SLEDAI score was higher in PL group in all evaluations, being the difference statistically significant at 4 months. Flare-up episodes were registered in two patients in CDP group and in ten patients in PL group. The estimated reactivation risk was 4.6 times greater in PL group as compared to CDP group. CONCLUSIONS: CDP at a 250 mg/day dose was able to prevent disease exacerbation, reduce the required prednisone dose, and help inducing a better control of patients with non life-threatening SLE. These data suggest that antimalarials might have a broader indication in the treatment of SLE other than solely the management of skin and articular manifestations.

Adult↗
PubMed2002

The influence of applicator angle on dosimetry in vaginal vault brachytherapy.

In vaginal vault brachytherapy, the critical normal tissues are bladder and rectum; doses to these tissues may be affected by the position of a single line applicator placed in the vagina. Dosimetry with the applicator lying at its "natural" angle in the vagina with the patient in the lithotomy position has been compared with the applicator held horizontal as defined by a spirit level in 30 consecutive patients. A mean change in angle of 19.7 degrees was found. This resulted in a mean decrease in ICRU (International Commission of Radiation Units and Measurements) rectal point dose when the applicator is horizontal of 12.9%, equivalent to a mean absolute dose reduction of 1.3 Gy for a prescription dose of 5.5 Gy at 5 mm depth. An increase in mean dose to the ICRU bladder point when the applicator is horizontal of 13.3%, equivalent to an absolute mean dose increase of 0.5 Gy per fraction for the same prescription dose, was also found. On the basis of these findings, it is recommended that vaginal vault brachytherapy is performed with a single line source held in the "corrected" horizontal position to reduce bowel dose as this is the most sensitive critical normal tissue.

Brachytherapy↗
PubMed1995

Cocaine's effects on food-reinforced pecking in pigeons depend on food-deprivation level.

Four pigeons deprived to 80% of their laboratory free-feeding weights pecked keys under a multiple fixed-ratio 30 fixed-interval 5-min schedule of food presentation. Components alternated strictly with 15-s timeouts separating them; each was presented six times. When rates of pecking were stable, 2 pigeons' weights were reduced to 70%, and the other 2 pigeons' weights were increased to 82.5% to 85% of free-feeding levels. Cocaine (1.0, 3.0, 5.6, and 10.0 mg/kg and saline) was administered 5 min prior to sessions. When each dose had been tested twice, pigeons' weights were adjusted to the level that they had not yet experienced, and cocaine was tested again. Cocaine reduced response rates in a dose-dependent manner under the fixed-ratio schedule and under the fixed-interval schedule at high doses, and increased rates under the fixed-interval schedule at low low doses. Reductions in pecking rates occurred at lower doses under both schedules in 3 of 4 pigeons when they were less food deprived compared to when they were more food deprived. Low doses of cocaine increased low baseline rates of pecking in the initial portions of the fixed-interval schedules by a greater magnitude when pigeons were more food deprived. Thus, food-deprivation levels altered both the rate-decreasing and rate-increasing effects of cocaine. The implications of these results for the mechanisms by which food deprivation increases cocaine self-administration and for the dependence of cocaine's effects on the baseline strength of operant behavior are discussed.

Animals↗
PubMed2005

Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: a review of the evidence.

The prophylactic use of myeloid growth factors reduces the risk of chemotherapy-induced neutropenia and its complications, including febrile neutropenia and infection-related mortality. Perhaps most importantly, the prophylactic use of colony-stimulating factors (CSFs) has been shown to reduce the need for chemotherapy dose reductions and delays that may limit chemotherapy dose intensity, thereby increasing the potential for prolonged disease-free and overall survival in the curative setting. National surveys have shown that the majority of patients with potentially curable breast cancer or non-Hodgkin's lymphoma (NHL) do not receive prophylactic CSF support. In this issue, the National Comprehensive Cancer Network presents guidelines for the use of myeloid growth factors in patients with cancer. These guidelines recommend a balanced clinical evaluation of the potential benefits and harms associated with chemotherapy to define the treatment intention, followed by a careful assessment of the individual patient's risk for febrile neutropenia and its complications. The decision to use prophylactic CSFs is then based on the patient's risk and potential benefit from such treatment. The routine prophylactic use of CSFs in patients receiving systemic chemotherapy is recommended in patients at high risk (>20%) of developing febrile neutropenia or related complications that may compromise treatment. Where compelling clinical indications are absent, the potential for CSF prophylaxis to reduce or offset costs by preventing hospitalization for FN should be considered. The clinical, economic, and quality of life data in support of these recommendations are reviewed, and important areas of ongoing research are highlighted.

Antineoplastic Agents↗
PubMedDate not supplied

Acute hematologic feasibility of G-CSF supported dose-escalated FEC therapy as adjuvant treatment after breast cancer surgery.

A study of the feasibility of gradually increased epirubicin and cyclophosphamide dosage in an FEC regimen with G-CSF (granulocyte colony stimulating factor) support in 18 high-risk breast cancer patients as adjuvant treatment was carried out. The FEC regimen was initiated with 5-fluorouracil 600 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 900 mg/m2 together with G-CSF 5 micrograms/kg subcutaneously on days 2-15 q 3 weeks for nine cycles, increasing individually through four dose levels to a maximum of 5-FU 600 mg/m2 (not escalated), epirubicin 120 mg/m2 and cyclophosphamide 1800 mg/m2. Transient cytopenias were regularly observed without major clinical complications. Rapid recovery and a biphasic overshoot of granulocytes required individualization of G-CSF support. During the 6-month treatment period, a general decline in granulocytes, platelets and haemoglobin was observed, resulting in maximal dose intensity in the middle of the treatment period. Compared to a conventional FEC regimen (5-Fluorouracil 600 mg/m2, Epirubicin 60 mg/m2, Cyclophosphamide 600 mg/m2 q 3 w) without dose reductions, it was feasible to increase the dose of epirubicin by more than 50 per cent with an increased dose intensity between 25 and 70 per cent. The dose of cyclophosphamide was increased by more than 100 per cent. All patients suffered from complete alopecia and moderate nausea, but there was no acute cardiac or severe mucosal toxicity. It was concluded that intensified, G-CSF supported FEC therapy can be safely administered in an outpatient setting, provided the patients are thoroughly informed and adequately monitored. High-risk patients are enrolled in a study comparing the described regimen and a myeloablative regimen including peripheral stem-cell support. Breast cancer seems to respond to chemotherapy in a dose dependent manner, suggesting the use of dose intensified regimens (1,8,9,11). This approach is currently under investigation in studies comparing standard regimens with myelo-ablative regimens in high-risk primary breast cancer (3,10). In a Scandinavian multicenter study (2), two high dose regimens, G-CSF supported dose-escalated FEC and myeloablative cyclophosphamide-thiotepacarboplatin with peripheral stem cell support, are compared as adjuvant therapy in operable high-risk breast cancer. This phase I study was performed to assess the feasibility and achievable dose intensity of an individually dose-escalated FEC regimen not in previous use.

Adult↗
PubMed2000

Phase I trial of all-trans retinoic acid in patients with treated head and neck squamous carcinoma.

Although retinoids show promise for prevention of second primary upper aerodigestive tract tumors, the optimum retinoid, dose, and schedule are unknown. All-trans retinoic acid (ATRA) has greater affinity for retinoic acid receptors and may be more active than other retinoids but has a shorter plasma half life and may up-regulate its own metabolism. We defined the maximum long-term tolerable dose, dosing frequency, pharmacokinetics, and toxicity of ATRA in patients with treated squamous cell carcinoma of the head and neck (SCCHN). Twenty-one patients were randomized to 45, 90, or 150 mg/m2 ATRA either once daily, or as divided doses every 8 h, for 1 year. Pharmacokinetics were assessed periodically. Fourteen men and seven women with previous SCCHN of initial stage I-IV were treated. Grade > or =3 toxicities (reversible) included headache and hypertriglyceridemia in 5 and 6 patients each, mucositis in 2 patients, and hyperbilirubinemia, elevated alkaline phosphatase, colitis, lipasemia, xerostomia, eczema, and arthritis in 1 patient each. The 150-mg/m2 dose was not tolerable. Doses were reduced for grade > or =3 toxicity in seven of eight patients at 90 mg/m2 daily. Three of nine patients at 45 mg/m2/day required dose reduction, two at the once-daily dose. Day 1 ATRA area under the plasma concentration versus time curve (AUC) increased with dose, and after 1-2 months of continued dosing, the AUC declined in 7 of 13 patients (54%) studied. ATRA AUC did not correlate with toxicity severity or frequency. Fifteen mg/m2/day every 8 h is a tolerable dose for 1 year in patients with treated SCCHN. ATRA pharmacokinetics did not correlate with toxicity.

Adult↗
PubMed1983

Pharmacokinetics of Cefmenoxime in normal and impaired renal function.

7 beta-[2-(2-Aminothiazol-4-yl)-(Z)-2-methoxy-iminoacetamido]-3-[(1- methyl-1H-tetrazol-5-yl)thiomethyl]-ceph-3-em-4-carboxylic acid hemihydrochloride (Cefmenoxime), a new cephalosporin with a broad spectrum of activity against gram-positive and gram-negative bacteria, was investigated pharmacokinetically. 10 healthy volunteers and 20 patients with renal disease each received 2 g of the substance i.v. The plasma levels were monitored for 6 h in healthy volunteers and for 24 h in the patients with renal disease. The analysis of the data showed that the majority of the curves could be properly evaluated only with the aid of a two-compartment model. Therefore a simple half-life cannot be given. Cefmenoxime is eliminated more rapidly than cefoperazone, but more slowly than cefotaxime. The area under the serum level curves (AUC) increases when renal function is impaired. There is a mathematical correlation between the AUC and the renal function parameters, plasma creatinine and glomerular filtration rate. This gives the dose reduction factors, allowing the calculation of the doses with the same AUC on restricted renal function as that observed in healthy persons after normal doses. Dosage recommendations are given in the form of tables regarding the questions 1. to what extent the dose may be reduced in impaired renal function without lowering the AUC and 2. what is the highest safe dose.

Cefmenoxime↗
PubMed1982

The influence of renal function on plasma levels and urinary excretion of acebutolol and its main N-acetyl metabolite.

The pharmacokinetics of acebutolol and its major N-acetyl metabolite diacetolol were determined following acute intravenous and chronic oral administration to 22 subjects with glomerular filtration rate (GFR) between 3 and 127 ml/min. Following chronic oral administration the mean terminal elimination half-life of unchanged acebutolol was about 10 hours independent of renal function, whereas the hall-life of the N-acetyl metabolite increased from 12.8 hr in subjects with normal renal function (GFR greater than 90 ml/min) to 24.0 hr in preuremic patients (GFR less than 10 ml/min). The mean area of the plasma level-time curve (AUC) of the metabolite was 14.2 mg 1-1 hr in patients with normal renal function and rose to a value of 81.4 mg 1-1 hr in preuremic patients. The mean AUC of the parent drug was not influenced by changes in renal function. The considerable accumulation of the acetyl metabolite, which has about the same beta blocking activity as the unchanged drug, necessitates dose reduction of acebutolol in the presence of different degrees of renal impairment (reduction by half of the normal daily dose in patients with GFR between 30 and 10 ml/min and by three quarters when GFR less than 10 ml/min). In subjects with normal renal function, the ratio between the AUC of the parent drug and that of its major N-acetyl metabolite was 3:1 after intravenous injection of the drug, while it was 1:2.5 following chronic oral administration, indicating a marked first pass metabolism of acebutolol.

Acebutolol↗
PubMed1997

Pharmacologic approaches to reversing multidrug resistance.

The rationale for modulation of multidrug resistance (MDR) by inhibitors of the multidrug transporter, P-glycoprotein (P-gp) includes the following: (1) P-gp is expressed by human cancers, either at diagnosis or after failure of chemotherapy; (2) P-gp expression at diagnosis has been associated with a poor prognosis in some types of cancer; (3) MDR related to P-gp expression can be reversed by modulators, resulting in enhanced therapeutic efficacy in cellular and animal models of drug resistance; and (4) the emergence of MDR related to P-gp expression can be prevented in cellular models by co-administration of MDR-related cytotoxins and modulators. Clinical trials of modulation of MDR have been limited by two major factors: inability to achieve adequate levels of the modulators to reverse drug resistance in patients and the presence of other mechanisms of resistance in tumor cells in addition to P-gp. The former limitation will hopefully be overcome by new, more potent and specific inhibitors of P-gp such as PSC 833. The latter will require further understanding of various alternative cellular mechanisms of resistance and the development of approaches to overcome or circumvent these mechanisms. PSC 833 is associated with significant drug interactions with MDR-related cytotoxic agents, which require dose reduction of the cytotoxins to achieve a dose exposure and toxicity similar to the chemotherapy agents without a modulator. These drug interactions are predictable and are at least in part due to inhibition of P-gp in normal tissues such as the liver and kidneys, where P-gp is known to play a role in drug excretion. Data from knockout mice, which lack P-gp expression, support the concept that P-gp is an important factor in MDR-related drug disposition. Early data from phase I and II trials with PSC 833 indicate that substantial inhibition of P-gp can be achieved in patients at clinically tolerable doses of both modulator and cytotoxins. The ultimate therapeutic benefit of MDR modulation with PSC 833 is currently being tested in phase III clinical trials in acute myeloid leukemias (AMLs) and multiple myeloma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection.

BACKGROUND: Renal transplant recipients experience adverse events attributed to corticosteroid therapy. METHODS: This was a multicenter, randomized, double-blind, 6-month, controlled steroid dose-reduction study in renal transplant recipients with an unblinded 6-month follow-up. In the low/stop arm, corticoste. roids were given at half the dosage of control for 3 months from the date of transplantation, and then withdrawn. Both arms received mycophenolate mofetil and cyclosporine. The primary endpoint was the incidence of biopsy-proven acute rejection at 6 months posttransplantation. RESULTS: There were 248 patients in the control group and 252 in the low/stop group. At 6 months the low/stop group had more biopsy-proven acute rejection episodes than the control (23% vs. 14%; P=0.008). At 12 months this increased to 25% vs. 15%. Most rejections were Banff grade I. Twelve-month graft loss was 5% in the low/stop group vs. 4% in the control. At 6 and 12 months serum cholesterol (P<0.01, P<0.01), triglycer. ides (P<0.01, P<0.01), and systolic blood pressure (P<0.001, P<0.001) were lower in the low/stop group. Diastolic pressure was lower (P<0.01) and lumbar spine bone density was greater (P<0.01) in the low/ stop group at 12 months. CONCLUSIONS: In renal transplant recipients treated with mycophenolate mofetil and cyclosporine, reduction and early withdrawal of the prophylactic corticosteroid dose is feasible without an unacceptable increase in serious rejection episodes. This is accompanied by a significant reduction of steroid-related adverse events.

Adolescent↗