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PubMed1997

Evaluation of a new ultraviolet-emitting rare-earth film-screen combination.

The performance of a 400 speed class DuPont Ultra Vision Rapid (UVR) film-screen combination has been evaluated and compared with that of DuPont Quanta Fast Detail screens with Cronex 10L film (QFD-200 speed class). The speed was calculated from the constructed characteristic curves (H&D) at different energies. Image quality was derived objectively using the Leeds test object TOR (CDR). An anthropomorphic phantom was then employed to determine image quality subjectively by means of radiologist appraisal. Lumbar spine and chest radiography of patients were performed to evaluate the potential for dose reduction in clinical conditions by measuring skin entrance doses with thermoluminescent dosimeters (TLDs). UVR provided better resolution (9 lp mm-1 as opposed to 8 lp mm-1) and contrast response than QFD. UVR has accommodated a wider exposure latitude than might be expected with conventional 400 speed class film-screen combinations. Use of UVR resulted in better image quality than use of QFD over a wide range of exposure factors. The use of UVR can result in a dose reduction of 50% with no loss in image quality.

Evaluation Studies as Topic↗
PubMed1990

Do chest radiographic findings reflect the clinical course of patients with sarcoidosis during corticosteroid withdrawal?

The use of serial chest radiographs to assess disease activity in patients with sarcoidosis is controversial. However, reliance on the symptomatic clinical course to assess disease activity may be misleading. As many patients being treated with corticosteroids have an abrupt clinical deterioration when doses of those medications are decreased, we questioned whether the chest radiograph could depict alterations in disease activity as measured by spirometry in this subset of patients. We retrospectively reviewed the clinical course of all patients with pulmonary sarcoidosis in whom the corticosteroid dose was reduced during a 6-month period. The 15 patients without fever, chills, or purulent sputum during that time were then examined to determine the presence (n = 10) or absence (n = 5) of a symptomatic relapse. All patients who had a symptomatic relapse also had a fall in forced vital capacity of at least 10%, suggesting an increase in disease activity. Serial chest radiographs were evaluated during and after corticosteroid dose reductions and after clinical recovery on higher steroid doses in the patients who had had a relapse. In eight patients, the disease was in radiographic stage 2 (hilar adenopathy and parenchymal lung disease); in seven patients it was in radiographic stage 3 (parenchymal lung disease alone). The disease did not change stage in any patient during the study. Chest radiographs worsened more frequently in patients who had a clinical relapse (seven of 10) than in those who did not have a relapse (zero of five, p less than .05). An alveolar chest radiographic pattern (n = 4) or reticulonodular pattern (n = 3) was noted in the seven patients who had a relapse, with worsening on radiographs often occurring before detection of relapse by symptomatology (four of seven) or spirometry (three of seven). Spirometry and radiographs improved or stabilized after an increase in corticosteroid dose in all 10 patients who had a relapse. We conclude that serial chest radiographs can reflect clinical relapse in patients with sarcoidosis during corticosteroid dose reduction. Furthermore, worsening seen on chest radiographs may be the first evidence of relapse.

Adrenal Cortex Hormones↗
PubMed2002

Protection against gamma-irradiation with 5-androstenediol.

We showed previously that treatment of gamma-irradiated female B6D2F1 mice with 5-androstenediol (AED) enhanced survival, stimulated myelopoiesis, and ameliorated radiation-induced decreases in circulating neutrophils and platelets. We have now tested survival in male CD2F1 mice, and we have investigated molecular and functional effects on neutrophils and bone marrow stromal cells and screened for toxicity in female B6D2F1 mice. AED (160 mg/kg, subcutaneously, 24 hours before irradiation) enhanced survival in male CD2F1 mice with a dose-reduction factor of 1.23, similar to the dose-reduction factor of 1.26 found previously for female B6D2F1 mice. Expression of CD11b, a developmental marker, was reduced on circulating neutrophils after either in vivo AED administration or whole-body gamma-irradiation (3 Gy), but neutrophil peroxidase activity was unchanged. Stromal cell progenitors (fibroblastoid colony-forming units) were reduced in marrow 5 days after AED injection in nonirradiated mice. Clinical chemistry, histopathology, and behavioral assays showed no evidence of toxicity. We conclude that AED and related steroids are attractive candidates to explore as countermeasures to high- and low-level ionizing radiation.

Androstenediol↗
PubMed1992

Investigation of the variability of etoposide pharmacokinetics in children.

PROBLEM: The interindividual variation of etoposide pharmacokinetics under different therapeutic schedules and the rationale of dose reduction in young children and newborns were investigated in the present study. PATIENTS AND METHODS: We evaluated pharmacokinetic parameters during short-term infusion in 21 therapy cycles (18 children) on different therapeutic schedules (66-200 mg/m2). In 33 patients state levels (Css) during continuous infusion of 125 mg/m2/96 h were analyzed by an HPLC-method. RESULTS: During short-term infusion half-life (3.3 +/- 0.7 h) and total body clearance (26 +/- 6 ml/min/m2) showed a relatively narrow range. Calculation of the area under the curve was standardized to a dosage of 100 mg/m2 (AUC/[100 mg/m2]). The AUC then was 68 +/- 17 (micrograms.h/ml)/(100 mg/m2) with a coefficient of variation of 25%. In the subgroup of 10 patients who received 150 mg/m2 the AUC was 106 +/- 15 micrograms.h/ml with only 14% coefficient of variation. In children < 2 years, pharmacokinetic parameters were within the normal range. Calculation of the doses the short-term infusion per kg resulted in a dose reduction or 31% (mean, n = 5) and in 22% (mean) lower AUC's. With continuous infusion of 125 mg/m2 etoposide the interpatient variability was greater with a 33% coefficient of variation of the Css (4.4 +/- 1.4 micrograms/ml; n = 24). Calculation of the doses per kg (age < 1 year) or 2/3.kg resulted in reduced Css. Standardization of these levels showed Css (125 mg/m2) of 4.6 +/- 1.4 micrograms/ml and a coefficient of variation of 31%. CONCLUSIONS: Interpatient variability of etoposide pharmacokinetics at least during short-term infusion is limited. Dose reduction is not substantiated in children < 2 years by our pharmacokinetic data.

Child↗
PubMed2006

Dose-dependent reductions in spatial learning and synaptic function in the dentate gyrus of adult rats following developmental thyroid hormone insufficiency.

Thyroid hormones are critical for the development and maturation of the central nervous system. Although somatic and neurological effects are well documented following severe thyroid hormone deprivation, much less is known of the functional consequences of moderate levels of hormone insufficiency. We have previously demonstrated that severe thyroid hormone reductions in the postnatal period are associated with impairments in synaptic transmission in the dentate gyrus. The present study was performed to examine the dose-response relationships of moderate levels of hormone disruption on synaptic function in the dentate gyrus in an in vivo preparation and to determine the effects on spatial learning. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a 47% and 65% reduction in serum T4, in the dams of the low and high-dose groups, respectively. At the time of testing of adult offspring, hormone status had returned to control levels. In littermates, field potentials evoked in the dentate gyrus in response to stimulation of the perforant path were assessed under urethane anesthesia. The data reveal dose-dependent reductions in synaptic transmission and impairments in long-term potentiation (LTP) of the EPSP component of the compound field potential. In contrast, LTP of the population spike measure was paradoxically enhanced. Spatial learning in the Morris water maze was profoundly impaired in high-dose animals. Although the majority of subjects in the low-dose group eventually acquired the task, their acquisition rate lagged behind control values. Reversal learning was assessed in all animals reaching criterion performance and found to be impaired in PTU-exposed animals relative to controls. These data support previous findings in area CA1 in vitro, extend observations associated with dentate gyrus synaptic function to a lower dose range, and provide correlative evidence of behavioral disruption in a hippocampal-dependent learning task following developmental thyroid hormone insufficiency.

Age Factors↗
PubMed1993

Chemoprevention of oral carcinogenesis by DL-alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor: dose-dependent reduction in 4-nitroquinoline 1-oxide-induced tongue neoplasms in rats.

The modifying effect of three doses of DL-alpha-difluoromethylornithine (DFMO) given p.o. during the post-initiation phase of tongue carcinogenesis initiated by 4-nitroquinoline 1-oxide (4-NQO) was studied in male ACI/N rats. Animals were given 4-NQO at 20 ppm for 8 weeks in the drinking water to induce tongue neoplasms. One week after the stop of 4-NQO treatment, rats were transferred to the drinking water containing DFMO at concentrations of 100, 1000, and 2000 ppm for 25 weeks. The other groups consisted of rats given 2000 ppm DFMO alone or untreated rats. Thirty-four weeks after the start of the experiment, all animals were necropsied, and the incidences of neoplasms and preneoplastic lesions in the tongue, polyamine levels in the bloods and tongue tissues, and cell proliferation estimated by the number and area of silver-stained nucleolar organizer regions in the tongue epithelium were compared among the groups. Feeding of DFMO at all doses significantly inhibited the incidence of tongue neoplasms compared to the group given 4-NQO alone. DFMO at levels of 1000 and 2000 ppm significantly reduced the incidence of preneoplastic lesions of the tongue. Results analyzed by the linear regression method suggested a dose-dependent inhibition in the incidences of neoplastic and preneoplastic lesions of the tongue with increasing levels of DFMO. Increased levels in polyamines in the blood and tongue tissue were significantly suppressed by the treatment of DFMO. Also, silver-stained nucleolar organizer region indices were significantly reduced by the DFMO exposure. These results indicate that increasing levels of DFMO in the drinking water inhibited 4-NQO-induced tongue carcinogenesis in a dose-dependent manner and such inhibition was related to reduction in the polyamine levels of blood and tissue and decrease in the cell proliferation.

4-Nitroquinoline-1-oxide↗
PubMed2002

Dose-escalating study of capecitabine plus gemcitabine combination therapy in patients with advanced cancer.

PURPOSE: The goals of this phase I study were to determine the maximum-tolerated doses of capecitabine and gemcitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT) and safety profile of this combination. PATIENTS AND METHODS: Eligible patients had advanced solid tumors that had failed to respond to standard therapy or for which no standard therapy was available, measurable or assessable disease, Karnofsky performance status > or = 70%, and acceptable organ function. Capecitabine was administered twice daily by mouth each day for 21 consecutive days followed by a 1-week break. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break. RESULTS: Forty patients were enrolled onto the study, and 33 are fully assessable for toxicity. The most common toxicities during the first cycle of chemotherapy were neutropenia and mucositis. Only one patient treated at gemcitabine and capecitabine doses of 800 and 2000 mg/m(2), respectively, met protocol-specified DLT criteria; however, at these doses 65% of successive cycles required dose reduction or delay for toxicity. No episodes of DLT were observed at gemcitabine and capecitabine doses of 1,000 and 1,660 mg/m(2), respectively, and 70% of cycles of therapy were delivered without dose reduction or delay. Therefore, these doses are recommended for further study. Tumor responses were observed in patients with metastatic colorectal and pancreatic cancer. CONCLUSION: Gemcitabine and capecitabine can be combined with acceptable toxicity at nearly full doses. Antitumor activity of the combination merits further investigation in phase II studies.

Administration, Oral↗
PubMed1996

Fractionation in medium dose rate brachytherapy of cancer of the cervix.

PURPOSE: To establish an optimum fractionation for medium dose rate (MDR) brachytherapy from retrospective data of patients treated with different MDR schedules in comparison with a low dose rate (LDR) schedule. METHODS AND MATERIALS: The study population consists of consecutive Stage IB-IIA-IIB patients who received radiotherapy alone with full dose brachytherapy plus external beam pelvic and parametrial irradiation from 1986-1993. Patients also receiving surgery or chemotherapy were excluded. The LDR group (n = 102, median follow-up: 80 months) received a median dose to Point A of two 32.5 Gy fractions at 0.44 Gy/h plus 18 Gy of external whole pelvic irradiation. The MDR1 group (n = 30, median follow-up: 45 months) received a mean dose of two 32 Gy fractions at 1.68 Gy/h. An individual dose reduction of 12.5% was planned for this group according to the Manchester experience, but only a 4.8% dose reduction was achieved. The MDR2 group (n = 10, median follow-up: 36 months) received a dose of two 24 Gy fractions at 1.65 Gy/h. The MDR3 group (n = 10, median follow-up 33 months) received a mean dose of three 15.3 Gy fractions at 1.64 Gy/h. And finally, the MDR4 group (n = 38, median follow-up: 24 months) received six 7.7 Gy fractions from two pulses 6 h apart in each of three insertions at 1.61 Gy/h. The median external pelvic dose to MDR schedules was between 12 and 20 Gy. The linear quadratic (LQ) formula was used to calculate the biologically effective dose (BED) to tumor (Gy10) and rectum (Gy3), assuming T1/2 for repair = 1.5 h. RESULTS: The crude central recurrence rate was 6% for LDR (mean BED = 95.4 Gy10) and 10% for MDR4 (mean BED = 77.0 Gy10) (p = NS). The remaining MDR groups had no recurrences. Grade 2 and 3 rectal or bladder complications were 0% for LDR (rectal BED = 109 Gy3) 83% for MDR1 (BED = 206 Gy3), and 30% for MDR3 (BED = 127 Gy3). The MDR2 and MDR4 groups presented no complications (BED, 123 Gy3, and 105 Gy3, respectively). The LQ formula appears to correlate with late complications of the different MDR regimens. A BED above 125 Gy3 was associated with Grade 2 + 3 rectal complications. Adequate central tumor control may be compromised with a tumor BED below 90-95 Gy10. CONCLUSIONS: Medium dose rate brachytherapy at 1.6 Gy/h to Point A has a marked dose rate effect. Increased fractionation is the cost of overcoming the less favorable therapeutic ratio for MDR than for LDR. A larger (25%) reduction of brachytherapy dose than previously reported is also necessary. Our most recently developed schedule for Stage I-II patients is three insertions on three treatment days with six 8.0 Gy brachytherapy fractionations, two on each treatment day, following or preceding an external whole pelvis dose of 18 Gy, and followed by additional external parametrial dose.

Adult↗
PubMed2005

Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.

PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.

Aged↗
PubMed2006

Comparison of two PEG-interferon alpha-2b doses (1.0 or 1.5 microg/kg) combined with ribavirin in interferon-naïve patients with chronic hepatitis C and up to moderate fibrosis.

Health regulatory approval of the 1.5 microg/kg body weight dose of pegylated interferon (PEG-I) alpha-2b in combination with ribavirin for the treatment of chronic hepatitis C was based on a study using PEG-I alpha-2b at doses of only 0.5 and 1.5 microg/kg body weight (BW), in spite of the previously shown flat dose-response curve at doses of > or =1.0 microg/kg. Our aim was to compare PEG-I alpha-2b 1.0 microg/kg with 1.5 microg/kg, both in combination with ribavirin. Open-label, randomized study in 227 patients with biopsy-proven chronic hepatitis C (Metavir < or =F2), receiving oral ribavirin (400 mg, twice daily) in combination with subcutaneous PEG-I alpha-2b (1.0 or 1.5 microg/kg, once weekly) for 24 weeks (genotype 2 or 3), or 48 weeks (other genotypes), followed by a 24-week drug-free period. Virologic response rates did not differ between the two doses of PEG-I alpha-2b: in patients infected with hepatitis C virus (HCV) genotype 1 or 4 treated with PEG-I 1.0 microg/kg BW, 38% (22/58) had a sustained virologic response compared with 39% (27/70) in the PEG-I 1.5 microg/kg BW dose group (P = ns). The corresponding values in patients infected with HCV genotype 2 or 3 were 71% (39/55) and 81% (29/36) respectively (P = ns). Adverse events led to transient or permanent dose reductions in fewer patients in the 1.0 microg/kg BW dose group (48/113 patients; 42%) than in the 1.5 microg/kg BW dose group (63/106 patients; 59%, P = 0.015). Furthermore, 89% of patients treated for 24 weeks but only 58% of patients treated for 48 weeks (P < 0.001) tolerated the treatment without relevant dose reduction or premature termination. In combination with ribavirin, PEG-I alpha-2b 1.0 microg/kg was as effective as 1.5 microg/kg but was better tolerated in patients with chronic hepatitis C and up to moderate fibrosis.

Adolescent↗
PubMedDate not supplied

Dose dependent reduction of glucose utilization by pentobarbital in rat brain.

A new method of determining the rate of glucose utilization in brain regions of individual rats has been used to measure the dose dependency of the reduction of the metabolic activity of the cerebral cortex by pentobarbital. Cerebral cortical glucose utilization is depressed to a basal level of 44% of the control rate when cerebral pentobarbital levels exceed 50 microgram per g of tissue. The major portion of this effect occurs between the cerebral pentobarbital range of 10--20 microgram per g, which can be achieved by 1/5 to 1/10 the normal anesthetic intraperitoneal dosage. If a depression of brain metabolism is responsible for the previously reported protection of the brain from ischemic damage, these data suggest a substantial reduction of brain metabolic rate is achieved in the rat at a barbiturate dosage which may be therapeutically relevant in the human after acute brain ischemia.

Animals↗
PubMedDate not supplied

The "shielding" effect of the guide wire during coronary brachytherapy with P-32 source.

Intracoronary beta irradiation (use of beta radiation for intracoronary irradiation) is an effective method in reducing neointimal proliferation after successful angioplasty and stent implantation. However, long-term results may be influenced by absolute dose and by the homogeneity in dose distribution. In our study, we investigated dose perturbation due to the presence of a conventional guide wire during irradiation. The Galileo III centering catheter and P-32 beta source were used. The 55 MD GAF Chromic foil was positioned within a phantom made of PMMA. The dose distribution at cylindrical surfaces has been assessed using GAF Chromic dosimetric foil MD55 (Nuclear Associates, USA). Our study demonstrated the significant dose reduction of 46% in the most "shaded" area. The dose reduction to 80% or less occupy the 60 degrees sector. This phenomenon can cause progression of late restenosis. In conclusion, the results suggest that technical improvements in centering catheter construction should be made to eliminate the "shielding" effect of the guide wire.

Angioplasty, Balloon, Coronary↗
PubMed2002

Side effects of therapy of hepatitis C and their management.

Interferon and ribavirin combination therapy for chronic hepatitis C produces a number of well-described side effects that are dominated by fatigue, influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Combination therapy with pegylated interferons (peginterferon alfa-2a and alfa-2b) yields an adverse event profile similar to standard interferon, although the frequency of certain adverse events may vary by preparation. Premature withdrawal from therapy due to adverse events was required in 10% to 14% of participants in registration trials of these agents. Most adverse events were safely and effectively managed by dose reduction using predetermined criteria. The most common indications for dose reduction were hematologic abnormalities, such as anemia and neutropenia, with the latter more frequent in peginterferon treatment arms. Recent data suggest that maintaining adherence to a prescribed treatment regimen can enhance antiviral response. Strategies to maximize adherence are being developed and, in the future, may include early identification of and therapy for depression and the selective use of hematopoietic growth factors to ameliorate hematologic abnormalities.

Antiviral Agents↗
PubMed2004

Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer.

An open-label, non-randomized, compassionate-use study was carried out to investigate the effects of oral capecitabine at a dose of 1 250 mg/m2 twice daily on days 1 to 14 every 21 days in anthracycline- and taxane-pretreated advanced/metastatic breast cancer patients. Forty-eight patients were enrolled from April 2000 to December 2001. Twenty-four patients (50%) had metastases to the liver, 18 to bone, 13 to lung, 10 to regional lymph nodes, 8 to pleura, 7 to the thoracic wall, 5 to skin, 3 to the mediastinum, 1 to breast and 1 had metastasis to the abdomen. Thirty-three patients (69%) had metastases to more than one site. Median age of the patients was 55 years (range 35-74). Three patients had an ECOG performance status (PS) of 0, 32 PS 1 and 13 PS 2, respectively. Fourteen patients (29%; 95% CI 16 to 42%) obtained a partial response (PR) while 16 (33%) had stable disease (SD) as the best response, of whom 6 had stabilization for more than 24 weeks. This gives a clinical benefit (PR + SD > 24 weeks) of 42% (95% CI 28 to 56). Dose reduction was necessary in 29% of the patients. Median dose reduction was 25%. Grades 2 and 3 hand-foot syndrome (PPE) was observed in 17 patients (36%). Eleven patients experienced grades 2 and 3 gastrointestinal toxicity, and haematological toxicity grade 3 was observed in 3 patients (6%). Median time to progression was 107 days (CI 95% 85 to 129), and median overall survival was 281 days (CI 95% 164 to 398). Third-line, oral capecitabine in anthracycline- and taxane-pretreated metastatic breast cancer appears to be effective and has an acceptable toxicity profile.

Administration, Oral↗
PubMedDate not supplied

The efficacy and side effects of continuous infusion intravenous morphine (CIVM) for pain and symptoms due to advanced cancer.

Morphine is the strong opioid of choice in the management of moderate-to-severe chronic cancer pain. The preferred route of administration is oral, in individually titrated doses, regularly scheduled around the clock We conducted a retrospective study of continuous intravenous morphine (CIVM) in a palliative medicine program in 107 consecutive patients. The results suggest CIVM is an effective, safe, and versatile method of morphine administration when used with a defined protocol. Efficacy was similar to that obtained by others with intravenous morphine sulfate and also for oral morphine. Safety was suggested by the low incidence of dose-limiting side effects, most of which responded to dose reduction. Particularly noteworthy was the flexibility of CIVM with dose reduction in 20 percent.

Adult↗
PubMed1992

[Cyclosporin interactions in kidney transplants].

Treatment with Cyclosporine has resulted in improved allograft survival. Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450IIIA microsomal enzyme. Pharmacokinetic drug interactions usually involve drugs which induce or inhibit the cytochrome P-450 system. We reviewed the Medical Charts of 53 renal transplant recipients immunosuppressed with Cyclosporine between 1985 and 1991. We analysed the relationship between Cyclosporine concentration, its dose and the change induced by concomitant administration of different drugs. Until December 1988, Cyclosporine was measured by solid-phase radioimmunoassay (RIA) using a polyclonal antibody. This method measures Cyclosporine and some of its metabolites. Since January 1989, Cyclosporine was measured in whole blood by radioimmunoassay (RIA-Kit Sandimmun, Sandoz), which used a specific monoclonal antibody which binds Cyclosporine and a non-specific monoclonal antibody which binds Cyclosporine and its metabolites. The therapeutic range recommended by Sandoz in whole blood using the specific monoclonal antibody is 100 to 400 ng/ml. We present 3 cases of probable pharmacokinetic drug interactions with Cyclosporine. The first patient received concomitantly isoniazide (150 mg/day). Cyclosporine levels were between 600 and 2085 ng/ml despite the dose reduction from 10 to 1.5 mg/kg/day (Fig. 1). The dose reduction of isoniazide to 100 mg/day resulted in reduction of Cyclosporine levels. Until December 1988 with the polyclonal antibody the median was 320 ng/ml (range: 185 to 760 ng/ml; n = 11).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2003

Renal function after liver transplantation: calcineurin inhibitor nephrotoxicity.

Renal failure, mainly due to calcineurin inhibitor (CNI) nephrotoxicity, is the most common complication following orthotopic liver transplantation (ltx). The aim of this study was to evaluate the incidence and course of renal failure in adult ltx patients. Severe acute renal failure in early postoperative period due to impaired hemodynamics and CNI nephrotoxicity, occurred in 14 patients, 3 of whom required dialysis. The creatinine clearance after ltx showed a tendency to decrease, but there was no statistically significant difference (P >.05) in the change in serum creatinine clearance levels between patients treated with tacrolimus (TAC) versus Cyclosporine (CsA) during the first 2 years of follow-up. Fourteen patients required conversion of their regimen because of CNI nephrotoxicity namely, dose reduction (n = 7) or discontinuation of CNI therapy with the replacement by mycophenolate mofetil (MMF) (n = 5) or SRL (n = 5). Dose reduction or CNI withdrawal significantly improved the creatinine clearance (P <.05) without affecting lives graft function. No episode of acute rejection was observed after conversion. Neither conversion of CsA to TAC nor the reverse maneuver significantly influenced the serum creatinine level (P >.05). Reduction of the CNI dose or CNI discontinuation or replacement with MMF or SRL in patients with stable liver but impaired renal function is safe, resulting in a significant improvement in renal function.

Acute Kidney Injury↗
PubMed2001

Coadministration of ketoconazole and cyclosporine for kidney transplant recipients: long-term follow-up and study of metabolic consequences.

In a prospective randomized study including 100 kidney transplant recipients, we previously reported on the safety and financial benefits of the coadministration of ketoconazole (keto) to cyclosporine (CsA)-treated kidney transplant recipients. In this study, we report on the long-term follow-up of these patients and their control group, as well as possible metabolic consequences of this drug combination. Evaluation of 51 keto-treated patients and their control group (49 patients) included graft function, lipogram, fasting blood glucose, liver function tests, serum calcium, phosphorus, and radiological and histopathologic assessments. Follow-up of these patients for 54 months showed that the CsA dose reduction was 72.9% at 12 months, decreased to 69.3% at the last follow-up. We also found that the mean keto dose required for CsA dose reduction decreased to 82.8 +/- 24.1 mg/d compared with the starting dose (100 mg/d). Diagnosis of acute rejection episodes was similar in both groups. However, in the control group, rejection episodes were more recurrent, with poorer response to treatment. Acute CsA nephrotoxicity was more common in the keto group, but this was encountered more at keto induction and was rapidly reversed on further reduction of CsA doses. Chronic graft dysfunction was statistically significantly less in the keto group during the first year. However, by the end of the study, the difference was not statistically significant. In this study, hepatotoxicity was similar in the two groups. On studying the metabolic consequences, we found that serum cholesterol, low-density lipoprotein, and triglyceride levels were lower in the keto group. Bone mineral contents in both groups were less than the mean values for age- and sex-matched healthy controls. From this study, we conclude that long-term use of low-dose keto in CsA-treated kidney transplant recipients is safe and cost-saving and may induce better graft function. Bone mineral contents, vitamin D blood levels, and lipid profiles are not affected by long-term keto coadministration in CsA-treated kidney transplant recipients.

Adult↗