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Results for “Maximum Tolerated Dose”

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At least 19 recordsLinked to original sources

PubMed2002

Toxicity of ultraviolet radiation exposure to the lens expressed by maximum tolerable dose.

The maximum tolerable dose (MTD2.3:16) for avoidance of cataract on exposure to ultraviolet radiation (UVR)-300 nm in the rat was here estimated at 3.65 kJ/m2. Sprague-Dawley rats were unilaterally exposed to UVR in the 300 nm wavelength region. One week after the exposure, the intensity of forward light scattering was measured. Toxicity for continuous response events can be estimated with MTD. Current safety standards for avoidance of cataract after exposure to UVR are based on a binary response event. It has, however, recently been shown that UVR-induced cataract is a continuous dose-dependent event. MTD provides a statistically well-defined criterion of toxicity for continuous response events.

Animals↗

PubMed2004

Pilot study of low-dose, divided maximum tolerated dose of CPT-11 in 21 consecutive patients with metastatic colorectal or gastric cancer.

PURPOSE: We devised a new treatment regimen, delivering a frequent low dose of CPT-11, calculated by dividing the maximum tolerated dose (MTD) to reduce its toxicity without impairing its efficacy. METHODS: CPI-11, 25 mg/m2, determined by dividing the MTD dose per month by 12, was given on days 1, 2, and 3 of every week, to 21 consecutive patients; 12 with metastatic colon cancer and 9 with metastatic gastric cancers. RESULTS: The total delivered dose of CPI-11 per patient was more than 1,000 mg in 17 (80.1%) of the 21 patients. Grade 3 marrow depression developed in 3 (14.3%) patients, and although nausea, vomiting, alopecia, and diarrhea developed in some patients, these side effects were all categorized as grade 2 or milder. The antitumor effect was evaluated in 18 patients with measurable lesions, who had received CPI-11 according to our regimen for at least 3 weeks. Of these 18 patients, 10, 7, and 1, respectively, had a found to have partial response, no change, or progression of disease, demonstrating a 55.6% efficacy rate [colon 6/10 (60.0%) and stomach 4/8 (50.0%)]. Moreover, time to progression (TTP) was greater than 90 days in 12 (75.0%) of these 18 patients. CONCLUSION: These results show that our low-dose, divided MTD of CPI-11 regimen is a promising method of reducing toxicity and strengthening the antitumor effect, justifying further large-scale comparative clinical studies to verify this potential.

Aged↗

PubMed1994

High-dose ifosfamide/carboplatin/etoposide: maximum tolerable doses, toxicities, and hematopoietic recovery after autologous stem cell reinfusion.

We treated 115 patients in a phase I/II dose-escalation study of ifosfamide/carboplatin/etoposide (ICE) followed by autologous stem cell rescue. Patients treated had a variety of diagnoses, including breast cancer (high-risk stage II disease with eight or more positive nodes, stage III disease, and responsive metastatic disease), non-Hodgkin's lymphoma, Hodgkin's disease, acute leukemia in first remission, and various solid tumors that were responsive to induction therapy. Patients received autologous bone marrow stem cells or peripheral blood stem cells primed by one of several methods. The maximum tolerated dose of ICE was determined to be ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2 when administered as a 6-day regimen. The dose-limiting toxicities included acute renal failure, severe central nervous system toxicity, and "leaky capillary syndrome" with hypoalbuminemia, profound fluid overload, and pulmonary insufficiency. Analysis of hematologic recovery based on stem cell source and influence of hematopoietic growth factor administration was undertaken. Hematopoietic growth factor use significantly reduced neutrophil engraftment time for patients receiving bone marrow stem cells, with evidence of earlier recovery times for patients receiving granulocyte colony-stimulating factor compared with granulocyte-macrophage colony-stimulating factor. Neutrophil recovery times varied based on the source of stem cells used, with the earliest engraftment times seen for patients receiving peripheral blood stem cells primed with cyclophosphamide and granulocyte colony-stimulating factor. Platelet recovery times were not statistically different for any of the subsets. In conclusion, the maximum tolerated dose of ICE has been defined, and the source of stem cells and the use of hematopoietic growth factors influence hematopoietic recovery.

Adolescent↗

PubMed2005

Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy.

PURPOSE: Bendamustine hydrochloride, an anti-neoplastic agent with unique mechanism of action, is known to cause impressive remissions in relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL). Optimal bendamustine dosing for CLL patients had not been finally established and a phase I/II study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of bendamustine. METHODS: The open-label, single-centre phase I/II study was conducted from March 2001 to September 2002 in Sofia, Bulgaria. The 15 study patients were extendedly pre-treated, but fludarabine-naive (3 female, 12 male, 47-72 years of age, 61 years on average). Bendamustine was given at a starting dose of 100 mg/m2 on days 1 and 2 every 3 weeks based on the previous results in lymphoma. RESULTS: Bendamustine was well tolerated in spite of heavy pre-treatment of the study participants. Toxicity corresponded to the known safety profile of bendamustine, with the exception of bilirubin elevation. The level of 110 mg/m2 was established as MTD. A bendamustine dose of 100 mg/m2 is the recommended dose for further clinical investigations. A 4-week interval is recommended to allow for sufficient recovery. Efficacy results confirmed powerful anti-neoplastic activity of bendamustine even in extendedly pre-treated CLL patients. Based on the remission criteria, nine patients were defined as responders (four CRs, two PR, three NC) and two patients as nonresponders to therapy. Four patients were not evaluable for response, because they had received less than three courses bendamustine. After a follow-up period of 15 months, the four patients with CR were still in remission. One patient with PR had relapsed, the other had ongoing response. CONCLUSIONS: Bendamustine is a very active and well-tolerated drug in patients with pre-treated and refractory CLL. Fludarabine-naivity of patients appears to markedly improve their bendamustine tolerability. First-line use of bendamustine is a safe option for CLL-patients requiring treatment, because bendamustine-owing to its unique pharmacodynamics-(1) is highly effective, (2) reasonably safe, and (3) does hardly produce cross-resistance against other anti-neoplastic drugs effective in this indication.

Aged↗

PubMed1984

[Maximum tolerated dose of tegafur in rats].

Maximum Tolerated Dose of Tegafur was estimated by per-oral administration in male Donryu rats. Tegafur was administered for 24 weeks at respective doses of 90 mg, 120 mg and 150 mg/kg/day. Six of 10 (60%) died during the treatment in those groups administered with 120 mg and 150 mg/kg/day, respectively. The cause of death of these rats was severe pneumonia. All 10 of the group given 60 mg/kg/day survived until end of the administration and were sacrificed for histological examination of organs. These rats showed apparent suppression of body weight gain compared with controls (p less than 0.001). Slight inflammation of the lungs was observed in all rats, congestion of the liver and local degeneration and necrosis of the liver cells in a few rats and cellular degeneration of bone marrow in one rat. There was no remarkable change in the digestive tract, kidney, thymus or reproductive organs. Accordingly, the Maximum Tolerated Dose of Tegafur was determined to be 90 mg/kg/day.

Administration, Oral↗

PubMed1995

Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays.

With a limited subset of National Cancer Institute/National Toxicology Program (NCI/NTP) bioassays, Gaylor (Regul. Toxicol. Pharmacol. 9, 101-108, 1989) showed that the regulatory virtually safe dose (VSD), corresponding to an estimated lifetime cancer risk of less than 10(-6), could be estimated within a factor of 10 simply by dividing the maximum tolerated dose (MTD), estimated from the results of a 90-day study, by 380,000. The purpose of this current study was to extend the analysis to all carcinogens in the Carcinogenic Potency Database (CPDB) utilizing the TD50 (average daily dose rate in mg/kg body wt/day that was estimated to halve the probability of remaining tumor-free at a specified tissue site throughout a 2-year study). Using the relationship between the upper bound on the low-dose slope (q1*) and the TD50 reported by Krewski et al. (Risk Anal. 13, 383-398, 1993) and the ratio of the maximum dose tested (Max-D)/TD50 obtained in our present analysis, an estimate of the regulatory VSD was given by the MTD/740,000, for NCI/NTP rodent carcinogens. This was about a factor of two lower than the limited analysis conducted by Gaylor. There was little difference when the chemicals were divided into mutagens and nonmutagens. Ninety-six percent (134 of the 139 NCI/NTP rodent carcinogens) of the regulatory VSDs calculated from the individual TD50s obtained from the 2-year bioassays were within a factor of 10 of the MTD/740,000.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Regulatory cancer risk assessment based on a quick estimate of a benchmark dose derived from the maximum tolerated dose.

The proposed U.S. Environmental Protection Agency carcinogen risk assessment guidelines employ a benchmark dose as a point of departure (POD) for low-dose risk assessment. If information on the carcinogenic mode of action for a chemical supports a nonlinear dose-response curve below the POD, a margin-of-exposure ratio between the POD and anticipated human exposure would be considered. The POD would be divided by uncertainty (safety) factors to arrive at a reference dose that is likely to produce no, or at most negligible, cancer risk for humans. If nonlinearity below the POD is not supported by sufficient evidence, then linear extrapolation from the incidence at the POD to zero would be used for low-dose cancer risk estimation. The carcinogen guidelines suggest that the lower 95% confidence limit on the dose estimated to produce an excess of tumors in 10% of the animals (LTD10) be used for the POD. Due to the relatively narrow range of doses in 2-year rodent bioassays and the limited range of statistically significant tumor incidence rates, the estimate of the LTD10 obtained from 2-year bioassays is constrained to a relatively narrow range of values. Because of this constraint, a simple, quick, and relatively precise determination of the LTD10 can be obtained by the maximum tolerated dose (MTD) divided by 7. All that is needed is a 90-day study to establish the MTD. It is shown that the LTD10 determined by this relatively easy procedure is generally within a factor of 10 of the LTD10 that would be estimated using tumor incidence rates from 2-year bioassays. Estimates of cancer potency from replicated 2-year bioassays, and hence estimates of cancer risk, have been show to vary by a factor of 4 around a median value. Thus, there may be little gain in precision of cancer risk estimates derived from a 2-year bioassay, compared to the estimate based on the MTD from a 90-day study. If the anticipated human exposure were estimated to be small relative to the MTD/7 = LTD10, there may be little value in conducting a chronic 2-year study in rodents because the estimate of cancer risk would be low regardless of the results of a 2-year bioassay. Linear extrapolation to a risk of less than 1 in 100,000 and use of an uncertainty factor, e.g., of 10,000, would give the same regulatory "safe dose." Linear extrapolation to a virtually safe dose associated with a cancer risk estimate of less than one in a million would be 10 times lower than the reference dose based on the LTD10/10,000.

Benchmarking↗

PubMed1989

Preliminary estimates of the virtually safe dose for tumors obtained from the maximum tolerated dose.

The purpose of this paper was to examine the correlation between the maximum tolerated dose (MTD) and the low-dose estimate of the virtually safe dose (VSD) for animal carcinogens. Chronic bioassay results from the National Cancer Institute/National Toxicology Program carcinogenesis screening program were used. Estimates of the VSD were obtained by linear low-dose extrapolation for which an adequate dose-response relationship existed at the same tumor site in the same sex for both rats and mice. Estimates of the VSD were compared with the MTD for 69 tumor sites from 38 chemicals for rats and mice. The MTDs ranged from high to low toxicity (1 ppb to 4.4% in the diet). The overall geometric mean of the ratio of the MTD to the VSD corresponding to a maximum estimated risk of 10(-6) was 3.8 x 10(5). Of the 138 cases, only 3 cases were more than a factor of 10 from the mean ratio. This suggested that a quick estimate of the VSD could be obtained by dividing the MTD, obtained from a subchronic study, by 400,000. Further, if the human exposure is less than 10(-7) X MTD, the estimated risk is likely to be negligible even if the chemical is a carcinogen. It may not be worthwhile to conduct a chronic bioassay for the purpose of demonstrating a negligible risk, if the chemical is likely to be carcinogenic, unless the human exposure is extremely low.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Dose escalation study for defining the maximum tolerated dose of continuous oral trofosfamide in pretreated patients with metastatic lung cancer.

BACKGROUND: Trofosfamide is increasingly used in the treatment of patients with several types of malignancies. However, the optimal dose of trofosfamide for patients with advanced cancer has not been systematically investigated yet. The aim of this study was to define the maximum tolerated dose (MTD) of continuous oral trofosfamide. PATIENTS AND METHODS: 16 patients with advanced lung cancer (14 nonsmall cell lung cancer, 2 small cell lung cancer; 10 male, 6 female; median age 64 years (range 46-82); median Karnofsky status 70%; median number of organs involved 3 (range 1-6)) were enrolled. All patients were previously treated with chemotherapy (median 2x, range 1-6) and 8/16 (50%) with radiotherapy. Patients received trofosfamide p.o. administered in 3 doses per day for 3 weeks (1 cycle) using a 3-patient-cohort dose-escalation strategy. Toxicities were graded according to the WHO Criteria. RESULTS: Patients received a median of 2 cycles of trofosfamide (range 1-4) at 3 dose levels (90, 125, and 175 mg/m2). Grade 3 and 4 neutropenia, anemia, and thrombocytopenia were observed in 20, 13.3, and 6.6%, respectively. Dose-limiting toxicities during the first cycle were grade 3 muscle weakness and anorexia observed in 1/6 patients in cohort 1 (trofosfamide 90 mg/m2), grade 3 neutropenia in 1/6, and encephalopathy in 1/6 patients in cohort 3 (trofosfamide 175 mg/m2). Therefore, the dose level of 125 mg/m2 was defined as the MTD. CONCLUSION: Trofosfamide at 125 mg/m2 administered in 3 doses per day was well tolerated. This dose level is recommended for further clinical studies.

Administration, Oral↗

PubMed2000

Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia.

BACKGROUND: This study investigated the ability of the modified continual reassessment method (MCRM) to determine the maximum tolerated dose of the opioid antagonist nalmefene, which does not reverse analgesia in an acceptable number of postoperative patients receiving epidural fentanyl in 0.075% bupivacaine. METHODS: In the postanesthetic care unit, patients received a single intravenous dose of 0.25, 0.50, 0.75, or 1.00 microg/kg nalmefene. Reversal of analgesia was defined as an increase in pain score of two or more integers above baseline on a visual analog scale from 0 through 10 after nalmefene administration. Patients were treated in cohorts of one, starting with the lowest dose. The maximum tolerated dose of nalmefene was defined as that dose, among the four studied, with a final mean probability of reversal of anesthesia (PROA) closest to 0.20 (ie., a 20% chance of causing reversal). The modified continual reassessment method is an iterative Bayesian statistical procedure that, in this study, selected the dose for each successive cohort as that having a mean PROA closest to the preselected target PROA of 0.20. RESULTS: The modified continual reassessment method repeatedly updated the PROA of each dose level as successive patients were observed for presence or absence of ROA. After 25 patients, the maximum tolerated dose of nalmefene was selected as 0.50 microg/kg (final mean PROA = 0.18). The 1.00-microg/kg dose was never tried because its projected PROA was far above 0.20. CONCLUSIONS: The modified continual reassessment method facilitated determination of the maximum tolerated dose ofnalmefene . Operating characteristics of the modified continual reassessment method suggest it may be an effective statistical tool for dose-finding in trials of selected analgesic or anesthetic agents.

Adult↗

PubMed2004

A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens.

The survival benefits of traditional maximum tolerated dose (MTD) cytotoxic therapy have been modest for the treatment of most types of metastatic malignancy and, moreover, often come with increased acute and chronic toxicity. Recent studies have demonstrated that the frequent administration of comparatively low doses of cytotoxic agents, with no extended breaks [low-dose metronomic (LDM) chemotherapy], may not only be at least as efficient as MTD therapy but also less toxic. This coincides with an apparent selectivity for "activated" endothelial cells of the tumor vasculature. However, the impact of LDM chemotherapy on the most sensitive target cell populations normally affected by MTD therapy (i.e., bone marrow progenitors, gut mucosa, and hair follicle cells) has not been analyzed in experimental detail. Therefore, we compared effects of LDM and MTD cyclophosphamide (CTX) on bone marrow and gut mucosa. Furthermore, we studied the potential impact of LDM CTX on angiogenesis in the context of wound healing and evidence of organ toxicity. We show absent or moderate hematologic and intestinal toxicity of LDM as opposed to MTD CTX. Of note was the finding of sustained lymphopenia, which is not unexpected given the use of CTX as immunosuppressive drug. There was no negative impact on wound healing or evidence of organ toxicity. LDM offers clear safety advantages over conventional MTD chemotherapy and therefore would appear to be ideal for long-term combination therapy with targeted antiangiogenic drugs.

Animals↗

PubMed2006

Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable cholangiocarcinomas and liver metastases of pancreatic cancer: a clinical study on maximum tolerable dose and treatment efficacy.

PURPOSE: To define the maximum tolerated dose (MTD) of hepatic intraarterial chemotherapy with gemcitabine, administered with and without starch microspheres, in patients with inoperable intrahepatic cholangiocarcinomas and liver metastases of pancreatic carcinomas. METHODS: Gemcitabine was administered on days 1 and 8 with intervals of 2 weeks between the cycles. In group A the initial gemcitabine dose of 1,000 mg/m(2) (without microspheres) was increased in 200-mg/m(2) steps up to a maximum dose of 2,000 mg/m(2). In group B the MTD with microspheres was assessed by giving an additional microsphere dose according to tumor extent and body weight, increasing gemcitabine starting from a dose-step below the MTD with microspheres. The MTD was evaluated via clinical and laboratory findings. RESULTS: Twenty-four patients were enrolled (12 males, 12 females, mean age 59.17 years; intrahepatic cholangiocarcinoma: n = 17, liver metastases of pancreatic carcinoma: n = 7). The MTD of gemcitabine without microspheres was reached at 1,400 mg/m(2), and of gemcitabine with microspheres at 1,800 mg/m(2). The comparative evaluation revealed statistically significant better data for the time to progression (p < 0.01) and survival for the group with microspheres (6.8 and 20.2 months) in comparison to the group without microspheres (4.2 and 13.5 months). CONCLUSION: This clinical study indicates that the intraarterial application of gemcitabine with doses higher than the recommended 1,000 mg/m(2) is well tolerated if combined with microspheres, and yields respectable results in patients who do not respond to systemic chemotherapy.

Adenocarcinoma↗

PubMed2006

Ultraviolet radiation-B-induced cataract in albino rats: maximum tolerable dose and ascorbate consumption.

PURPOSE: To investigate the maximum tolerable dose (MTD) for cataract induced by ultraviolet radiation-B (UVB) in 7-week-old albino rats and to study the effect of UVB eye exposure on lens ascorbate content. METHODS: Fifty 7-week-old albino Sprague Dawley rats were unilaterally exposed in vivo to 300-nm UVB under anaesthesia, receiving 0, 0.25, 3.5, 4.3 and 4.9 kJ/m(2). The MTD was estimated based on lens forward light scattering measurements. Lens ascorbate content was determined in the processed lens using high performance liquid chromatography with UVR detection. RESULTS: Animals exposed to UVB doses >or=3.5 kJ/m(2) developed cortical cataracts. The MTD for avoidance of UVB-induced cataract was estimated to 3.01 kJ/m(2). UVB exposure decreased lens ascorbate concentration in the exposed lens in line with UVB dose, H(e), according to the models: C = C(NonCo) + C(Co)e(-kH(e) ) for exposed lenses; C = C(NonCo) + C(Co) for non-exposed lenses, and C(d) = C(Co)(e(-kH(e) ) - 1). Parameters for consumable and non-consumable ascorbate were estimated to C(NonCo) = 0.04 and C(Co) = 0.11 micromol/g wet weight of lens. For lens ascorbate difference, tau = 1/k = 0.86 kJ/m(2). A total of 63% of UVB consumable ascorbate has been consumed after only tau = 0.86 kJ/m(2), while MTD(2.3 : 16) = 3.01 kJ/m(2), indicating that ascorbate decrease is in the order of 3.5 times more sensitive to detecting UVR damage in the lens than forward light scattering. CONCLUSIONS: The MTD for avoidance of UVB-induced cataract in the 7-week-old albino Sprague Dawley rat was estimated to be 3.01 kJ/m(2). In vivo UVB exposure of the rat eye decreases lens ascorbate content following an exponential decline, and suprathreshold doses cause greater effect than subthreshold doses.

Animals↗

PubMed2003

Population-based maximum tolerated dose of irinotecan and carboplatin.

A novel schema of intrapatient dose escalation was applied to determine a population-based maximum tolerated dose (pMTD) for irinotecan (CPT-11, Camptosar) and carboplatin (Paraplatin) in a phase I trial. A total of 74 patients with advanced solid tumors were enrolled with the following characteristics: men/women, 46/28; median age, 61 years; 51 patients with and 23 patients without prior chemotherapy; performance status of 0-1 (93%) and 2 (7%). Patients were started at dose level 1 with irinotecan at 200 mg/m2, and carboplatin at an area under the concentration-time curve (AUC) of 5 mg/mL x min, administered every 21 days. Depending on degree of toxicity observed, the dose for each patient in each subsequent cycle was determined according to a predetermined schema of dose levels. Individual maximum tolerated dose (iMTD) was determined for each patient. The pMTD was defined as the highest dose level for which the incidence of dose-limiting toxicity occurred in less than 33% of the patient population. The most common dose-limiting toxicity included neutropenia (58%), thrombocytopenia (15%), diarrhea (8%), and nausea/emesis (7%). The iMTD ranged from dose level-3 (irinotecan at 100 mg/m2 and carboplatin at an AUC of 4) to dose level 5 (irinotecan at 350 mg/m2 and carboplatin at AUC 6). The pMTD was determined to be dose level-1 and 1 for previously chemotherapy-treated and--untreated patients, respectively. Fifty-nine patients were assessable for response. Of note, a response rate of 40% was observed in 15 patients with relapsed small-cell lung cancer previously treated with platinum-based therapy. We recommend dose level 1 of irinotecan (200 mg/m2) and carboplatin (AUC 5) for chemotherapynaive patients, and dose level-1 of irinotecan (150 mg/m2) and carboplatin (AUC 5) for chemotherapy-treated patients in phase II trials.

Adult↗

PubMed2000

Maximum tolerated doses of methotrexate and 7-hydroxy-methotrexate in a model of acute toxicity in rats.

PURPOSE: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD(50) for reasons of animal welfare. METHODS: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8 11.3 g/kg MTX and 0.1-1.2 g/kg 7-OH-MTX. RESULTS: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. CONCLUSIONS: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.

Animals↗

PubMed2004

Maximum tolerable dose of cyclophosphamide and azathioprine in Pakistani patients with primary renal disease.

OBJECTIVE: The immunosuppressive regimens, at present, mainly rely on western guidelines that were derived from studies conducted in western populations. No such study exists for South Asian population, which is home to almost two billion people different in both genetics and environment from west. Locally derived thresholds for side effects markedly different from western figures may warrant re-adjustment of current local immunosuppressive regimens that are at present based largely on western guidelines. In order to define optimum dose for Cyclophosphamide (CYC) and Azathioprine (AZA) based immunosuppressive therapy, we conducted this study to find out maximum tolerable doses of azathioprine (AZA) and cyclophosphamide (CYC) beyond which neutropenia and thrombocytepenia are most likely to occur in patients with primary renal pathology. METHOD: Patients with systemic vasculitis and idiopathic glomerulonephritis who were on CYC and AZA were identified through review of medical records at a tertiary care hospital in Pakistan (The Aga Khan University Hospital, Karachi). Patients were categorized under three principal diagnosis i.e. systemic lupus erythematosus (SLE), primary (idiopathic) glomerulonephritis (GN) and Wegener's granulomatosis (WG). The Receiver Operating Curve (ROC) was used to calculate the maximum tolerable dose for both CYC and AZA. RESULTS: We identified 94 patients aged 6-82 years (median 44.5 years) with primary renal disease (Wegener's granulomatosis n=13, Systemic lupus erythematosis n=62 and idiopathic glomerulonephritis n=19) who received CYC or AZA. Of these 94 patients, 36.2% (n=34) received CYC and 63.8% (n=60) received AZA. The mean dose of CYC was 1.54 +/- 0.50 mg/kg of body weight (range: 0.77-2.93). The mean dose of AZA was 1.64 +/- 0.59 mg/kg of body weight (range: 0.47-2.97). The maximum tolerable doses calculated for CYC and AZA were 1.25 mg/kg and 1.30 mg/kg of body weight respectively. The maximum tolerable dose for CYC and AZA among males could not be calculated, because of insufficient number of patients who developed neutropenia and thrombocytopenia. The maximum tolerable doses for CYC and AZA among females were 1.34 mg/kg and 1.03 mg/kg of body weight respectively. Also we found out that AZA was relatively more likely to cause neutropenia and thrombocytopenia (p=0.07). CONCLUSION: We thereby recommend that CYC should be initiated at a dose no more than 1 mg/kg of body weight and AZA at an initial dose of 0.75-1.0 mg/kg of body weight. The dose may be adjusted later on the basis of clinical response and laboratory reports.

Adolescent↗

PubMed2006

A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation.

This open-label, dose-escalation study assessed the maximum tolerated dose (MTD) of the new antifungal micafungin in patients undergoing haematopoietic stem cell transplantation (HSCT). Participants received 3, 4, 6 or 8 mg/kg/day micafungin intravenously from 7 days to a maximum of 28 days or until neutropaenia resolved. The MTD was defined as the highest dose not causing the same Grade 3 or 4 adverse event in three or more patients. All 36 participants received >/=8 days treatment for a median of 18 days (range: 8-28); 1 patient withdrew consent and a further 11 discontinued to receive another systemic antifungal agent for a suspected infection. No case of confirmed invasive fungal infection occurred. Adverse events were those expected for patients undergoing HSCT and showed no evidence of dose-related toxicity. Criteria for MTD were not met; no patient had a Grade 3 or 4 adverse event considered causally related to micafungin. Thus, the MTD of micafungin can be inferred to be 8 mg/kg/day or higher.

Adult↗

PubMed1984

A method for determining the maximum tolerated dose for acute in vivo cytogenetic studies.

A method for establishing a maximum tolerated dose for use in in vivo cytogenetic studies is proposed. Probit analyses were performed on acute (ip and po) LD50 studies for triethylenemelamine, chlorambucil, methyl methanesulphonate, glycidol, phenol, Triton X-15, and dimethylsulphoxide. The concentrations corresponding to the calculated LD30, LD10 and LD1 values were given both ip and po to groups of female and male rats. Half of the animals in each group were killed about 20 hr after treatment for bone marrow cytogenetic analyses, and body weights were recorded for 10 days for the other half. The following conclusions were drawn: (1) LD50 values and consequently the maximum tolerated dose (MTD) values differ for males and females; (2) the mitotic index is not a reliable indicator of toxicity; (3) the LD1 value approximates the MTD for these compounds; (4) this value and hence the MTD is not a fixed percentage of the LD50 value; (5) body-weight changes appear to be an accurate parameter for determining whether or not an animal received an MTD level.

Animals↗