Increased doxorubicin levels in hepatic tumors with reduced systemic drug exposure achieved with complete hepatic venous isolation and extracorporeal chemofiltration

1993 ◽  
Vol 33 (3) ◽  
pp. 251-257 ◽  
Author(s):  
Steven A. Curley ◽  
Diana L. Stone ◽  
George M. Fuhrman ◽  
David C. Hohn ◽  
Zahid H. Siddik ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Hepatic Tumors ◽  
Systemic Drug Exposure ◽  
Systemic Drug

scholarly journals Intrathecal Riluzole for the Treatment of Patients With Amyotrophic Lateral Sclerosis

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Nicholas M Boulis
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Side Effects ◽  
Oral Administration ◽  
Oral Therapy ◽  
Drug Exposure ◽  
Oral Treatment ◽  
Oral Drug ◽  
Systemic Drug Exposure ◽  
Lateral Sclerosis ◽  
Systemic Drug

Abstract INTRODUCTION Oral riluzole is the only approved treatment known to improve survival in patients with amyotrophic lateral sclerosis (ALS), with modest efficacy and dosing limited by hepatic toxicity and asthenia. We postulated that a continuous intrathecal (IT) delivery of low daily doses of riluzole could elevate spinal cord (SC) concentrations well above those achievable with oral treatment alone, without increasing side-effects. METHODS A 6-wk and a 24-wk GLP study were conducted to evaluate the safety of IT riluzole in purpose-bred hound dogs. Oral riluzole, equivalent to 50 mg BID in humans, was administered in combination with one of 3 IT doses given through continuous infusion. Plasma, SC, and brain concentrations of riluzole were measured, along with assessments of safety and tolerability. RESULTS In the 6-wk study, when combining the oral and IT routes, IT infusion significantly increased SC concentrations well above those achieved with oral drug administration alone, without increasing brain concentrations. All IT doses in combination with oral administration were well tolerated by the animals. In the 6-mo study, the lowest dose used in the 6-wk study was dropped and a higher dose was added. This highest dose of IT riluzole was not tolerated by the dogs and yielded SC and brain concentrations significantly higher than achieved in any of our previous studies. CONCLUSION Continuous IT administration of riluzole when combined with oral administration can increase the SC concentration of riluzole above those achievable with oral therapy, without increasing the risk for adverse events associated with systemic drug exposure or off-target side-effects in the brain. Therefore, IT riluzole infusion when used in conjunction with oral therapy may safely enhance lower motor neuron neuroprotection and improve the survival benefit of the drug through enhanced SC delivery, and, with a careful selection of IT doses, it could be implemented in patients with ALS.

Phase I trial of concurrent intraperitoneal and continuous intravenous infusion of fluorouracil in patients with refractory cancer.

1988 ◽  
Vol 6 (1) ◽  
pp. 158-162 ◽  
Author(s):  
B Reichman ◽  
M Markman ◽  
T Hakes ◽  
N Kemeny ◽  
D Kelsen ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Infusion ◽  
Phase I Study ◽  
Clinical Utility ◽  
Phase I Trial ◽  
Drug Exposure ◽  
Continuous Intravenous Infusion ◽  
Future Studies ◽  
Systemic Drug Exposure ◽  
Systemic Drug

In an effort to maximize both local-regional and systemic drug exposure to tumor in the peritoneal cavity, a phase I study was conducted that examined the simultaneous daily intraperitoneal (IP) and continuous intravenous infusion (CVI) of fluorouracil (5-FU) to 32 patients with refractory cancer. IP 5-FU administered at 1,000 mg/d with concurrent 5-FU by CVI at 1,000 mg/m2/d for four consecutive days was well tolerated. One patient with a primary gastrointestinal (GI) malignancy with minimal volume disease experienced a surgically defined complete remission. In theory, this regimen may demonstrate clinical utility as an adjuvant treatment of certain GI malignancies. Future studies are planned in this clinical setting.

scholarly journals Oral Lichenoid Reaction: An Uncommon Side Effect of Rituximab

2019 ◽  
Vol 2019 ◽  
pp. 1-3 ◽  
Author(s):  
Amerigo Giudice ◽  
Francesco Liborio ◽  
Fiorella Averta ◽  
Selene Barone ◽  
Leonzio Fortunato
Keyword(s):  
Side Effect ◽  
Oral Lichen Planus ◽  
Drug Exposure ◽  
B Cell Lymphoma ◽  
Systemic Drug Exposure ◽  
Lichenoid Reactions ◽  
The Right ◽  
Oral Lichen ◽  
Histopathological Result ◽  
Systemic Drug

Oral lichenoid reactions (OLR) can be caused by systemic drug exposure. To the best of our knowledge, this is the second report describing a case of OLR induced by rituximab administration in a patient with a diagnosis of non-Hodgkin B-cell lymphoma. After 5 doses of rituximab, a typical pattern of OLP was identified with bilateral and symmetrical lesions on the buccal mucosa and on the right lingual margin. This temporal relationship suggested a probable association between oral lesions and drug therapy. The clinical diagnosis of a rituximab-induced OLR was confirmed by an incisional biopsy reporting a histopathological result of lichenoid mucositis consistent with oral lichen planus. Because of the increasing use of rituximab, it is necessary to know and recognize this uncommon side effect.

scholarly journals Symmetrical drug-related intertriginous and flexural exanthema due to clindamycin

2019 ◽  
Vol 12 (8) ◽  
pp. e230077 ◽  
Author(s):  
Virginia Cabrera Hernandez ◽  
Monica Gonzalez Afonso ◽  
Ariel Callero Viera ◽  
Lidon Martin-Fernandez Martin
Keyword(s):  
Drug Exposure ◽  
Systemic Exposure ◽  
Standard Test ◽  
Skin Tests ◽  
Hypersensitivity Response ◽  
Cutaneous Eruption ◽  
Systemic Involvement ◽  
Gold Standard Test ◽  
Systemic Drug Exposure ◽  
Systemic Drug

Systemic drug exposure can produce a skin reaction consisting of symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) occurs after systemic exposure to a drug in which the patient was not previously sensitised, either in the first dose or after several doses. The mechanism of SDRIFE is unknown but is hypothesised to be the result of a delayed hypersensitivity response resulting in a cutaneous eruption some days after the exposure to the drug. The diagnosis should be clinical, based on the history and examination, but skin tests can also be performed to confirm sensitisation. But, as always, the gold-standard test is oral provocation. It is important to know this clinical entity to prevent re-exposure to the responsible allergen in the future.

scholarly journals Intratracheal Administration of Chloroquine-Loaded Niosomes Minimize Systemic Drug Exposure

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1677
Author(s):  
Hesham A. Saafan ◽  
Kamilia M. Ibrahim ◽  
Yasmeena Thabet ◽  
Sara M. Elbeltagy ◽  
Rana A. Eissa ◽  
...  
Keyword(s):  
Drug Exposure ◽  
In Vitro Release ◽  
Dry Powder Inhaler ◽  
Free Drug ◽  
Angle Of Repose ◽  
Dry Powder ◽  
Intratracheal Administration ◽  
Pulmonary Administration ◽  
Systemic Drug Exposure ◽  
Systemic Drug

Pulmonary administration provides a useful alternative to oral and invasive routes of administration while enhancing and prolonging the accumulation of drugs into the lungs and reducing systemic drug exposure. In this study, chloroquine, as a model drug, was loaded into niosomes for potential pulmonary administration either via dry powder inhalation or intratracheally. Chloroquine-loaded niosomes have been prepared and extensively characterized. Furthermore, drug-loaded niosomes were lyophilized and their flowing properties were evaluated by measuring the angle of repose, Carr’s index, and Hausner ratio. The developed niosomes demonstrated a nanosized (100–150 nm) spherical morphology and chloroquine entrapment efficiency of ca. 24.5%. The FT-IR results indicated the incorporation of chloroquine into the niosomes, whereas in vitro release studies demonstrated an extended-release profile of the drug-loaded niosomes compared to the free drug. Lyophilized niosomes exhibited poor flowability that was not sufficiently improved after the addition of lactose or when cryoprotectants were exploited throughout the lyophilization process. In vivo, intratracheal administration of chloroquine-loaded niosomes in rats resulted in a drug concentration in the blood that was 10-fold lower than the oral administration of the free drug. Biomarkers of kidney and liver functions (i.e., creatinine, urea, AST, and ALT) following pulmonary administration of the drug-loaded nanoparticles were of similar levels to those of the control untreated animals. Hence, the use of a dry powder inhaler for administration of lyophilized niosomes is not recommended, whereas intratracheal administration might provide a promising strategy for pulmonary administration of niosomal dispersions while minimizing systemic drug exposure and adverse reactions.

P.2.c.023 Are moclobemide trough concentrations an adequate predictor of the systemic drug exposure

2008 ◽  
Vol 18 ◽  
pp. S337-S338
Author(s):  
A. Rakic Ignjatovic ◽  
B. Miljkovic ◽  
D. Todorovic ◽  
I. Timotijevic ◽  
M. Pokrajac
Keyword(s):  
Drug Exposure ◽  
Systemic Drug Exposure ◽  
Trough Concentrations ◽  
Systemic Drug

Once Daily IV Busulfan Given with Fludarabine in Allogeneic Stem Cell Transplantation Conditioning: High vs Low Busulfan AUC Does Not Alter Toxicities or Transplant Outcome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1763-1763
Author(s):  
Michelle Geddes ◽  
Shabal B. Kangarloo ◽  
Farrukh Naveed ◽  
Ahsan M. Chaudhry ◽  
Oluyemi Jeje ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Drug Exposure ◽  
Once Daily ◽  
Concentration Time ◽  
Systemic Drug Exposure ◽  
Grade Ii ◽  
Treatment Related Mortality ◽  
Systemic Drug ◽  
Related Mortality

Abstract Background: Busulfan (Bu), a bifunctional alkylating agent used in conditioning regimens for allogeneic hematopoietic stem cell transplantation (HSCT), has unpredictable oral intestinal absorption. Subsequent marked variability in systemic drug exposure increases the risk of relapsed leukemia or graft failure in patients with a low area under the plasma concentration-time curve (AUC), and for toxicities with a high AUC. Purpose: To assess once daily intravenous (IV) busulfan for interpatient variability in AUC, transplant outcomes and toxicities in patients with high and low systemic busulfan exposures, and to evaluate therapeutic AUC. Methods: 68 patients ages 19–63 with hematologic malignancies received once daily IV Bu (Busulfex, ESP Pharma) between July 2000 and August 2004 at a myeloablative dose of 3.2 mg/m2 on days −5 to −2 and fludarabine 50mg/m2 on days −6 to −2 inclusive prior to HSCT. Additional TBI 200cGy x 2 was given to 24 patients with acute leukemia. Graft-vs-host disease (GVHD) prophylaxis for all pts comprised cyclosporine A, short course methotrexate with folinic acid and antithymocyte globulin in divided doses over 3 consecutive days pretransplant finishing day 0. Busulfan concentrations in plasma were determined by UV-HPLC. All concentration-time plasma Bu data were analyzed by non-compartmental analysis using WinNonlin Version 4.1 software (Pharsight Corporation, Mountain View, CA, USA). Results: The range of AUC was 2184 to 7513 μ M.min (med 4822 μ M.min). Patients were analyzed in 2 groups of 34 patients with exposures below (L) or above (H) the median AUC and followed for 12–61 months (med 26). Groups consisted of diverse malignancies with no difference in median age (L 46y, H 43y), number of unrelated or mismatched related donors (L 32%, H 38%), standard-risk leukemias (L 32%, H 29%), and TBI (L 41%, H 32%). Median days of engraftment for platelets >20 (19d) and neutrophils >0.5 (16d) were identical. There was no significant difference between the low or high AUC groups in 3y projected OS (L 69±8% vs H 67±8%), treatment-related mortality (TRM, L 16±7% vs H 21±7%), median months progression-free survival (L 17, H 19), venoocclusive disease (L 0%, H 6%), stomatitis ≥ grade II (L 82%, H 97%), hemmorhagic cystitis (L 15%, H 18%), acute GVHD grade III–IV (L 6%, H 18%), or grade II liver toxicity (L 12%, H 3%). Rate of relapse did not differ between groups (L 29%, H 24%). One patient in the high AUC group with subtherapeutic dilantin levels had a seizure. There was a trend to increased TRM with death in 3 of 8 patients (38%) with an AUC >6000 μ M.min, compared to 10 of 60 patients (17%) with AUC <6000 μ M.min (p=0.09). Conclusions: Although once daily IV Bu dosing provides a more predictable AUC than oral dosing, there remains 3–4 fold variability in systemic drug exposure. In this heterogeneous group of patients, differences in AUC within this range had little impact on survival, treatment related mortality or significant toxicities. This data suggests targeting AUC around 5000–6000 μ M.min with or without TBI is feasible and that although more data is required to assess the whether high exposures (>6000 μ M.min) increase risk, in general dosing without PK monitoring is safe.

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