ABSTRACT
OBJECTIVE: Recently, Zirconia and polyaryletherketone (PEEK) have attracted increasing interest as reliable and safe materials in dental applications, mainly because of their good biomechanical characteristics. The aim of this study was to investigate the response to different loads by prosthetic frameworks for supported fixed partial dentures (FPDs), thus simulating osseointegrated implants. MATERIALS AND METHODS: The specimens were divided into two groups (n= 5 each). Group A: FDPs in zirconia-ceramic; Group B: FDPs in PEEK-composite. These 2 groups were subjected to vertical loads so to evaluate structural deformation; then, they have been analyzed by scanning electron microscopy (SEM) at different magnifications. RESULTS: In tested samples, different types of mechanical failures have been observed. In Zirconia-specimens, chipping is the main failure noticed in this study, mostly in distal margins of the structure. Also, peek-specimens show failure and fracture. CONCLUSIONS: Zirconia and PEEK could be considered both good materials, but several investigations are needed to use these materials as an alternative to metals for fixed partial dentures.
Subject(s)
Benzophenones , Polymers , Polyethylene Glycols , Ketones , Zirconium/chemistry , Dental Restoration Failure , Materials Testing , Dental MaterialsABSTRACT
PURPOSE: Stress is a multifactorial and complex pathway, gaining growing attention from the healthcare community. Surgeons are subjected to higher levels of stress, due to surgical procedures that are demanding and repetitive; unfortunately, high-stress levels may also cause side-effects, as surgical mistakes. This study aimed to evaluate the efficacy of specific probiotics strains formula on stress levels in oral and maxillofacial surgeons, to improve their quality of life. METHODS: We have investigated the hormonal (salivary Cortisol; sC), immune (salivary Immunoglobulin A; sIgA) and cardiovascular (Heart rate, HR, and systolic blood pressure, SBP) responses induced by stress conditions in 40 oral surgeons, randomly selected and allocated, according to their experience level, in three categories: senior, expert, and junior. RESULTS: The results described how the number of heartbeats/ minute and SBP are slightly raised in all surgeons at different timepoints. Such data allow us to assess that work-related stress can induce an increase in cardiovascular parameters, even if they are not significantly modified by the use of probiotics. On the other hand, our data indicate that 10 weeks of probiotic integration may induce the improvement of other stress-related physiological parameters in oral surgeons with different degrees of surgical experience, such as the salivary cortisol levels, even under stress conditions. Moreover, in the test group (probiotics administration), the immunoglobulin levels were higher than the control (placebo administration) group: this happens as a consequence of the regular use of probiotics, which may induce an increased number of IgA producing cells. DISCUSSION: Our data indicated that 10 weeks of probiotics-enriched diet modify some stress-related physiological parameters in oral surgeons with different degrees of surgical experience, but it does not impact on the overall cardiovascular risk.
Subject(s)
Oral and Maxillofacial Surgeons/psychology , Probiotics/therapeutic use , Stress, Physiological/drug effects , Adult , Blood Pressure , Clinical Competence , Double-Blind Method , Heart Rate , Humans , Hydrocortisone/metabolism , Male , Middle Aged , Quality of Life , Saliva/metabolismABSTRACT
The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, -2, -3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP), and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker timecourses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, -2, and -3 production, and VEGF degradation. No effect was identified on sKIT. A tumor model using sVEGFR-3 dynamics as driver predicted SLD data well. An IDR model, with axitinib exposure stimulating the response, characterized dBP increase. In a time-to-event model the SLD timecourse predicted OS better than exposure, biomarker- or dBP-related metrics. This type of framework can be used to relate pharmacokinetics, efficacy, and safety to long-term clinical outcome in mRCC patients treated with VEGFR inhibitors. (ClinicalTrial.gov identifier NCT00569946.).
Subject(s)
Antineoplastic Agents , Carcinoma, Renal Cell , Imidazoles , Indazoles , Kidney Neoplasms , Models, Biological , Protein Kinase Inhibitors , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Axitinib , Biomarkers, Tumor/metabolism , Blood Pressure/drug effects , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/physiopathology , Humans , Imidazoles/adverse effects , Imidazoles/therapeutic use , Indazoles/adverse effects , Indazoles/therapeutic use , Kaplan-Meier Estimate , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Kidney Neoplasms/physiopathology , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-kit/metabolism , Treatment Outcome , Tumor Burden , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Vascular Endothelial Growth Factor Receptor-3/metabolismABSTRACT
Pharmacometric models were developed to characterize the relationships between lesion-level tumor metabolic activity, as assessed by the maximum standardized uptake value (SUVmax) obtained on [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET), tumor size, and overall survival (OS) in 66 patients with gastrointestinal stromal tumor (GIST) treated with intermittent sunitinib. An indirect response model in which sunitinib stimulates tumor loss best described the typically rapid decrease in SUVmax during on-treatment periods and the recovery during off-treatment periods. Substantial interindividual and interlesion variability were identified in SUVmax baseline and drug sensitivity. A parametric time-to-event model identified the relative change in SUVmax at one week for the lesion with the most pronounced response as a better predictor of OS than tumor size. Based on the proposed modeling framework, early changes in FDG-PET response may serve as predictor for long-term outcome in sunitinib-treated GIST.
Subject(s)
Gastrointestinal Neoplasms/diagnostic imaging , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/diagnostic imaging , Gastrointestinal Stromal Tumors/drug therapy , Indoles/administration & dosage , Indoles/pharmacokinetics , Pyrroles/administration & dosage , Pyrroles/pharmacokinetics , Adult , Fluorodeoxyglucose F18 , Gastrointestinal Neoplasms/metabolism , Gastrointestinal Stromal Tumors/metabolism , Humans , Models, Biological , Models, Statistical , Nonlinear Dynamics , Positron-Emission Tomography/methods , Radiopharmaceuticals , Sunitinib , Survival Analysis , Survival Rate , Treatment Outcome , Tumor BurdenABSTRACT
A mixed effect model describing median overall survival (mOS) in patients with advanced hepatocellular carcinoma (aHCC) treated with antiangiogenic therapy (AAT) was developed from literature data. Data were extracted from 59 studies, representing 4,813 patients. The final model included estimates of mOS after AAT (8.5 months) or placebo (7.1 months) administration. The mOS increased 21% when the AAT was sorafenib (SOR) or 42% when locoregional therapy was coadministered. The mOS decreased when patients received prior systemic therapy (↓7%) or concomitant chemotherapy (↓4%) or the percentage of patients with hepatitis B increased (↓â¼0.4%/%). Clinical trial simulations of a phase II comparative trial predicted an mOS ratio (placebo:AAT) of 0.687 or 0.831, with a 65% or 22% probability of demonstrating superiority, for SOR or other AATs, respectively. Additionally, the 95% confidence interval (CI) of the simulated median mOS ratio for non-SOR AATs was similar to the 95% CI of the hazard ratio (HR) observed in the trial.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Hepatocellular/drug therapy , Clinical Trials, Phase II as Topic/statistics & numerical data , Liver Neoplasms/drug therapy , Network Meta-Analysis , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Aged , Carcinoma, Hepatocellular/epidemiology , Computer Simulation/statistics & numerical data , Female , Humans , Liver Neoplasms/epidemiology , Male , Middle Aged , Niacinamide/therapeutic use , SorafenibABSTRACT
Bone regeneration is an interesting field of biomedicine. The most recent studies are aimed to achieve a bone regeneration using mesenchymal stem cells (MSCs) taken from more accessible sites: oral and dental tissues have been widely investigated as a rich accessible source of MSCs. Dental Pulp Stem Cells (DPSCs) and human Periapical Cysts Mesenchymal Stem Cells (hPCy-MSCs) represent the new generation MSCs. The aim of this study is to compare the gene expression of these two innovative cell types to highlight the advantages of their use in bone regeneration. The harvesting, culturing and differentiating of cells isolated from dental pulp as well as from periapical cystic tissue were carried out as described in previously published reports. qRT-PCR analyses were performed on osteogenic genes in undifferentiated and osteogenic differentiated cells of DPSC and hPCy-MSC lineage. Real-time RT-PCR data suggested that both DPSCs and hPCy-MSCs cultured in osteogenic media are able to differentiate into osteoblast/odontoblast-like cells: however, some differences indicated that DPSCs seem to be directed more towards dentinogenesis, while hPCy-MSCs seem to be directed more towards osteogenesis.
Subject(s)
Cell Differentiation , Dental Pulp/metabolism , Gene Expression Regulation , Mesenchymal Stem Cells/metabolism , Osteogenesis , Radicular Cyst/metabolism , Adult , Female , Humans , MaleABSTRACT
Dental pulp stem cells (DPSCs) are stem cells found in the dental pulp. The ability of DPSCs to differentiate towards odontoblastic and osteoblastic phenotype was reported first in the literature, then in the following years, numerous studies on odontogenesis were carried out, starting from mesenchymal stem cells isolated from tissues of dental and oral origin. The aim of this research was to evaluate the behaviour of DPSCs grown on silicon nanoporous and mesoporous matrices and differentiated towards the osteogenic phenotype, but also to investigate the use of DPSCs in pilot studies focused on the biological compatibility of innovative dental biomaterials. Twenty-eight silicon samples were created with standardized procedures. These scaffolds were divided into samples made of silicon bulk, nanoporous silicon, mesoporous silicon, nanoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS) and methanol (MeOH), nanoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS)/toluene, mesoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS) and methanol (MeOH) andmesoporous silicon functionalized with (3-Aminopropyl) Trimethoxysilane (APTMS)/toluene. DPSC proliferation on the tested silicon scaffolds was analyzed at 3 and 5 days. The assay showed that DPSCs proliferated better on mesoporous scaffolds functionalized with APTMS/toluene compared to a silicon one. These results show that the functionalization of silicon scaffold with APTMS/toluene supports the growth of DPSCs and could be used for future applications in tissue engineering.
Subject(s)
Dental Pulp/cytology , Stem Cells/cytology , Tissue Scaffolds , Adult , Cell Differentiation , Cell Proliferation , Cells, Cultured , Humans , Nanostructures , Porosity , Silicon , Tissue EngineeringABSTRACT
OBJECTIVES: CHARGE is an acronym referring to the aspects of this rare syndromic condition. Patients with CHARGE association are today considered as subjects lacking in pathognomonic dental alterations. The present study is aimed at adding to the body of evidence of the cases reported in literature and the continuous clinical research which show a clinical picture which is strongly associated with patients afflicted by this syndrome. PATIENTS AND METHODS: We report a case-series of 8 patients with CHARGE syndrome. The dental features associated with CHARGE syndrome are from case-reports, but without a congruity that can lead to a definition of the dental condition typical of the CHARGE phenotype. CONCLUSIONS: The systemic problems affecting these patients are predominant in compromising their quality of life: this is the reason for a frequent lack of a diagnostics and interceptive phase, relative to oral diseases. We report new oral pathological conditions affecting CHARGE patients. Knowledge of these pathological conditions may induce dentists to carry out specific diagnoses of these patients, thus, avoiding the deterioration of oral conditions.
Subject(s)
CHARGE Syndrome/pathology , Maxillofacial Abnormalities/pathology , Mouth Diseases/pathology , Child , Female , Humans , Quality of LifeABSTRACT
A modeling framework relating exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor (sVEGFR)-2, -3, soluble stem cell factor receptor (sKIT)), and tumor growth to overall survival (OS) was extended to include adverse effects (myelosuppression, hypertension, fatigue, and hand-foot syndrome (HFS)). Longitudinal pharmacokinetic-pharmacodynamic models of sunitinib were developed based on data from 303 patients with gastrointestinal stromal tumor. Myelosuppression was characterized by a semiphysiological model and hypertension with an indirect response model. Proportional odds models with a first-order Markov model described the incidence and severity of fatigue and HFS. Relative change in sVEGFR-3 was the most effective predictor of the occurrence and severity of myelosuppression, fatigue, and HFS. Hypertension was correlated best with sunitinib exposure. Baseline tumor size, time courses of neutropenia, and relative increase of diastolic blood pressure were identified as predictors of OS. The framework has potential to be used for early monitoring of adverse effects and clinical response, thereby facilitating dose individualization to maximize OS.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e85; doi:10.1038/psp.2013.62; advance online publication 4 December 2013.
ABSTRACT
The predictive value of longitudinal biomarker data (vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, and soluble stem cell factor receptor (sKIT)) for tumor response and survival was assessed based on data from 303 patients with imatinib-resistant gastrointestinal stromal tumors (GIST) receiving sunitinib and/or placebo treatment. The longitudinal tumor size data were well characterized by a tumor growth inhibition model, which included, as significant descriptors of tumor size change, the model-predicted relative changes from baseline over time for sKIT (most significant) and sVEGFR-3, in addition to sunitinib exposure. Survival time was best described by a parametric time-to-event model with baseline tumor size and relative change in sVEGFR-3 over time as predictive factors. Based on the proposed modeling framework to link longitudinal biomarker data with overall survival using pharmacokinetic-pharmacodynamic models, sVEGFR-3 demonstrated the greatest predictive potential for overall survival following sunitinib treatment in GIST.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e84; doi:10.1038/psp.2013.61; advance online publication 20 November 2013.
ABSTRACT
Osteonecrosis of the jaw is a severe bone disorder traditionally associated with periodontal disease, local malignancy, chemotherapy, glucocorticoid therapy, or trauma. Recently a growing number of publications reported the occurrence of osteonecrosis of the jaw in patients undergoing treatment with bisphosphonates. The mechanism by which bisphosphonates might contribute to the development of osteonecrosis of the jaw is far from being fully elucidated. Suppression of bone turnover, infection, tissue hypoxia and cellular toxicity were proposed as possible mechanisms by which bisphosphonates may exert adverse effects on bone metabolism. Here, we studied 25 consecutive patients treated with bisphosphonates for osteoporosis or tumoral pathologies. We provide good evidence of hyperactive osteoclastic bone resorption and suggest a direct cytotoxic effect of bisphosphonates on bone tissue through induction of osteocyte cell death. We also demonstrate that bisphosphonates only have limited adverse effects on bone vascular network.
Subject(s)
Bone Density Conservation Agents/adverse effects , Diphosphonates/adverse effects , Jaw Diseases/chemically induced , Jaw/pathology , Osteonecrosis/chemically induced , Aged , Aged, 80 and over , Bone Resorption/drug therapy , Bone Resorption/pathology , Female , Humans , Jaw Diseases/pathology , Male , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Middle Aged , Osteoclasts/drug effects , Osteoclasts/ultrastructure , Osteonecrosis/pathologyABSTRACT
To assess the QTc prolongation by ritonavir (RTV) 100 mg and explore its potential use as CYP3A inhibitor in thorough QTc (TQT) studies. Randomized, crossover study of single-dose RTV 100 mg, placebo, and moxifloxacin (MFLX) 400 mg in 65 healthy subjects with serial triplicate electrocardiograms obtained for 12 h post-dose. Largest mean placebo-adjusted QTcF increase from baseline (90% confidence interval (CI)) for RTV 100 mg was noninferior to placebo (0.16 ms (-1.38, 1.69)). Study sensitivity was validated by detecting the largest mean placebo-adjusted QTcF increase from baseline (90% CI) for MFLX of 8.31 ms (6.44, 10.18). A single dose of RTV 100 mg does not cause QTc prolongation in healthy subjects. Based on the potent CYP3A4 inhibition, lack of QTc effect and better safety profile, RTV 100 mg could replace ketoconazole as the CYP3A4 inhibitor in TQT studies.
Subject(s)
Cytochrome P-450 Enzyme Inhibitors , HIV Protease Inhibitors/adverse effects , Imidazoles/therapeutic use , Liver/drug effects , Long QT Syndrome/chemically induced , Reverse Transcriptase Inhibitors/therapeutic use , Ritonavir/adverse effects , Sulfur Compounds/therapeutic use , Adult , Aza Compounds/pharmacology , Cross-Over Studies , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical/methods , Drug Therapy, Combination , Electrocardiography , Female , Fluoroquinolones , HIV Protease Inhibitors/pharmacokinetics , Heart Rate/drug effects , Humans , Ketoconazole/pharmacology , Liver/enzymology , Long QT Syndrome/physiopathology , Male , Middle Aged , Moxifloxacin , Quinolines/pharmacology , Reference Values , Reproducibility of Results , Research Design , Ritonavir/pharmacokinetics , Treatment OutcomeABSTRACT
The low productivity and escalating costs of drug development have been well documented over the past several years. Less than 10% of new compounds that enter clinical trials ultimately make it to the market, and many more fail in the preclinical stages of development. These challenges in the "critical path" of drug development are discussed in a 2004 publication by the US Food and Drug Administration. The document emphasizes new tools and various opportunities to improve drug development. One of the opportunities recommended is the application of "model-based drug development (MBDD)." This paper discusses what constitutes the key elements of MBDD and how these elements should fit together to inform drug development strategy and decision-making.
Subject(s)
Clinical Trials as Topic/methods , Dose-Response Relationship, Drug , Drug Approval , Drug Design , Models, Biological , Pharmacology , Research Design , Alzheimer Disease/drug therapy , Alzheimer Disease/psychology , Amines/pharmacology , Amines/therapeutic use , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Anticholesteremic Agents/pharmacology , Anticholesteremic Agents/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Caproates/pharmacology , Caproates/therapeutic use , Cholesterol/blood , Clinical Trials as Topic/legislation & jurisprudence , Clinical Trials as Topic/statistics & numerical data , Cognition/drug effects , Computer Simulation , Cyclohexanecarboxylic Acids/pharmacology , Cyclohexanecarboxylic Acids/therapeutic use , Gabapentin , Glycoproteins/pharmacology , Glycoproteins/therapeutic use , Guidelines as Topic , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Immunologic Factors/pharmacology , Immunologic Factors/therapeutic use , Meta-Analysis as Topic , Models, Statistical , Muscarinic Agonists/pharmacology , Muscarinic Agonists/therapeutic use , Neuralgia, Postherpetic/drug therapy , Neutrophil Infiltration/drug effects , Oximes/pharmacology , Oximes/therapeutic use , Pharmacokinetics , Reproducibility of Results , Stroke/drug therapy , Stroke/immunology , United States , United States Food and Drug Administration , gamma-Aminobutyric Acid/pharmacology , gamma-Aminobutyric Acid/therapeutic useABSTRACT
Hurthle cell neoplasm is a rare form of thyroid tumors, comprising from 1.5% to 10% of all tumors. Hurthle cell nodules are clinically indistinguishable from other nodular thyroid diseases. The histologic features of Hurthle cell neoplasm don't allow us to exactly distinguish benign nodules from malignant ones. Accurate histologic valutation is possible and necessary for a correct diagnosis and therapy of Hurthle cell tumors. The adenomas usually exhibit a follicular pattern; the carcinomas include a subset of Hurthle cell tumors with different biological behavior, including malignant follicular variants and papillary ones. The authors are in favour of total thyroidectomy for carcinomas and lobectomy plus isthectomy for adenomas; in case of carcinomas, the lymphadenectomy reduces the incidence of local relapse and is necessary in case of lymphnode involvement. Adjuvant radiation therapy is successful in preventing recurrences, in symptomatic metastates as palliative therapy and control recurrence of advanced resected tumors.
Subject(s)
Adenoma, Oxyphilic/surgery , Thyroid Neoplasms/surgery , Adenoma, Oxyphilic/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Thyroid Neoplasms/pathologyABSTRACT
Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.
Subject(s)
Amphotericin B/pharmacokinetics , Antifungal Agents/pharmacokinetics , Amphotericin B/administration & dosage , Animals , Antifungal Agents/administration & dosage , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Female , Lipids/chemistry , Models, Biological , Rabbits , Reproducibility of ResultsABSTRACT
The purpose of this study was to identify the pharmacokinetics of Amphotericin B Colloidal Dispersion in patients undergoing bone marrow transplantations with systemic fungal infections and to assess the influence of ABCD on renal function. Seventy-five patients (42 females, 33 males) with a median age of 34.5 years and median weight of 70.0 kg were enrolled in the study. The plasma concentration data was available in 51/75 patients and was best described by a two-compartment model; both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Serum creatinine values over the duration of therapy were available in 59/75 patients. Overall, there was no net change in renal function over the duration of therapy.
Subject(s)
Amphotericin B/pharmacokinetics , Antifungal Agents/pharmacokinetics , Bone Marrow Transplantation , Fungemia/drug therapy , Kidney/drug effects , Mycoses/drug therapy , Adolescent , Adult , Amphotericin B/administration & dosage , Amphotericin B/therapeutic use , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Child , Child, Preschool , Creatinine/blood , Deoxycholic Acid/therapeutic use , Dose-Response Relationship, Drug , Drug Combinations , Female , Humans , Kidney Function Tests , Male , Middle Aged , Treatment OutcomeABSTRACT
The multiple dose pharmacokinetics of pegylated liposomal doxorubicin (PL-DOX), known as DOXIL (US) and CAELYX (EU), was characterized in dogs and a pharmacokinetic/pharmacodynamic model to identify a relationship between drug exposure and the probability of observing treatment-related palmar-plantar erythrodysesthesia (PPE) was developed. Twenty dogs were assigned to PL-DOX groups (2/sex/ group) that received intravenous PL-DOX doses of 0.5 mg/kg ql, 2, or 4 weeks; 1.0 mg/kg q2weeks; or 1.5 mg/kg q4weeks for 12 weeks. Blood was collected for HPLC analysis of doxorubicin concentration pre-dose and periodically up to 120 h after dosing three times during treatment. Plasma drug concentration was modeled using iterative 2-stage analysis. Dermal lesions (PPE) were scored twice weekly for six regions of each dog using a 0-6 severity scale; maximum severity was 36. PPE score data were modeled using an approach in which the % probability of PPE was related to a hypothetical effect site by a series of Hill-type functions. Pharmacokinetics were best modeled as a one-compartment open model. Vss (ml/kg), CLt (ml/hr/kg) and half-life (h) were 44.1, 1.39 and 23.1, respectively. Cmax increased linearly with dose. CLt decreased with repeated doses. 5 A two-compartment pharmacodynamic model, which correctly predicted 97% of the observed lesion severity, was developed to establish the relationship of lesion severity to dose intensity (a measure of drug exposure incorporating the effect of both dose level and dosing frequency, which can be expressed in units of mg/kg/week). The model demonstrated that maximal PPE was positively correlated with dose intensity, the major factor that affects the incidence and severity of dermal lesions. 6 The model can be used to predict acceptable dose intensities in humans utilizing body surface area conversion factors and comparative AUCs for dogs and humans. It predicts that a dose intensity of 10-12.5 mg/m2 of PL-DOX will be well tolerated in patients. The results of recent clinical studies are consistent with this prediction.
Subject(s)
Doxorubicin/pharmacology , Erythema/chemically induced , Liposomes/chemistry , Skin Ulcer/chemically induced , Animals , Dogs , Dose-Response Relationship, Drug , Doxorubicin/blood , Doxorubicin/toxicity , Female , MaleABSTRACT
PURPOSE: The pharmacokinetics (PK), biodistribution and therapeutic efficacy of cisplatin encapsulated in long-circulating pegylated (Stealth) liposomes (SPI-077) were compared with those of nonliposomal cisplatin in two murine (C26 colon carcinoma and Lewis lung) tumor models. METHODS: In therapeutic effectiveness studies, mice bearing murine C26 or Lewis lung tumors received multiple intravenous doses of SPI-077 or cisplatin in a variety of treatment schedules and cumulative doses. In the PK and biodistribution study, mice received a single intravenous bolus injection of 3 mg/kg of either SPI-077 or cisplatin 14 days after inoculation with 10(6) C26 tumor cells. Plasma and tissues were analyzed for total platinum (Pt) content by graphite furnace (flameless) atomic absorption spectrophotometery (GF-AAS). RESULTS: Efficacy studies showed that SPI-077 had superior antitumor activity compared to the same cumulative dose of cisplatin. When lower doses of SPI-077 were compared to cisplatin at its maximally tolerated dose in Lewis lung tumors, equivalent SPI-077 antitumor activity was seen at only half the cisplatin dose. Higher cumulative doses of SPI-077 were well tolerated and had increased antitumor effect. SPI-077 PK were characterized by a one-compartment model with nonlinear (saturable) elimination, whereas cisplatin PK were described by a two-compartment model with linear elimination. SPI-077 had a 55-fold lower [corrected] volume of distribution, 3-fold higher peak plasma levels, and a 60-fold larger plasma AUC compared with cisplatin. In addition, SPI-077-treated animals displayed a 4-fold reduction in Pt delivered to the kidneys (primary target organ of toxicity) relative to cisplatin, but a 28-fold higher tumor AUC than cisplatin. CONCLUSIONS: Based on the results of our studies, encapsulation of cisplatin in long-circulating pegylated liposomes has overcome limitations experienced with other liposomal cisplatin formulations. SPI-077 has a prolonged circulation time and increased tumor Pt disposition, and its antitumor effect is significantly improved compared to cisplatin in murine colon and lung cancer models.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Cisplatin/pharmacology , Cisplatin/pharmacokinetics , Algorithms , Animals , Antineoplastic Agents/administration & dosage , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/metabolism , Cisplatin/administration & dosage , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Drug Carriers , Injections, Intravenous , Liposomes , Mice , Mice, Inbred BALB C , Neoplasm Transplantation , Rats , Spectrophotometry, Atomic , Tissue DistributionABSTRACT
The topoisomerase I inhibitor GL147211C [7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-campto thecin trifluoroacetate], a camptothecin analogue, has significant activity in tumor cell cytotoxicity assays in vitro and antitumor activity in both animal tumor models and human patients. Its toxicity is significant, however, effectively limiting the amount of drug that can be administered and its clinical utility. To determine whether the therapeutic index of GL147211C could be improved, the drug was encapsulated in long-circulating, pegylated (STEALTH) liposomes (SPI-355). The pharmacokinetics and antitumor activity of SPI-355 were compared to those of nonliposomal GL147211C. The plasma pharmacokinetics of SPI-355 in rats were typical of those of other pegylated liposomal formulations, with significantly increased blood circulation time; the dose-corrected area under the curve and Cmax of SPI-355 (10 mg/kg) were 1250- and 35-fold higher, respectively, than those of nonliposomal GL14711C (8.72 mg/kg). The comparative antitumor activity of SPI-355 and nonliposomal GL1472211C was evaluated in nude mice implanted with HT29 colon carcinoma xenografts. SPI-355 was 20-fold more effective than GL147211C in inhibiting tumor growth (1 mg/kg SPI-355 and 20 mg/kg GL147211C) and produced durable complete remissions of tumors at well-tolerated dose levels that were >5-fold lower than the maximally tolerated dose of GL147211C, which induced no durable complete responses. Signs of toxicity were similar between the two drugs, but liposome encapsulation increased the toxicity of drug approximately 4-fold, with increased weight loss and several deaths with SPI-355 (5 mg/kg SPI-355 versus 20 mg/kg GL147211C). Despite the increased toxicity seen with SPI-355, the therapeutic index of the liposomal formulation was increased approximately 5-fold over that of nonliposomal GL147211C, suggesting that such a pegylated liposomal formulation could demonstrate increased therapeutic index in human patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Camptothecin/analogs & derivatives , Colonic Neoplasms/drug therapy , Enzyme Inhibitors/pharmacology , Topoisomerase I Inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Camptothecin/pharmacokinetics , Camptothecin/therapeutic use , Colonic Neoplasms/metabolism , Drug Carriers , Drug Screening Assays, Antitumor , HT29 Cells , Humans , Liposomes , Male , Mice , Mice, Nude , Neoplasm Transplantation , Rats , Rats, Sprague-Dawley , Transplantation, Heterologous , Treatment OutcomeABSTRACT
OBJECTIVE: To characterize the population pharmacokinetics of pegylated-liposomal doxorubicin in patients with acquired immunodeficiency disease (AIDS)-related Kaposi's sarcoma and to explore the relationship between response of the cutaneous Kaposi's sarcoma lesions to treatment and measures of drug exposure. METHODS: Forty-three male patients (median age, 40 years; age range, 28 to 50 years), body surface area, 1.89 m2; range, 1.5 to 2.3 m2) with AIDS and at least five biopsy-proven cutaneous Kaposi's sarcoma lesions were randomized to receive either a 10 or 20 mg/m2 dose of study drug for their first cycle and the alternate dose 3 weeks later. Patients continued to receive the study drug at a dose of 20 mg/m2 every 3 weeks. Serial blood samples were obtained after the first two doses and analyzed by HPLC for determination of total plasma doxorubicin concentration. Kaposi's sarcoma lesion response was categorized as either progressive disease, stable disease, partial response, or complete response. Classification and regression tree (CART) analysis was used to determine the relationship between drug exposure and categorical lesion response. Iterative two-stage analysis was used to characterize both the pharmacokinetics of pegylated-liposomal doxorubicin and to model the probabilities of achieving a specific lesion response. RESULTS: The pharmacokinetics of pegylated-liposomal doxorubicin were best described by a two-compartment linear structural model. Lesion response was significantly related to both the average daily maximum doxorubicin concentration (Cmax,avg) and dose intensity. CONCLUSIONS: The pharmacokinetics of pegylated-liposomal doxorubicin are strikingly different from conventional doxorubicin. Identification of both Cmax,avg and dose intensity as predictors of lesion response will provide guidelines for future dosing regimen designs.