Silver-doped calcium silicate sol-gel glasses with a cotton-wool-like structure for wound healing.

Skin has excellent capacity to regenerate, however, in the event of a large injury or burn skin grafts are required to aid wound healing. The regenerative capacity further declines with increasing age and can be further exacerbated with bacterial infection leading to a chronic wound. Engineered skin substitutes can be used to provide a temporary template for the damaged tissue, to prevent/combat bacterial infection and promote healing. In this study, the sol-gel process and electrospinning were combined to fabricate 3D cotton-wool-like sol-gel bioactive glass fibers that mimic the fibrous architecture of skin extracellular matrix (ECM) and deliver metal ions for antibacterial (silver) and therapeutic (calcium and silica species) actions for successful healing of wounds. This study investigated the effects of synthesis and process parameters, in particular sintering temperature on the fiber morphology, the incorporation and distribution of silver and the degradation rate of fibers. Silver nitrate was found to decompose into silver nanoparticles within the glass fibers upon calcination. Furthermore, with increasing calcination temperature the nanoparticles increased in size from 3 nm at 600 °C to ~25 nm at 800 °C. The antibacterial ability of the Ag-doped glass fibers decreased as a function of the glass calcination temperature. The degradation products from the Ag-doped 3D non-woven sol-gel glass fibers were also found to promote fibroblast proliferation thus demonstrating their potential for use in skin regeneration.

Hyaluronic acid hydrogels reinforced with laser spun bioactive glass micro- and nanofibres doped with lithium.

The repair of articular cartilage lesions in weight-bearing joints remains as a significant challenge due to the low regenerative capacity of this tissue. Hydrogels are candidates to repair lesions as they have similar properties to cartilage extracellular matrix but they are unable to meet the mechanical and biological requirements for a successful outcome. Here, we reinforce hyaluronic acid (HA) hydrogels with 13-93-lithium bioactive glass micro- and nanofibres produced by laser spinning. The glass fibres are a reinforcement filler and a platform for the delivery of therapeutic lithium-ions. The elastic modulus of the composites is more than three times higher than in HA hydrogels. Modelling of the reinforcement corroborates the experimental results. ATDC5 chondrogenic cells seeded on the composites are viable and more proliferation occurs on the hydrogels containing fibres than in HA hydrogels alone. Furthermore, the chondrogenic behavior on HA constructs with fibres containing lithium is more marked than in hydrogels with no-lithium fibres.

Can an amino acid-based oral rehydration solution be effective in managing immune therapy-induced diarrhea?

Immune checkpoint inhibitor (ICPi) therapy has transformed the way we treat cancer. However, its immune related adverse events (irAEs) can be debilitating and life threatening. Immune therapy-induced diarrhea (ITID) is one of the most commonly encountered irAEs and can lead to expensive and prolonged hospitalizations. The current standard of care for grade 3 or 4 ITID involves ICPi discontinuation, the initiation of steroids, and infliximab for refractory disease. This treatment regimen reverses the desired anti-tumor effect of ICPis, can lead to side effects, and is cost-ineffective. We report the first case of the successful treatment of grade 3 ITID with steroids and an amino acid-based oral rehydration solution (AA-ORS), enterade. Research suggests that AA-ORS may be used to reduce diarrhea and adequately hydrate patients, in contrast to glucose-based oral rehydration solutions, which have been implicated as a contributing factor to diarrhea in cancer patients. We hypothesize that an AA-ORS may mitigate ITID via safer and more economically viable means than the current standard of care, but more controlled trials are needed to test this hypothesis.

Sol-gel derived lithium-releasing glass for cartilage regeneration.

Wnt-signalling cascade is one of the crucial pathways involved in the development and homeostasis of cartilage. Influencing this pathway can potentially contribute to improved cartilage repair or regeneration. One key molecular regulator of the Wnt pathway is the glycogen synthase kinase-3 enzyme, the inhibition of which allows initiation of the signalling pathway. This study aims to utilise a binary SiO2-Li2O sol-gel derived glass for controlled delivery of lithium, a known glycogen synthase kinase-3 antagonist. The effect of the dissolution products of the glass on chondrogenic differentiation in an in vitro 3D pellet culture model is reported. Dissolution products that contained 5 mM lithium and 3.5 mM silicon were capable of inducing chondrogenic differentiation and hyaline cartilaginous matrix formation without the presence of growth factors such as TGF-ß3. The results suggest that sol-gel derived glass has the potential to be used as a delivery vehicle for therapeutic lithium ions in cartilage regeneration applications.

A synthetic redox biofilm made from metalloprotein-prion domain chimera nanowires.

Engineering bioelectronic components and set-ups that mimic natural systems is extremely challenging. Here we report the design of a protein-only redox film inspired by the architecture of bacterial electroactive biofilms. The nanowire scaffold is formed using a chimeric protein that results from the attachment of a prion domain to a rubredoxin (Rd) that acts as an electron carrier. The prion domain self-assembles into stable fibres and provides a suitable arrangement of redox metal centres in Rd to permit electron transport. This results in highly organized films, able to transport electrons over several micrometres through a network of bionanowires. We demonstrate that our bionanowires can be used as electron-transfer mediators to build a bioelectrode for the electrocatalytic oxygen reduction by laccase. This approach opens opportunities for the engineering of protein-only electron mediators (with tunable redox potentials and optimized interactions with enzymes) and applications in the field of protein-only bioelectrodes.

Lithium-silicate sol-gel bioactive glass and the effect of lithium precursor on structure-property relationships.

ABSTRACT: This work reports the synthesis of lithium-silicate glass, containing 10 mol% of Li 2 O by the sol-gel process, intended for the regeneration of cartilage. Lithium citrate and lithium nitrate were selected as lithium precursors. The effects of the lithium precursor on the sol-gel process, and the resulting glass structure, morphology, dissolution behaviour, chondrocyte viability and proliferation, were investigated. When lithium citrate was used, mesoporous glass containing lithium as a network modifier was obtained, whereas the use of lithium nitrate produced relatively dense glass-ceramic with the presence of lithium metasilicate, as shown by X-ray diffraction, 29 Si and 7 Li MAS NMR and nitrogen sorption data. Nitrate has a better affinity for lithium than citrate, leading to heterogeneous crystallisation from the mesopores, where lithium salts precipitated during drying. Citrate decomposed at a lower temperature, where the crystallisation of lithium-silicate crystal is not thermodynamically favourable. Upon decomposition of the citrate, a solid-state salt metathesis reaction between citrate and silanol occurred, followed by the diffusion of lithium within the structure of the glass. Both glass and glass-ceramic released silica and lithium ions in culture media, but release rate was lower for the glass-ceramic. Both samples did not affect chondrocyte viability and proliferation.

Reversible assembly of pH responsive branched copolymer-stabilised emulsion via electrostatic forces.

The judicious compositional and structural design of a branched co-polymeric surfactant allows for the production of highly stable oil in water emulsion droplets with reversible electrostatic aggregation behaviour.

Ductile silica/methacrylate hybrids for bone regeneration.

Bioglass® was the first synthetic material capable of bonding with bone without fibrous encapsulation, and fulfils some of the criteria of an ideal synthetic bone graft. However, it is brittle and toughness is required. Here, we investigated hybrids consisting of co-networks of high cross-linking density polymethacrylate and silica (class II hybrid) as a potential new generation of scaffold materials. Poly(3-(methoxysilyl)propyl methacrylate) (pTMSPMA) and tetraethyl orthosilicate (TEOS) were used as sol-gel precursors and hybrids were synthesised with different inorganic to organic ratios (Ih). The hybrids were nanoporous, with a modal pore diameter of 1 nm. At Ih = 50%, the release of silica was controlled by varying the molecular weight of pTMSPMA while retaining a specific surface area above 100 m2 g-1. Strain to failure increased to 14.2%, for Ih = 50% using a polymer of 30 kDa, compared to 4.5% for pure glass. The modulus of toughness (UT) increased from 0.73 (pure glass) to 2.64 GPa. Although, the hybrid synthesised in this report did not contain calcium, pTMSPMA/SiO2 hybrid was found to nucleate bone-like mineral on its surface after 1 week of immersion in simulated body fluid (SBF), whereas pure silica sol-gel glass did not. This increase in apatite forming ability was due to the ion-dipole complexation of calcium with the ester moieties of the polymer that were exposed after release of soluble silica from TEOS. No adverse cytotoxicity for MC3T3-E1 osteoblast-like cells was detected and improved cell attachment was observed, compared to a pure silica gel. pTMSPMA/SiO2 hybrids have potential for the regeneration of hard tissue as they overcome the major drawbacks of pure inorganic substrates while retaining cell attachment.

A structural and physical study of sol-gel methacrylate-silica hybrids: intermolecular spacing dictates the mechanical properties.

Sol-gel hybrids are inorganic/organic co-networks with nanoscale interactions between the components leading to unique synergistic mechanical properties, which can be tailored, via a selection of the organic moiety. Methacrylate based polymers present several benefits for class II hybrids (which exhibit formal covalent bonding between the networks) as they introduce great versatility and can be designed with a variety of chemical side-groups, structures and morphologies. In this study, the effect of high cross-linking density polymers on the structure-property relationships of hybrids generated using poly(3-trimethoxysilylpropyl methacrylate) (pTMSPMA) and tetraethyl orthosilicate (TEOS) was investigated. The complexity and fine scale of the co-network interactions requires the development of new analytical methods to understand how network evolution dictates the wide-ranging mechanical properties. Within this work we developed data manipulation techniques of acoustic-AFM and solid state NMR output that provide new approaches to understand the influence of the network structure on the macroscopic elasticity. The concentration of pTMSPMA in the silica sol affected the gelation time, ranging from 2 h for a hybrid made with 75 wt% inorganic with pTMSPMA at 2.5 kDa, to 1 minute for pTMSPMA with molecular weight of 30 kDa without any TEOS. A new mechanism of gelation was proposed based on the different morphologies derived by AC-AFM observations. We established that the volumetric density of bridging oxygen bonds is an important parameter in structure/property relationships in SiO2 hybrids and developed a method for determining it from solid state NMR data. The variation in the elasticity of pTMSPMA/SiO2 hybrids originated from pTMSPMA acting as a molecular spacer, thus decreasing the volumetric density of bridging oxygen bonds as the inorganic to organic ratio decreased.

RAFT Polymerization of N-[3-(Trimethoxysilyl)-propyl]acrylamide and Its Versatile Use in Silica Hybrid Materials.

Reversible addition-fragmentation chain transfer (RAFT) polymerization and characterization of an alkoxysilane acrylamide monomer using a trithiocarbonate chain transfer agent are described. Poly(N-[3-(trimethoxysilyl)propyl]acrylamide) (PTMSPAA) homopolymers are obtained with good control over the polymerization. A linear increase in the molecular weight is observed whereas the polydispersity values do not exceed 1.2 regardless of the monomer conversion. Moreover, PTMSPAA is used as a macro-RAFT agent to polymerize N-isopropylacrylamide (NIPAM). By varying the degree of polymerization of NIPAM within the block copolymer, different sizes of thermoresponsive particles are obtained. These particles are stabilized by the condensation of the alkoxysilane moieties of the polymers. Furthermore, a co-network of silica and PTMSPAA is prepared using the sol-gel process. After drying, transparent mesoporous hybrids are obtained with a surface area of up to 400 m(2) g(-1).

A unified in vitro evaluation for apatite-forming ability of bioactive glasses and their variants.

The aim of this study was to propose and validate a new unified method for testing dissolution rates of bioactive glasses and their variants, and the formation of calcium phosphate layer formation on their surface, which is an indicator of bioactivity. At present, comparison in the literature is difficult as many groups use different testing protocols. An ISO standard covers the use of simulated body fluid on standard shape materials but it does not take into account that bioactive glasses can have very different specific surface areas, as for glass powders. Validation of the proposed modified test was through round robin testing and comparison to the ISO standard where appropriate. The proposed test uses fixed mass per solution volume ratio and agitated solution. The round robin study showed differences in hydroxyapatite nucleation on glasses of different composition and between glasses of the same composition but different particle size. The results were reproducible between research facilities. Researchers should use this method when testing new glasses, or their variants, to enable comparison between the literature in the future.

Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea.

Chemotherapy-induced diarrhea (cid) is a common side effect of cancer treatment and can cause significant morbidity and mortality. Diarrhea is frequently severe enough to require a dose reduction of, a delay in, or a discontinuation of chemotherapy. Diarrhea-associated mortality has been reported to be as high as 3.5% in clinical trials of irinotecan and bolus 5-fluorouracil in colorectal cancer. The frequency of cid and its impact on patient management are frequently under-recognized in clinical practice.A Canadian working group, consisting of medical oncologists and an oncology pharmacist, was formed in 2001 to review the optimal approach to managing cid and to identify and implement new areas of research. The recommendations that follow are the result of the group's work.Acute medical management of cid includes loperamide or diphenoxylate as first-line agents. Subcutaneous octreotide is recommended for intractable grade 2 diarrhea and may be considered for grade 1 cid that does not resolve with high-dose loperamide. Hospitalization is recommended for patients with grades 3 and 4 cid; in-hospital care includes rehydration, antibiotic therapy, and octreotide.A chemotherapy dose reduction is generally advised for patients who have experienced grade 3 or 4 diarrhea in a previous chemotherapy cycle. If a dose reduction is not desired, prophylaxis with intramuscular long-acting release octreotide may be considered.The foregoing recommendations are based on expert opinion and require validation in prospective clinical trials.

High-dose indium 111In pentetreotide radiotherapy for metastatic atypical carcinoid tumor.

Indium In 111 pentetreotide imaging of neuroendocrine tumors that overexpress somatostatin receptors has become standard for localization of these tumors. This radioligand is internalized into the cell and can induce receptor-specific cytotoxicity by emission of Auger electrons. We hypothesized that high-dose 111In-pentetreotide could be therapeutic in patients with somatostatin receptor-expressing tumors. Our 35-year-old patient had atypical carcinoid tumor metastatic to cervical, supraclavicular, mediastinal, and mesenteric lymph nodes and to the liver and bone. Chemotherapy had stabilized the disease but with severe gastrointestinal side effects. After a diagnostic 111In-pentetreotide scan, the patient was given eight courses (180 mCi each) of 111In-pentetreotide therapy to selectively target somatostatin receptor-expressing tumor cells. The disease was stable for approximately 14 months. The patient had two additional courses of 111In-pentetreotide therapy (360 mCi each). She died of the disease approximately 18 months after initiation of 111In-pentetreotide therapy.

In situ radiotherapy with 111In-pentetreotide. State of the art and perspectives.

111In-pentetreotide (Octreoscan) and other radiolabeled somatostatin analogs are useful in the management of well differentiated neuroendocrine malignancies such as carcinoid or islet cell neoplasms. These radiopeptides bind to membrane bound somatostatin receptors (sst 1-5) which are over-expressed in a wide variety of neoplasms, especially those arising from the neuroectoderm. Imaging advances allow for the noninvasive determination of the presence of sst receptors by combining radioactivity [111Indium with a somatostatin analog, DTPA-D-phe1-octreotide (pentetreotide)]. Radiolabeled somatostatin analogs bind to membrane receptors and internalization of the complex occurs. Auger emitting somatostatin analogs offer a novel and significantly less toxic approach to controlling neoplastic diseases by delivering targeted radiation specifically to receptor bearing cells while sparing receptor negative cells. Responses of 62-69% in 85 patients with metastatic neuroendocrine tumors treated with high dose (6-19.6 GBq) 111In-pentetreotide, specifically targeting tumor somatostatin receptors, have been reported. Objective responses observed included biochemical and radiographic responses with prolonged survival. This article will discuss and review the multi-center data available to date, the mechanisms of action of radiolabeled somatostatin analogs, dosimetry, clinical response parameters, and toxicity.

Long-acting formulations of somatostatin analogues.

Somatostatin has represented a significant breakthrough in the treatment of patients with hormonally-acting, neuroendocrine gastroenteropancreatic neoplasms, even if its short half-life made it impractical in the clinic. In recent years, new long-acting formulations have been developed from the native peptide. The long-lasting formulation of the somatostatin analogue octreotide (octreotide-LAR) can be administered once-monthly and has been shown to provide similar efficacy to subcutaneous octreotide administered three times a day in the control of flushing and diarrhoea associated with the carcinoid syndrome. Another-long acting somatostatin analogue, lanreotide, is available in a slow-release form, lanreotide-SR. In a multicentre 6-month trial on carcinoid tumour patients, 30 mg lanreotide-SR were administered intramuscularly every 14 days, obtaining the control of symptoms in the majority of subjects. Thus, both octreotide-LAR administered monthly, and lanreotide-SR administered every 10-14 days, have been shown to be an effective tool in the treatment of carcinoid tumours, providing, in addition, a substantial improvement in patient compliance.

Experiences with high dose radiopeptide therapy: the health physics perspective.

One of the new, promising areas of nuclear medicine involves radiolabeled low-molecular-weight peptides for the diagnosis and management of cancer. Somatostatin analogous peptides bind to membrane receptors on tumors with high specificity. These analogues, when radiolabeled with 123I, 131I, 99mTc, or (111)In, allow for external scintigraphic imaging or radioguided surgical resection of tumors. Somatostatin analogues with high tumor binding affinity have also been used for high-dose radiotherapy at the Medical Center of Louisiana since 1994. Although we had extensive prior experience with relatively high-dose 131I administration for thyroid ablation, our personnel protection, contamination control, and other safety techniques required significant modification to ensure effective contamination and radiation exposure control. As therapy with radiolabeled peptides becomes more widely utilized, the controls developed at our institution may be implemented by others to maintain exposures ALARA.

Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease.

OBJECTIVES: To study the applicability of a newly developed echocardiographic scoring system in the assessment of carcinoid valvular heart disease. BACKGROUND: We investigated prospectively the development, progression and regression of carcinoid valvular heart disease in patients with carcinoid syndrome by serial echocardiography, correlating these features with urinary 5-HIAA levels and clinical data collected during therapy with somatostatin analog. METHODS: Twenty-three patients with carcinoid syndrome underwent serial echocardiographic examinations. An echocardiographic carcinoid valvular heart disease (CVHD) % score was determined from points assigned for tricuspid and pulmonary valve structure and function. RESULTS: Fifteen patients had no CVHD at study entry (group 1), while 8 patients had findings of CVHD (group 2). Five patients in group q developed new CVHD (1B), while one demonstrated progression of CVHD (2B). The remaining patients did not develop (1A) or had no progression of CVHD (2B). Despite major declines in 5-HIAA levels during therapy in most patients, CVHD did not regress. There were significantly lower levels of median baseline 5-HIAA (98.8 vs. 256 mg/24 h), posttreatment 5-HIAA (50.3 vs. 324 mg/24 h) and posttreatment 5-HIAA time integral (37.3 vs. 192 g/24 h* days) in group A vs. B (p < 0.05). However, only posttreatment 5-HIAA levels independently predicted the development or progression of CVHD by multiple step-wise regression analysis (p < 0.005), with a threshold observed in the 100 mg/24 h range. CONCLUSIONS: We designed a new echocardiographic scoring system to evaluate CVHD. Correlating echocardiographic scores with biochemical and clinical markers showed that only posttreatment 5-HIAA levels independently predicted the development or progression of CVHD. This study strengthens the association between serotonin secretion and CVHD, as well as introducing a new technique for serial follow-up of these patients.

Hepatic artery chemoembolization for management of patients with advanced metastatic carcinoid tumors.

BACKGROUND: Patients with advanced metastatic carcinoid tumors who have disease progression despite conventional therapy are left with few therapeutic options. Hepatic artery chemoembolization (HACE) may play a role in palliating these patients' symptoms. METHODS: Fifteen patients with biopsy-proven advanced bilobar hepatic carcinoid metastases who demonstrated progression of symptoms and/or tumor size despite treatment with somatostatin analogues were treated with intra-arterial chemotherapy and HACE to determine efficacy and safety. Five days of intra-arterial 5-fluorouracil (1 g/m2) were followed by HACE with adriamycin (60 mg), cisplatin (100 mg), mitomycin C (30 mg), and polyvinyl alcohol (Ivalon); 200 micron to 710 micron). Patients were continued on octreotide at the same dose (150 to 2000 microg subcutaneous q 8 hours) before, during, and after the procedure. RESULTS: Efficacy of treatment was assessed by comparing pretreatment and 3-month clinical, laboratory, radiographic, and quality of life parameters. Symptoms were improved in 8 of 12 patients who had diarrhea, 7 of 12 who had flushing, 9 of 12 who had abdominal pain, and in 4 of 7 who had malaise. Elevated tumor markers decreased in all patients. Biochemical markers (mean +/- SE) at 3 months decreased by 60% +/- 6% for 5-HIAA, 75% +/- 10% for chromogranin A and 50% +/- 7% for neuron-specific enolase. Tomographic assessment revealed tumor liquefaction in 10 of 13 patients. The Karnofsky performance status improved from a mean of 66 +/- 2 to 84 +/- 2 (P <0.001). Median follow-up was 16 months, with 13 deaths occurring from 1 week to 71 months after treatment. CONCLUSIONS: Hepatic artery chemoembolization improves symptoms of carcinoid syndrome, has a high tumor response rate, and improves short-term quality of life in this group of patients with advanced hepatic carcinoid disease.

In situ radiotherapy with 111In-pentetreotide: initial observations and future directions.

PURPOSE: Somatostatin and its analogues, such as octreotide and lanreotide, are used to treat neuroendocrine malignancies. Somatostatin analogues bind to somatostatin receptors (sst 1-5), which are differentially expressed in a wide variety of neoplasms. Following ligand receptor binding, a fraction of these complexes internalize. Internalization of radiolabeled somatostatin analogues, especially those that emit Auger electrons, may allow treatment of somatostatin-receptor-positive tumors by delivering a radioactive isotope to the cancer cell in a targeted fashion. 111In-pentetreotide, an sst-2-preferring somatostatin analogue, has been used for scintigraphic evaluation and management of neuroendocrine cancer patients. We hypothesized that binding and internalization of 111In-pentetreotide, an Auger electron emitter, may induce receptor-specific cytotoxicity and could be a useful therapeutic agent in somatostatin-receptor-expressing malignancies. METHODS: To test this hypothesis, subjects who had failed conventional therapy and had somatostatin-receptor-positive malignancies, as determined by positive uptake on a 6.0 mCi 111In-pentetreotide scan, were treated with two monthly 180 mCi intravenous injections of 111In-pentetreotide. CT scans were obtained before therapy and within 30 days following the completion of the second 111In-pentetreotide dose. Toxicity was evaluated using standard criteria. RESULTS: Fourteen patients were studied from February 1997 to August 1997. Clinical benefit occurred in six of 10 gastroenteropancreatic tumor patients. Objective partial radiographic responses occurred in two of 14 patients, and significant tumor necrosis (defined by changes in Hounsfield units) developed in six of the 10 gastroenteropancreatic tumor patients. Possible treatment-related toxicity included two patients experiencing grade 3/4 myelosuppression, and two patients had no measurable toxicity. The most common toxicity was grade 1/2 hemoglobin (N = 6). CONCLUSION: One hundred eighty millicurie (180-mCi) doses of 111In-pentetreotide are well tolerated and are an effective therapy in some subjects with somatostatin receptor-expressing tumors. The maximal tolerated dose of 111In-pentetreotide and the optimal dosing schedules remain to be determined.

Pharmacokinetics of an intravenous-oral versus intravenous-mesna regimen in lung cancer patients receiving ifosfamide.

PURPOSE: To compare the pharmacokinetics of the approved I.V. (intravenous) mesna regimen and an investigational I.V.-oral regimen that could be used in outpatients who receive ifosfamide. PATIENTS AND METHODS: The I.V. regimen consisted of three I.V. mesna doses given at 0, 4, and 8 hours after ifosfamide administration. The investigational regimen included an I.V. mesna dose given concurrently with ifosfamide, followed 2 and 8 hours later by oral administration of mesna tablets. I.V. and oral mesna doses equaled 20% and 40%, respectively, of the ifosfamide dose. The study subjects were 12 lung cancer patients who received ifosfamide 1.2 g/m2 daily for 5 days. The patients were randomized to receive either the I.V.-oral or I.V. mesna regimen on day 1, followed by crossover to the other regimen on days 2 through 5 of ifosfamide treatment. The urinary profiles of mesna and dimesna excretion were determined on days 1, 2, and 5; pharmacokinetic parameters for blood samples were determined only on day 5. RESULTS: During the first 12 hours after ifosfamide administration, the amount of mesna excreted and the profile of urinary mesna excretion was similar for both regimens; however, the I.V.-oral regimen showed less fluctuation in the excretion rate and higher trough values. During hours 12 to 24, about eightfold more mesna was excreted by patients given the I.V.-oral than the I.V. regimen. CONCLUSION: These pharmacokinetic data show that the I.V.-oral regimen should be at least as uroprotective as the I.V. mesna regimen. Patients may also benefit from the I.V.-oral regimen because of the higher trough values during hours 0 through 12 and the sustained urinary mesna excretion during hours 12 through 24.