The Effect of Daily Methylsulfonylmethane (MSM) Consumption on High-Density Lipoprotein Cholesterol in Healthy Overweight and Obese Adults: A Randomized Controlled Trial.

Interventions to decrease inflammation and improve metabolic function hold promise for the prevention of obesity-related diseases. Methylsulfonylmethane (MSM) is a naturally occurring compound that demonstrates antioxidant and anti-inflammatory effects. Improvements in measures of metabolic health have been observed in mouse models of obesity and diabetes following MSM treatment. However, the effects of MSM on obesity-related diseases in humans have not been investigated. Therefore, the purpose of this investigation was to determine whether MSM supplementation improves cardiometabolic health, and markers of inflammation and oxidative status. A randomized, double-blind, placebo-controlled design was utilized with a total of 22 overweight or obese adults completing the study. Participants received either a placebo (white rice flour) or 3 g MSM daily for 16 weeks. Measurements occurred at baseline and after 4, 8, and 16 weeks. Outcome measures included fasting glucose, insulin, blood lipids, blood pressure, body composition, metabolic rate, and markers of inflammation and oxidative status. The primary finding of this work shows that high-density lipoprotein cholesterol was elevated at 8 and 16 weeks of daily MSM consumption compared to baseline, (p = 0.008, p = 0.013). Our findings indicate that MSM supplementation may improve the cholesterol profile by resulting in higher levels of high-density lipoprotein cholesterol.

Pharmacokinetic assessment of constituents of Boswellia serrata, pine bark extracts, curcumin in combination including methylsulfonylmethane in healthy volunteers.

OBJECTIVES: Dietary supplements are increasingly used by people with osteoarthritis. Boswellia serrata extract, curcumin, pine bark extract and methylsulfonylmethane have been identified as having the largest effects for symptomatic relief in a systematic review. It is important to understand whether any pharmacokinetic interactions are among the major constituents of these supplements so as to provide information when considering the combination use of these supplements. The aim of this study was to investigate the pharmacokinetics of the constituents alone and in combination. METHODS: This study was a randomized, open-label, single-dose, four-treatment, four-period, crossover study with 1-week washout. The pharmacokinetics of the constituents of these supplements when dosed in combination with methylsulfonylmethane were compared to being administered alone. Plasma samples were obtained over 24 h from 16 healthy participants. Eight major constituents were analysed using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay. KEY FINDINGS: The pharmacokinetics of each constituent was characterized, and there were no significant differences in the pharmacokinetic profiles of the constituents when administered as a combination, relative to the constituents when administered alone (P > 0.05). CONCLUSIONS: These data suggest that interactions between the major constituents of this supplement combination are unlikely and therefore could be investigated to manage patients with osteoarthritis without significant concerns for possible pharmacokinetic interactions.

Phase I study of KRP-116D, a 50% w/w dimethyl sulfoxide aqueous solution, on the systemic absorption from bladder by intravesical instillation in healthy Japanese subjects.

OBJECTIVE: This was a single-institution, single-dose, single-arm phase 1 study in healthy adult males to evaluate the safety and absorption of dimethyl sulfoxide (DMSO) from the bladder into the body when KRP-116D (a 50% w/w DMSO solution) was intravesically administered and allowed to remain in the bladder for 15 minutes. METHODS: Six healthy adult males were enrolled in this study. KRP-116D (50 mL) was instilled directly into the bladder via a catheter where it was allowed to remain for 15 minutes under lidocaine anesthesia in accordance with the usage of RIMSO-50 (50% w/w DMSO solution) approved in the USA. The residual DMSO solution in the bladder was collected 15 minutes after instillation. The concentrations of DMSO in the plasma and the recovered solution were analyzed by a validated high-performance liquid chromatography (HPLC) method. The concentration in the residual DMSO solution was multiplied by the solution volume and divided by the dosage to calculate the recovery rate of DMSO. RESULTS: Plasma DMSO was detected in one of six subjects, and in the remaining five subjects DMSO was not detected (<19.6 µg/mL). The recovery rate of DMSO from the bladder was 60.7% to 93.7%. The only drug-related adverse event was breath odor (garlic-like breath) observed in four of six subjects (66.7%). CONCLUSION: Absorption of DMSO from the bladder was low (16.3%), and the systemic exposure was limited. Most of the DMSO was recovered from the bladder. KRP-116D 50 mL was well tolerated and safe.

Pharmacokinetics, disposition, and plasma concentrations of dimethyl sulfoxide (DMSO) in the horse following topical, oral, and intravenous administration.

Compartmental models were used to investigate the pharmacokinetics of intravenous (i.v.), oral (p.o.), and topical (TOP) administration of dimethyl sulfoxide (DMSO). The plasma concentration-time curve following a 15-min i.v. infusion of DMSO was described by a two-compartment model. Median and range of alpha (t1/2α ) and beta (t1/2ß ) half-lives were 0.029 (0.026-0.093) and 14.1 (6.6-16.4) hr, respectively. Plasma concentration-time curves of DMSO following p.o. and TOP administration were best described by one-compartment absorption and elimination models. Following the p.o. administration, median absorption (t1/2ab ) and elimination (t1/2e ) half-lives were 0.15 (0.01-0.77) and 15.5 (8.5-25.2) hr, respectively. The plasma concentrations of DMSO were 47.4-129.9 µg/ml, occurring between 15 min and 4 hr. The fractional absorption (F) during a 24-hr period was 47.4 (22.7-98.1)%. Following TOP administrations, the median t1/2ab and t1/2e were 1.2 (0.49-2.3) and 4.5 (2.1-11.0) hr, respectively. Plasma concentrations were 1.2-8.2 µg/ml occurring at 2-4 hr. Fractional absorption following TOP administration was 0.48 (0.315-4.4)% of the dose administered. Clearance (Cl) of DMSO following the i.v. administration was 3.2 (2.2-6.7) ml hr-1  kg-1 . The corrected clearances (ClF ) for p.o. and TOP administrations were 2.9 (1.1-5.5) and 4.5 (0.52-18.2) ml hr-1  kg-1 .

Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis.

Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome.

A long-lived ferrocene-conjugated iridium(III) complex for sensitive turn-on luminescence detection of traces of DMSO in water and human serum.

The development of an efficient sensor for the determination of the DMSO content in aqueous solution is highly desirable in a number of chemical industries. Presented herein is a ferrocene-conjugated iridium(III) complex, which exhibits remarkable capability to detect traces of DMSO (<1% v/v) in aqueous solution through a turn-on luminescence sensing mechanism. The extraordinary sensitivity and selectivity of this newly developed complex for DMSO renders it as one of the most powerful DMSO sensors known.

Small Intestinal Absorption of Methylsulfonylmethane (MSM) and Accumulation of the Sulfur Moiety in Selected Tissues of Mice.

The principal dietary sources of sulfur, the amino acids methionine and cysteine, may not always be consumed in adequate amounts to meet sulfur requirements. The naturally occurring organosulfur compound, methylsulfonylmethane (MSM), is available as a dietary supplement and has been associated with multiple health benefits. Absorption of MSM by the small intestine and accumulation of the associated sulfur moiety in selected tissues with chronic (8 days) administration were evaluated using juvenile male mice. Intestinal absorption was not saturated at 50 mmol, appeared passive and carrier-independent, with a high capacity (at least 2 g/d-mouse). The 35S associated with MSM did not increase in serum or tissue homogenates between days 2 and 8, indicating a stable equilibrium between intake and elimination was established. In contrast, proteins isolated from the preparations using gel electrophoresis revealed increasing incorporation of 35S in the protein fraction of serum, cellular elements of blood, liver, and small intestine but not skeletal muscle. The potential contributions of protein synthesis using labeled sulfur amino acids synthesized by the gut bacteria and posttranslational sulfation of proteins by incorporation of the labeled sulfate of MSM in 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and subsequent transfer by sulfotransferases are discussed.

Quantification of dimethylsulfoxide (DMSO) in equine plasma and urine using HILIC-MS/MS.

This paper describes quantitative methods for the determination of dimethylsulfoxide (DMSO) in equine plasma and urine based on simple precipitation and dilution followed by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry (HILIC-MS/MS). DMSO is a polar solvent with analgesic and anti-inflammatory properties. Its pharmacological features make it prohibited in horse racing. However, since DMSO is naturally present in the horses' environment, international threshold values have been implemented for plasma and urine (1 and 15 µg/mL, respectively). Previously presented quantitative methods for the determination of DMSO are based on gas chromatography, thus demanding a tedious extraction step to transfer the analyte from the aqueous bodily fluid to an injectable organic solvent. The column used in the presented method was an Acquity BEH HILIC and the mobile phase was a mixture of ammonium acetate buffer and acetonitrile delivered as a gradient. Hexadeuterated DMSO (2 H6 -DMSO) was used as the internal standard. Validation was performed in the range of the international thresholds concerning selectivity, carry-over, linearity, precision, accuracy, stability and inter-individual matrix variation. The results fulfilled the predefined criteria and the methods were considered fit for purpose. Successful applications on real equine doping control samples were carried out with determined DMSO concentrations exceeding the international thresholds. Copyright © 2016 John Wiley & Sons, Ltd.

Impact of low- and high-molecular-mass components of human serum on NAMI-A binding to transferrin.

Imidazolium trans-tetrachloridodimethylsulfoxideimidazolruthenate(III), NAMI-A, a novel antimetastatic ruthenium complex was investigated towards affinity to transferrin (Tf), whether Tf-Ru adducts might be formed after its intravenous injection. Studies were focused on the holotransferrin due to its preferential binding to transferrin receptor. Here, we showed that holotransferrin is able to bind NAMI-A as readily as apotransferrin. The simulation of biological conditions of human serum performed by application of simplified serum models allowed to analyse ruthenium distribution between transferrin and albumin. The presence of physiological concentration of albumin (ca. 18-fold excess over Tf) resulted in a twofold decrease of ruthenium binding to Tf. Interestingly, the introducing of low-molecular-mass components of serum dramatically increased the ruthenation of Tf. Intermolecular competition binding studies between transferrin and albumin showed that both proteins bound similar amount of ruthenium species. Investigation of NAMI-A binding to Tf in human serum showed that this protein was not the major binding partner for Ru complex. However, in spite of many competing proteins still the ruthenation of Tf was observed. The lack of free Ru species (protein unbounded) after incubation with human serum allowed to make an assumption of high affinity of NAMI-A towards serum proteins.

Simultaneous observation of the metabolism of cisplatin and NAMI-A in human plasma in vitro by SEC-ICP-AES.

Single drug-based cancer therapies are frequently associated with the development of drug resistance. To overcome this problem, combination therapy with two or more anticancer drugs is a promising strategy, but clinical studies are logistically challenging and costly. Intermediary in vitro studies, however, can provide critical insight to decide whether one should proceed to in vivo studies. To this end, cisplatin and the Ru-based anticancer drug NAMI-A were added to human plasma and the size distribution of Pt-containing and Ru-containing entities was determined over a 2 h period. The results revealed a dramatically different rate of plasma protein binding for each drug and/or their hydrolysis products. Both drugs bound to the same apparent plasma proteins, but crucially they did not adversely affect each other's metabolism. Therefore, combination therapy of patients with these metallodrugs should be further assessed in clinical studies in order to systematically develop an effective combination therapy protocol to prevent the resurgence of cancer.

Synthesis and detection of toltrazuril sulfone and its pharmacokinetics in horses following administration in dimethylsulfoxide.

Triazine-based antiprotozoal agents are known for their lipophylic characteristics and may therefore be expected to be well absorbed following oral administration. However, although an increase in lipid solubility generally increases the absorption of chemicals, extremely lipid-soluble chemicals may dissolve poorly in gastrointestinal (GI) fluids, and their corresponding absorption and bioavailability would be low. Also, if the compound is administered in solid form and is relatively insoluble in GI fluids, it is likely to have limited contact with the GI mucosa, and therefore, its rate of absorption will be low. Based on the above considerations, we sought a solvent with low or no toxicity that would maintain triazine agents in solution. As the oral route is most preferred for daily drug therapy, such a solvent would allow an increased rate of absorption following oral administration. In present study, it was demonstrated that dimethylsulfoxide (DMSO) increased the oral bioavailability of toltrazuril sulfone (Ponazuril) threefold, relative to oral administrations of toltrazuril sulfone suspended in water. The cross-over study of toltrazuril sulfone formulated in DMSO indicated that the absolute oral bioavailability of toltrazuril sulfone in DMSO is 71%. The high bioavailability of the DMSO-preparation suggests that its daily oral administration will routinely yield effective plasma and cerebral spinal fluid (CSF) concentrations in all horses treated. Also, this improved formulation would allow clinicians to administer loading doses of toltrazuril sulfone in acute cases of Equine Protozoal Myeloencephalitis. Another option would involve administration of toltrazuril sulfone in DMSO mixed with feed (1.23 kg daily dose) meeting the US Food and Drug Administration (FDA) recommendations for the levels of DMSO permissible in pharmaceutical preparations.

Maternal and cord serum exposure to PCB and DDE methyl sulfone metabolites in eastern Slovakia.

Polychlorinated biphenyls (PCBs) were commercially produced between 1959 and 1984 in eastern Slovakia. Improper handling led to a highly contaminated local environment and high levels of PCBs in humans and wildlife in the Michalovce area. The aim of this study was to analyse serum for methylsulfonyl metabolites of PCB (MeSO(2)-PCBs) and DDE (3-MeSO(2)-DDE) in serum samples from pregnant women and in a selected number of paired cord blood samples to assess maternal sulfone levels and patterns, and transplacental transfer of these metabolites. The donating women were from two districts in eastern Slovakia. A liquid-liquid extraction method together with separation of substance groups and further clean-up on silica gel columns were applied prior to analysis by gas chromatography/mass spectrometry. 3-MeSO(2)-DDE was the major methyl sulfone in most of the samples followed by a yet not identified MeSO(2)-hexaCB, 4'-MeSO(2)-CB101, 4'-MeSO(2)-CB87 and 4-MeSO(2)-CB149. The women from the contaminated area had three times higher concentrations of the MeSO(2)-PCBs than women from the reference area. This is the first report on methyl sulfone metabolites of PCB and DDE in human cord serum. It is shown that these metabolites are transported through the placenta. The levels of MeSO(2)-PCBs in the maternal serum were about 1.5 times higher than in the corresponding cord serum on a lipid weight basis. For 3-MeSO(2)-DDE, the levels were about the same in maternal and cord serum. The difference in the maternal:cord ratio, comparing MeSO(2)-PCBs with 3-MeSO(2)-DDE might be due to differences in transport through the placenta caused by their different affinities for lipoproteins and plasma proteins.

Collection strategies and cryopreservation of umbilical cord blood.

The aim of this study was to compare (a) two different umbilical cord blood (UCB) collection methods while the placenta is still in the uterus (in utero), and (b) to evaluate the efficacy of four cryopreservation protocols based on UCB haematopoiestic stem cell (HSC) recovery. We analysed UCB samples collected with our original collection system designed for active Syringe/Flush/Syringe method or by standard in utero method. For comparing different cryopreservation procedures, dimethyl sulphoxide (DMSO) at final concentration of 5 and 10% was used and combined with our own controlled-rate or uncontrolled-rate cryopreservation. A total of 99 samples were collected. A significantly higher UCB volume, total nucleated cell and mononuclear cell were seen following the first collection strategy (n= 49; mean +/- SD, 103 +/- 35.4 mL; 12.34 +/- 5.27 x 10(8); 595 +/- 3.47 x 10(6)) vs. the second strategy (n= 50; 86 +/- 29.3 mL; 9.87 +/- 4.47; 424 +/- 2.82 x 10(6)) respectively (P < 0.01). The discard rate was 14% for the first and 36% for the second collection strategy (P < 0.01). It was shown that the most efficient procedure was the controlled-rate protocol combined with lower (5%) DMSO concentration. Using active Syringe/Flush/Syringe method, we collected UCB with greater volumes and with lower discard rate compared to the standard by gravity technique. The data presented also showed much better recovery of UCB cells when controlled-rate freezing procedure and 5% DMSO were combined.

Determination of ruthenium originating from the investigational anti-cancer drug NAMI-A in human plasma ultrafiltrate, plasma, and urine by inductively coupled plasma mass spectrometry.

We present a highly sensitive, rapid method for the determination of ruthenium originating from the investigational anti-cancer drug NAMI-A in human plasma ultrafiltrate, plasma, and urine. The method is based on the quantification of ruthenium by inductively coupled plasma mass spectrometry and allows quantification of 30 ng L(-1) ruthenium in plasma ultrafiltrate and urine, and 75 ng L(-1) ruthenium in human plasma, in 150 microL of matrix. The sample pretreatment procedure is straightforward and only involves dilution with appropriate diluents. The performance of the method, in terms of accuracy and precision, fulfilled the most recent FDA guidelines for bioanalytical method validation. Validated ranges of quantification were 30.0 to 1 x 10(4) ng L(-1) for ruthenium in plasma ultrafiltrate and urine and 75.0 to 1 x 10(4) ng L(-1) for ruthenium in plasma. The applicability of the method and its superiority to atomic-absorption spectrometry were demonstrated in two patients who were treated with intravenous NAMI-A in a phase I trial. The assay is now successfully used to support pharmacokinetic studies in cancer patients treated with NAMI-A.

A new automated cell washer device for thawed cord blood units.

BACKGROUND: The current available techniques to wash out DMSO from thawed umbilical cord blood (UCB) units are based essentially on standard centrifugation in an open system with various degrees of cell loss. STUDY DESIGN AND METHODS: We evaluated the capacity of a new automated closed device (Cytomate, Baxter, IL) to wash out the DMSO from thawed UCB units, saving at the same time the progenitor and accessory cells in terms of CD34+ cells and MNCs. We modified the standard software of the device and calculated the cell recovery on 25 UCB units. Moreover, we set up a new gas chromatographic method to exactly detect the DMSO removal rate. RESULTS: To evaluate the efficiency of the Cytomate device, we considered the postthawing (prewashing) versus postwashing cell recovery. The average recovery (%) in terms of total nucleated cells was 63.30 (range, 40.12-89.00), CD34+ cells was 70.20 (range, 11.51-89.01), CD3+ cells was 61.01 (range, 28.80-87.08), CD4+ cells was 62.53 (range, 30.62-96.73), CD8+ cells was 57.4 (range, 26.87-94.72), CD19+ cells was 63.33 (range, 39.10-90.33), CD16+/56+ cells was 70.67 (range, 8.91-98.40), CFU-GM was 74.33 (range, 20.23-98.60), total CFUs was 82.34 (range, 14.83-247.12), and viability was 89.67(range, 70.74-98.30). The total working time required was, on average, 15 minutes (range, 7-20). CONCLUSIONS: The Cytomate device demonstrated a satisfying efficiency in cell recovery and in maintaining the clonogenic power of the UCB graft. The removal rate of DMSO was practically complete with evident advantages for the recipient. Finally, the entire manipulation performed in a closed system revealed to be safe, maintaining the sterility of the graft.

Snake infrared receptors respond to dimethylsulfoxide in the blood stream.

1. We used extracellular recording of the infrared (IR)-sensitive trigeminal ganglion (TG) neurons (primary neurons) of a crotaline snake, Trimeresurus flavoviridis, which has very sensitive thermoreceptors, to examine changes in the IR response induced by dimethylsulfoxide (DMSO), in vivo. 2. The responses in the TG were recorded after each concentration of DMSO (1, 10, and 25%) was administered in the bloodstream. 3. At a constant temperature, DMSO dose-dependently potentiated the IR-triggered discharges of IR-sensitive TG neurons in this snake. 4. It is suggested that the increased IR response to DMSO is due to its chemical effect, or to an indirect effect via its vasoactive role in the thermoreceptors of IR-sensitive snakes.

[Intravesical ionophoresis of medicines (an experimental study)]. / Vnutripusyrnyi ionoforez lekarstvennykh preparatov (éksperimental'noe issledovanie).

The depth of drug penetration into the wall of the urinary bladder in intravesical ionophoresis (IVIP), IVIP influence on functional condition of the lower urinary tracts were studied on 15 female dogs. Functional condition of the lower urinary tracts was characterized by pressure in the urinary bladder, "volume-pressure" index, bioelectric activity of the urethra. The pressure was registered by electromanometry. Bioelectric activity of the urethra was studied with electromyography and tetrapolar rheography. The above indices were registered synchroneously on a multichannel recorder. Intraoperative cystomanometry was made in 7 tyopental narcotized animals. Samples of blood and vesicular tissue were taken for immunofluorescent study before and after IVIP. Medicines were accumulated best in mucous and submucous layers (0.039 +/- 0.0012 and 0.0338 +/- 0.0050 mcm/mg tissue, respectively). After IVIP intravesical pressure was, on the average, lower in the same filling volumes as before IVIP. A mean amplitude of spontaneous fluctuations of pressure in the urinary bladder in its filling after IVIP was also lower than the baseline. After IVIP, pressure in the urinary bladder in voiding was much lower than before the procedure, maximal capacity of the urinary bladder and elasticity of the wall increased. Bioelectrical activity of the urethral wall was registered in the same mean pressure and capacity as before IVIP. Intensity of micturition after IVIP course decreased both at rest and in diuretic load with lasix. Time to micturition was increased with an increase in the number of procedures of IVIP. Thus, the experimental study showed pathogenetic validity of intravesical ionophoresis of medicines in the treatment of chronic recurrent cystitis.

Validated method for the determination of the novel organo-ruthenium anticancer drug NAMI-A in human biological fluids by Zeeman atomic absorption spectrometry.

NAMI-A is a novel ruthenium-containing experimental anticancer agent. We have developed and validated a rapid and sensitive analytical method to determine NAMI-A in human plasma, plasma ultrafiltrate and urine using atomic absorption spectrometry with Zeeman correction. The sample pretreatment procedure is straightforward, involving only dilution with an appropriate hydrochloric acid buffer-solution. Because the response signal of the spectrometer depended on the composition of the sample matrix, in particular on the amount of human plasma in the sample, all unknown samples were diluted to match the matrix composition in which the standard line was prepared (plasma-buffer 1:10 v/v). This procedure enabled the measurement of samples of different biological matrices in a single run. The validated range of determination was 1.1-220 microM NAMI-A for plasma and urine, and 0.22-44 microM for plasma ultrafiltrate. The lower limit of detection was 0.85 microM in plasma and urine and 0.17 microM in plasma ultrafiltrate. The lower limit of quantitation was 1.1 and 0.22 microM, respectively. The performance of the method, in terms of precision and accuracy was according to the generally accepted criteria for validation of analytical methodologies. The applicability of the method was demonstrated in a patient who was treated in a pharmacokinetic phase I trial with intravenous NAMI-A.

Fate of the antimetastatic ruthenium complex ImH [trans-RuCl4(DMSO)Im] after acute i.v. treatment in mice.

The content of ruthenium in blood and different organs of healthy CBA mice was determined by AAS after single i.v. treatment of 200 mg kg-1 of NAMI-A, a new antimetastatic ruthenium compound. Ruthenium concentration in blood falls 5 min after i.v. treatment. In the kidney, ruthenium concentration is markedly higher than in any other analysed tissue. No ruthenium was detected in brains. Pharmacokinetic parameters for a mono- or a bi-compartment model are identifiable: t1/2 is 10.45 h vs 12.02 (t1/2 alpha 0.023 h + t1/2 beta 12 h) with Cltot of 1.60 ml*h-1 vs 1.59); Vd is 24.15 vs 27.48 ml and (model dependent) AUC is 689 vs 694 mg*L-1*h. AUC(0-->infinity) calculated by noncompartmental method (linear trapezoidal rule) is 719.77 mg*L-1*h. NAMI-A is rapidly cleared from the blood compartment immediately after i.v. administration. Apparently, there is no differential accumulation of ruthenium in the lungs which might account for a selective antimetastatic effect caused by a cytotoxic concentration in this site, nor in any other specific organ examined.

Prevention and management of extravasation of cytotoxic drugs.

Extravasation of certain cytotoxic agents during peripheral intravenous administration may cause severe local injuries. Most extravasation can be prevented with the systematic implementation of careful administration techniques. However, the management of this complication, the aim of which is to prevent progression to tissue necrosis and ulceration, remains an important challenge in the care of cancer patients. Many antidotes have been evaluated experimentally and a few may be able to reduce the local toxicity of the more common vesicant cytotoxic drugs. Because no randomised trial on the management of cytotoxic drug extravasation in humans has ever been completed, recommendations must be based on the more consistent experimental evidence and on cumulative clinical experience from available case reports and uncontrolled studies, which are reviewed in this article. Empirical guidelines recommend the use of topical dimethylsulfoxide (DMSO) and cooling after extravasation of anthracyclines or mitomycin, locally injected hyaluronidase after extravasation of vinca alkaloids, and locally injected sodium thiosulfate (sodium hyposulfite) after extravasation of chlormethine (mechlorethamine; mustine). Plastic surgery may be necessary when conservative treatment fails to prevent ulceration. The possibility of late local reactions must also be considered in the management of patients receiving chemotherapy.