The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review.

INTRODUCTION: Probiotics may benefit irritable bowel syndrome (IBS) symptoms, but randomised controlled trials (RCTs) have been conflicting; therefore a systematic review was conducted. METHODS: MEDLINE (1966 to May 2008), EMBASE (1988 to May 2008) and the Cochrane Controlled Trials Register (2008) electronic databases were searched, as were abstracts from DDW (Digestive Diseases Week) and UEGW (United European Gastroenterology Week), and authors were contacted for extra information. Only parallel group RCTs with at least 1 week of treatment comparing probiotics with placebo or no treatment in adults with IBS according to any acceptable definition were included. Studies had to provide improvement in abdominal pain or global IBS symptoms as an outcome. Eligibility assessment and data extraction were performed by two independent researchers. Data were synthesised using relative risk (RR) of symptoms not improving for dichotomous data and standardised mean difference (SMD) for continuous data using random effects models. RESULTS: 19 RCTs (18 papers) in 1650 patients with IBS were identified. Trial quality was generally good, with nine reporting adequate methods of randomisation and six a method of concealment of allocation. There were 10 RCTs involving 918 patients providing outcomes as a dichotomous variable. Probiotics were statistically significantly better than placebo (RR of IBS not improving=0.71; 95% CI 0.57 to 0.88) with a number needed to treat (NNT)=4 (95% CI 3 to 12.5). There was significant heterogeneity (chi(2)=28.3, p=0.001, I(2)=68%) and possible funnel plot asymmetry. Fifteen trials assessing 1351 patients reported on improvement in IBS score as a continuous outcome (SMD=-0.34; 95% CI -0.60 to -0.07). There was statistically significant heterogeneity (chi(2)=67.04, p<0.001, I(2)=79%), but this was explained by one outlying trial. CONCLUSION: Probiotics appear to be efficacious in IBS, but the magnitude of benefit and the most effective species and strain are uncertain.

Initiation of apoptosis by photodynamic therapy using a novel positively charged and water-soluble near infra-red photosensitizer and white light irradiation.

Our aim was to investigate the photophysical and photodynamic properties of a new, water-soluble positively charged and chemically stable photosensitizer: tetrahydroporphyrin tetratosylat (THPTS). Absorption, fluorescence and (1)H NMR spectra and the intracellular distribution of THPTS were measured. The apoptosis in choroidal melanoma cells was measured using cell death detection ELISA and caspase-8 activity assay. THPTS-PDT efficiency was studied in Balb/c mice bearing C26 colon carcinoma. Subcutaneously located tumors were irradiated with a white light source at a fluence rate of 100 mW/cm(2). THPTS was administrated 3 h before illumination. The tumoricidal effect was examined 24 h after THPTS-PDT by vital staining with 0.4-ml 1% Evans blue solution, intraperitoneally injected to each mouse. THPTS showed a strong absorption band at 760 nm. Its purity, measured by (1)H NMR, is better than 99%. At 24-h incubation period, CLSM revealed THPTS fluorescence in mitochondria and cell nucleus. THPTS possesses no toxic effect in preincubated CM cells without irradiation, and THPTS-PDT causes efficient apoptosis. THPTS-PDT using white light irradiation at a dose of 480 J/cm(2) caused necrosis with a depth of 8 mm in subcutaneously located C26 colon carcinoma in Balb/c-mice. In accordance with the present results, the THPTS seems to be of interest for further in vivo investigations with broad-band white light sources.

Does co-administration of a non-selective opiate antagonist enhance acceleration of transit by a 5-HT4 agonist in constipation-predominant irritable bowel syndrome? A randomized controlled trial.

Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.

Mechanism of tumor destruction following photodynamic therapy with hematoporphyrin derivative, chlorin, and phthalocyanine.

The effect of photodynamic therapy on the tumor microvasculature in the first few hours after treatment was studied at the light and electron microscopy levels. BALB/c mice with EMT-6 tumor received ip injections of hematoporphyrin derivative, chlorin, or phthalocyanine, and 24 hours later, the tumors were treated with light at 100 J/cm2 at the appropriate therapeutic wavelength for each photosensitizer. Animals were killed and their tumors removed at time 0, 30 minutes, 1 hour, and 2, 4, 6, 8, 12, 16, and 24 hours after treatment. The results indicate that for all three sensitizers the effects of photodynamic therapy leading to rapid necrosis of tumor tissue are not the result of direct tumor cell kill but are secondary to destruction of the tumor microvasculature. The first observable signs of destruction occur in the subendothelial zone of the tumor capillary wall. This zone, composed of dense collagen fibers and other connective tissue elements, is destroyed in the first few hours after phototherapy. However, the ultrastructural changes seen in this zone are different for the hematoporphyrin derivative, compared with chlorin and phthalocyanine. Binding of photosensitizers to the elements in this zone as well as altered permeability and transport through the endothelial cell layer because of the increased intraluminal pressure may be key features of tumor destruction.

Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging.

Convection-enhanced drug delivery (CEDD) is a novel approach to enhance the delivery of drugs directly into brain tumors. We have used diffusion-weighted MRI (DWMRI) to monitor the effects of intratumoral CEDD in three brain tumor patients treated with Taxol. Clear changes in the images and the water diffusion parameters were observed shortly after the initiation of treatment. Initially, a bright area corresponding to decreased diffusion appeared, followed by the appearance of a dark area of increased diffusion within the bright area. The time to appearance of the dark area varied among the patients, suggesting different response rates. In this work, we have demonstrated the feasibility of using DWMRI as a noninvasive tool to achieve unique early tissue characterization not attainable by other conventional imaging methods.

Burn care standards in Israel: lack of consensus.

UNLABELLED: In recent years, the need for a national burn center based on ABA guidelines has emerged in Israel. The formation of such a center is now underway in the Chaim Sheba Medical Center. As a first step in the standardization of burn care in Israel, we have conducted a nation-wide survey among burn care personnel (physicians, nurses and other burn team members), regarding different aspects of the treatment of burn patients. METHODS: A questionnaire comprised of 30 questions regarding the severity of burns admitted, the site of initial management, wound care (both burn/skin-graft sites and donor sites), dressing changes protocols, sterility precautions, hydrotherapy, and pressure dressings was presented to 70 health-care professionals involved in the treatment of burns. RESULTS AND DISCUSSION: Seventy-seven percent of interviewed personnel participated in the survey. Consensus was found regarding most local (topical) wound care, (SSD for clean non-facial burns, Sulfamylon (mafenide-acetate) for contaminated non-facial burns, Threolone (chloramphenicol 3% and prednisolone 0.5%) or Bacitracin for facial burns, Paraffin gauzes with or without Sulfamylon for donor and graft sites). Dressing changes regimes were also agreed upon generally. However, there was no consensus regarding the ideal time for the removal of donor site dressings and this issue will need to be resolved. Other important findings are that both Edinborough University Solution of Lime (EUSOL), which has been deemed unsuitable for burn treatment due to toxic effects, and hydrotherapy, which has been proposed as a source of infection and contamination, are still widely used. We anticipate that these issues will be settled in our unified national burn care protocols (which are currently under development and revision).

The kinetics of protoporphyrin fluorescence during ALA-PDT in human malignant skin tumors.

Fluorescence monitoring during photodynamic therapy (PDT) with the use of topical 5-aminolevulinic acid (ALA) was carried out in patients bearing superficial and nodular basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and Kaposi's sarcomas. A new diagnostic-therapeutic system based on an incoherent CW light source was used for fluorescence spectral measurements and imaging. The results showed that photoirradiation reduced ALA-induced protoporphyrin IX (PP) fluorescence in all tumors. The rate of PP photobleaching in superficial BCC and SCC tumors was significantly higher than in large nodular BCC tumors. The results showed that the differences in kinetics of fluorescence reduction could be attributed to the tumor thickness. One hour after photoirradiation with a light dose of 170 J/cm2 a phenomenon of re-appearance and recovery of PP fluorescence was observed in the large deeply penetrating BCC tumors and Kaposi's sarcoma lesions. In such cases an additional light treatment was performed. The results of the study demonstrated that fluorescence monitoring is very appropriate for the definition of an optimal ALA-PDT clinical protocol.

Photothermic treatment of pigmented B16 melanoma using a broadband pulsed light delivery system.

Pulsed photothermic treatment (PTT) of pigmented B16 mice melanoma tumors was carried out using a Photodyne incoherent light delivery system. Tumor heating with average temperature of 41-44 degrees C was observed during broadband photoirradiation (600-800 nm) at light doses of 60-120 J/cm(2) delivered using 0.6 J/cm(2) pulses (2 ms) at 1 Hz repetition rate. Electron microscopy of tumor samples revealed pronounced structural changes in microvasculature and melanosomes. Pulsed PTT caused damage to endothelial cells and vascular walls, swelling of mitochondria and melanosomal disruption without nuclear alteration. Significant tumor response with necrosis formation followed by tumor regression was observed by a tumor growth study after PTT at 120 J/cm(2).

Temperature monitoring during photodynamic therapy of skin tumors with topical 5-aminolevulinic acid application.

Temperature monitoring during photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) cream application was performed on 22 patients with solar keratoses (SK) and basal cell carcinoma (BCC). The lesions were located on the forehead, nose, ear and cheek. Temperature measurements during photoirradiation, with a power density of 100 mW/cm2 from an incoherent light source (light delivery system for PDT), were carried out by noncontact (infrared thermal imaging radiometer) and contact (thermocouple) methods. Thermal imaging analysis revealed nonuniform temperature distribution in the irradiated areas. The temperature gradually increased from the peripheral to the central zone of the area. The results showed that photoirradiation induced heating of the skin tumors to 39.5-42.5 degrees C during the PDT procedure. The temperature of normal skin areas disposed symmetrically to the lesions on the contralateral side at the same conditions of irradiation (without prior ALA application) was about 42-43.5 degrees C. The surface temperature differences (delta T) between the normal and tumor tissues after 10 min of irradiation were 3.3 +/- 0.5 degrees C in the forehead areas, 2.5 +/- 0.4 degrees C in the nose areas and 0.8 +/- 0.3 degrees C in the ear areas.

Overzealous resuscitation of an extremely malnourished patient with nutritional cardiomyopathy.

Overzealous resuscitation of the severely malnourished patient may be associated with life-threatening complications. A variety of electrolyte, hemodynamic, septic, and nutritional derangements may result in sudden decompensation and even death. We present a case that dramatically illustrates these complications and focuses on the key role of underlying nutritional cardiomyopathy.

Assessment of human colon cancer protein kinetics in vivo.

BACKGROUND: Malignancies enlarge because protein synthesis exceeds the rate of breakdown; however, the specific protein kinetic pattern remains unknown. Determining in vivo protein kinetic rates for a tumor may be useful for quantifying individual responses to a specific therapy. The aim of this study was to assess whether the growth of tumors is related to an increase in protein synthesis or an inhibition of protein breakdown. METHODS: Five patients (age, 59 +/- 3 years) with adenocarcinoma of the colon undergoing colonoscopy were studied. Tissue protein synthesis and breakdown rates were measured in vivo for both segments of colon cancer and adjacent normal-appearing colonic mucosa by using a primed, continuous infusion of 1(13)C leucine with tissue biopsy and quantitation of regional blood flow by laser Doppler flowmetry. RESULTS: Segments of colon cancer had a significantly (p < 0.05) greater rate of protein synthesis as quantitated by both the fractional rate of protein synthesis (Ca 45.4% +/- 5.0%/day versus nl mucosa 35.7% +/- 3.1%/day; mean +/- SEM) and by the tissue synthesis rate (Ca 69.4 +/- 9.0 versus nl mucosa 51.6 +/- 5.2 mumol/L leucine/day/100 gm tissue). Regional blood flow was significantly elevated in the cancer (Ca 110.9 +/- 5.8 versus nl mucosa 91.2 +/- 2.9 ml/min/100 gm), which contributed to commensurate rates of tissue breakdown (Ca 28.6 +/- 2.0 versus nl mucosa 28.2 +/- 2.4 mumol/L leucine/day/100 gm). CONCLUSIONS: These results illustrate that human colon cancers grow in vivo as a result of increases in protein synthesis. Furthermore, increases in regional blood flow limit the rate of tissue protein breakdown of colon cancer, thereby contributing to growth of the malignancy. These findings support the contention that therapeutic strategies aimed at negating this inherent increase in protein synthesis or limiting blood flow may effectively limit the growth of malignancies. This methodology may also provide an index for evaluating the effectiveness of future therapies aimed at reducing tumor growth for individual patients.

Comparison of gastric volumes in response to isocaloric liquid and mixed meals in humans.

AIMS: To compare gastric volume responses to ingestion of isocaloric liquid or mixed (solid-liquid) meals and document the intra- and interindividual reproducibility of gastric volume measurement using single photon emission computed tomography (SPECT) imaging after i.v. 99mTc-pertechnetate. METHODS: Eight healthy volunteers performed two studies at least 9 months apart. Gastric volumes were measured after a 317 kcal liquid nutrient meal. Within 2 weeks of the second liquid meal study, participants performed a third study, ingesting an isocaloric mixed meal. The order of the mixed and second liquid meals was randomized; Bland-Altman plot displayed data on repeated studies with liquid meal and paired t-test compared gastric volumes after mixed or liquid isocaloric meals. RESULTS: Fasting and postprandial gastric volumes associated with the two liquid meals were not significantly different; inter- and intra-individual coefficients of variation were 13 and 13.8%. In response to the mixed meal, there was a lower absolute postprandial volume and lower change in gastric volume over fasting volume compared with the response to the liquid meal (P = 0.0001). CONCLUSION: The SPECT measurement of gastric volumes in response to a nutrient liquid meal is reproducible. The magnitude of the volume response is greater after the liquid meal compared with the isocaloric mixed meal.

The use of porphyrins for eradication of Staphylococcus aureus in burn wound infections.

The assessment of deuteroporphyrin-hemin complex as an agent for the treatment of burn wounds infected with a multiple-drug resistant strain of Staphylococcus aureus was performed. The effect of the porphyrin on the survival of the infectious bacteria was first assayed in culture, and later tested as well in a burned infected animal model. The addition of deuteroporphyrin and hemin, separately or together (as a complex) to a growing culture of S. aureus was monitored during 8 hours. It was found that deuteroporphyrin alone was strongly bactericidal only after photosensitization. On the other hand, hemin alone was moderately bactericidal but light independent. A combination of both deuteroporphyrin and hemin was extremely potent even in the dark and did not require illumination to eradicate the bacteria. The in vivo experiments by application of the above porphyrins in combination to infected burn wounds in guinea pigs was an effective way to reduce dramatically the contaminating S. aureus. Reduction of more than 99% of the viable bacteria was noted after the porphyrin mixture was dropped on the eschar or injected into the eschar, an effect that lasted for up to 24 hours. The deuteroporphyrin-hemin complex may be suggested as a new bactericidal treatment of S. aureus infected burns since it was found to be a potent and promising anti-Staphylococcal agent.

Enhancement of ALA-PDT damage by IR-induced hyperthermia on a colon carcinoma model.

The interaction of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) and hyperthermia is not well understood. In the present study, significant enhancement of tumor damage was observed after simultaneous application of ALA-PDT and IR-induced hyperthermia using a broad-band incoherent light source. One hour after systemic administration of ALA at a dose of 200 mg/kg, subcutaneously transplanted C26 colon carcinoma tumors were irradiated with two bands of the VersaLight system, red (R, 580-720 nm) and red plus IR (R + IR, 580-720 nm and 1250-1600 nm). Photoirradiation using the R + IR band at different fluence rates and exposures caused mild heating of the tumor to 39-43 degrees C at a 3 mm depth. Electron microscopy after ALA + R, ALA + R + IR and R + IR treatments showed early mitochondrial swelling that was more pronounced in the ALA + R + IR group. Tumor necrosis assessment, using histology and vital staining, revealed an enhancement of tumor necrosis depth in the ALA + R + IR group compared to ALA + R and R + IR. The results showed that subhyperthermic heating to 39-39.5 degrees C in the ALA + R + IR group decreased the threshold light dose required for 100% tumor necrosis from 210 J/cm2 (observed in the ALA + R group) to 140 J/cm2. A tumor growth delay test, based on tumor volume measurement, also revealed significant enhancement of antitumor effect after application of ALA + R + IR compared to ALA + R.

In vivo tumor oxygen tension measurements for the evaluation of the efficiency of photodynamic therapy.

Among the sequence of events which occur during photodynamic therapy (PDT) are depletion of oxygen and disruption of tumor blood flow. In order to more clearly understand these phenomena we have utilized transcutaneous oxygen electrodes to monitor tissue oxygen disappearance. These results provide, for the first time, non-invasive real-time information regarding the influence of light dose on tissue oxygenation during irradiation. Measurements were conducted on transplanted VX-2 skin carcinomas grown in the ears of New Zealand white rabbits. Rabbits were treated with Photofrin II and tumors were irradiated with up to 200 kJ/m2 (500 W/m2) of 630-nm light. Substantial reductions in tumor oxygen tension were observed upon administration of as little as 20 kJ/m2. For a series of brief irradiations, oxygen tension was modulated by the appearance of laser light. Tissue oxygen reversibility appeared to be dependent upon PDT dose. Long-term, irreversible tissue hypoxia was recorded in tumors for large (200 kJ/m2) fluences. These results suggest that transcutaneous oxygen tension may be useful as a general indicator of the effectiveness of PDT and as an in situ predictor of the energy required to elicit tumor damage.

Percutaneous endoscopic gastrojejunostomy: a dual center safety and efficacy trial.

Although jejunal tube placement through a percutaneous endoscopic gastrostomy (PEG) has not been proven to be preferable to PEG feeding, it would be theoretically advantageous for those patients prone to gastrointestinal aspiration. However, reliable placement of a small bowel feeding tube through a PEG has been technically difficult. We have previously reported successful placement of a percutaneous endoscopic gastrojejunostomy (PEG/J) with minimal complications. These results are in contrast to other series that report technical difficulty, frequent tube dysfunction and gastric aspiration. We describe an over-the-wire PEG/J technique performed by multiple operators at two medical centers. Gastrostomy tube placement was successful in 94% of patients. Initial placement of the jejunal tube was successful in 88% of patients. Second attempts were 100% successful. The average procedure time was 36 minutes. The distal duodenal and jejunal placement of the jejunal tube resulted in no episodes of gastroduodenal reflux. Complications included jejunal tube migration (6%), clogging (18%), and unintentional removal (11%). The majority of patients were ultimately converted to either oral or intragastric feedings. We conclude that the PEG/J system is a reliable, reproducible method of small bowel feeding and is associated with no episodes of tube feeding reflux when the jejunal tube is positioned in the distal duodenum or beyond. Furthermore, it provides a temporary nutritional bridge for those patients who are later transitioned to either PEG or oral feeding.

Macrophage suspensions prepared from a blood unit for treatment of refractory human ulcers.

This paper presents an innovative method for the treatment of refractory wounds, starting with a blood unit, that is based on a biological approach. Local wound repair is one of the major unresolved clinical problems. Age, infection, clinical conditions such as diabetes mellitus, cardiac, renal, lung and liver failure, malnutrition and immunological deficiencies are among the reasons for wound repair delay or failure. Many chronic ulcers resist conventional treatment and do not heal for months and years, thus causing substantial morbidity and even mortality. The method for macrophage suspension treatment consists of introducing into the wound live cells that play a major role in the process of wound healing. The suspension is prepared from a blood unit of a healthy donor in a cost-effective, closed, sterile system. In the process of preparation, the macrophages are activated by hypo-osmotic shock to enhance their various functions in wound repair. The cells are applied to the wound either by local injection or by direct deposition into the wound. In most cases (90%), only one treatment is sufficient. Since 1995, macrophage suspensions have been used successfully in more than 1000 patients in several hospitals in Israel, without any side effects. Our results show that the use of a macrophage suspension is a safe and effective therapeutic strategy that shortens the healing period, reduces risk of complications and morbidity and improves the quality of life for long-suffering patients. This treatment requires no hospitalization and can be given on an ambulatory basis.

In vivo photodynamic therapy with the new near-IR absorbing water soluble photosensitizer lutetium texaphyrin and a high intensity pulsed light delivery system.

An in vivo fluorescence monitoring and photodynamic therapy (PDT) study was performed using the new photosensitizer lutetium texaphyrin (Lu-Tex). This photosensitizer is water soluble and has the additional advantage of strong absorption near 730 nm. C26 colon carcinoma was transplanted in the foot of BALB/c mice. In vivo fluorescence spectroscopy was applied to study Lu-Tex tissue distribution kinetics. For this purpose, fluorescence intensity both in the foot with the tumor and in the normal foot was measured in vivo by the laser-induced fluorescence (LIF) system. For PDT, both feet of the mice were irradiated simultaneously with the use of a new high intensity pulsed light delivery system, the Photodyne. The results of the LIF measurements showed that the maximal fluorescence intensity ratio between the normal and tumor bearing foot (FIR) was observed 24-48 h after the agent injection. Photoirradiation with doses from 90 to 240 J cm-2 (0.6 J cm-2 per 2 ms pulse, 1 Hz) 24 h after injection of Lu-Tex at a dose of 10 mg kg-1 caused significant tumor necrosis and delay in the tumor growth rate. The antitumor effect was enhanced with increasing light doses. Normal tissue response to PDT with Lu-Tex was determined as the damage index of the normal foot, which was irradiated simultaneously with the tumor bearing foot. The normal tissue response after PDT with Lu-Tex was compared with 5-aminolevulinic acid (ALA) induced protoporphyrin IX (PP), chlorin e6 (Chl) and Photofrin (PII) at the same values of antitumor effect. The results showed that at 50, 80 and 100% inhibition of tumor growth the orders of the values of normal foot damage indexes were as follows: ALA > Lu-Tex > or = PII > Chl, PII > ALA > Lu-Tex > Chl and PII > Lu-Tex > ALA > Chl respectively.

Topical application of 5-aminolevulinic acid, DMSO and EDTA: protoporphyrin IX accumulation in skin and tumours of mice.

Topical 5-aminolevulinic acid (ALA) application in three different creams was carried out on mice bearing subcutaneously transplanted C26 colon carcinoma. The creams contained (a) 20% ALA alone, (b) ALA with 2% dimethylsulphoxide (DMSO) and (c) ALA, DMSO and 2% edetic acid disodium salt (EDTA). Protoporphyrin IX (PP) production in the tumour and in the skin overlying the tumour was studied by two methods: laser-induced fluorescence (LIF) and chemical extraction. The kinetics of PP production in the skin and in the tumour, as studied by the LIF method, was similar for all three cream preparations. The PP fluorescence intensity in the tissues reached its maximum 4-6 h after application of the creams. Quantitative analysis showed that the PP concentration after treatment was more pronounced in the skin than in the tumour. The efficiency of porphyrin production in the skin by the creams used was in the following order: ALA-DMSO-EDTA > ALA-DMSO > ALA. In the tumour the enhancing effect of DMSO and EDTA on PP accumulation induced by ALA was observed mainly in the upper 2 mm section. However, the concentration of PP in the tumour was found to be approximately the same for ALA-DMSO and ALA-DMSO-EDTA cream combinations. The possible mechanisms of the effect of DMSO and EDTA are discussed.