Evaluation of anti-inflammatory activity of kaurenol: Experimental evaluation and mechanistic insights.

BACKGROUND: Kaurenol, a diterpene alcohol found in Copaifera langsdorffii Desf. (known as "copaiba"), is historically used in traditional medicine for inflammatory conditions. OBJECTIVES: This study aims to comprehensively assess the potential anti-inflammatory and antinociceptive properties of kaurenol. METHODS: To this end, the following experiments were conducted to evaluated toxicity: locomotor performance and acute toxicity; nociception: acetic acid-induced writhing and formalin-induced antinociception; and anti-inflammatory activity: carrageenan and dextran-induced paw edema at 10, 20, and 40 mg/kg, and measurement of nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in macrophages at 1, 3, and 9 µg/ml. RESULTS: Kaurenol did not show significant locomotor changes, acute toxicity, and central analgesic activity in the first phase of formalin test at dosages tested. Kaurenol showed 53%, 64%, 64%, and 58% of inhibition in the acetic acid-induced writhing, second phase of formalin test, carrageenan and dextran-induced paw edema, respectively. CONCLUSION: The anti-inflammatory activity was associated with the regulation of NO release and probably with the regulation of mediators, such as serotonin and prostaglandin in vascular permeability, as well as by being associated with the regulation of IL-6 and IL-10. Kaurenol display anti-inflammatory activity but has no analgesic activity.

Fermented rice bran supplementation attenuates colonic injury through modulating intestinal aryl hydrocarbon receptor and innate lymphoid cells in mice with dextran sodium sulfate-induced acute colitis.

This study investigated the effects of fermented rice bran (FRB) on modulating intestinal aryl hydrocarbon receptor (AhR) expression, innate lymphoid cell (ILC)3 populations, the fecal microbiota distribution, and their associations with dextran sodium sulfate (DSS)-induced acute colitis. C57BL/6 mice were assigned to four groups: 1) NC group, normal mice fed the AIN-93M diet; 2) FRB group, normal mice fed a diet supplemented with 5% FRB; 3) NCD group, DSS-treated mice fed AIN-93M; 4) FRBD group, DSS-treated mice fed a 5% FRB-supplemented diet. DSS was administered for 5 d and followed by 5 d for recovery. At the end of the experiment, mice were sacrificed. Their blood and intestinal tissues were collected. Results showed that there were no differences in colonic biological parameters and function between the NC and FRB groups. Similar fecal microbiota diversity was noted between these two groups. Compared to the non-DSS-treated groups, DSS administration led to increased intestinal permeability, enhanced inflammatory cytokine production and disease severity, whereas tight junctions and AhR, interleukin (IL)-22 expressions were downregulated, and the ILC3 population had decreased. Also, gut microbiota diversity differs from the non-DSS-treated groups and more detrimental bacterial populations exist when compared to the FRBD group. FRB supplementation in DSS-treated mice attenuated fecal microbial dysbiosis, decreased intestinal permeability, improved the barrier integrity, upregulated AhR and IL-22 expression, maintained the ILC3 population, and pathologically mitigated colonic injury. These findings suggest enhanced ILC3- and AhR-mediated functions may be partly responsible for the anti-colitis effects of FRB supplementation in DSS-induced colitis.

Effects of Huzhangoside C on Dextran Sodium Sulfate-Stimulated Colitis in Mice.

Chronic inflammation is a major risk factor for cancer. Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, ultimately leading to a breakdown of intestinal barrier function. Clematis florida var. plena is a folk prescription used to treat inflammation and rheumatism in She pharmacy. The bioactivity of C. florida var. plena is primarily due to triterpene saponins. Huzhangoside C (HZ) is an active component of C. florida var. plena. In this study, the anti-inflammatory effect of HZ on a mouse colitis model induced by dextran sulfate sodium (DSS) was investigated. Result indicated a notable reduction in body weight loss and colon length shortening in HZ-mediated mice compared to DSS-stimulated control mice. Furthermore, inflammatory signaling mechanisms involving interleukin-6 and tumor necrosis factor-α were suppressed in HZ-treated mice. HZ treatment significantly suppressed the expression of nuclear factor kappa B (NF-κB), STAT3, and iNOS in colon tissue. After HZ treatment, malondialdehyde and nitric oxide levels were significantly decreased, while Nrf-2, superoxide dismutase, and glutathione expression levels were notably improved. The result indicated that HZ could activate the Nrf-2 signal cascade, inhibit the expression of NF-κB, eNOS, and STAT3, and enhance the intestinal barrier function of DSS stimulated ulcerative colitis intestinal injury. The results suggest that HZ is potential anti-inflammatory agent for treating IBD.

Antiedematogenic and Analgesic Activities of Abietic Acid in Mice.

Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.

The Vegetable 'Kale' Protects against Dextran-Sulfate-Sodium-Induced Acute Inflammation through Moderating the Ratio of Proinflammatory and Anti-Inflammatory LPS-Producing Bacterial Taxa and Augmenting the Gut Barrier in C57BL6 Mice.

Kale (Brassica oleracea var. acephala), a food rich in bioactive phytochemicals, prevents diet-induced inflammation and gut dysbiosis. We hypothesized that the phytochemicals protect against the lipopolysaccharide (LPS)-induced acute inflammation which results from gut dysbiosis and loss of gut barrier integrity. We designed this study to test the protective effects of the whole vegetable by feeding C57BL/6J mice a rodent high-fat diet supplemented with or without 4.5% kale (0.12 g per 30 g mouse) for 2 weeks before administering 3% dextran sulfate sodium (DSS) via drinking water. After one week, DSS increased the representation of proinflammatory LPS (P-LPS)-producing genera Enterobacter and Klebsiella in colon contents, reduced the representation of anti-inflammatory LPS (A-LPS)-producing taxa from Bacteroidales, reduced the expression of tight junction proteins, increased serum LPS binding protein, upregulated molecular and histopathological markers of inflammation in the colon and shortened the colons. Mice fed kale for 2 weeks before the DSS regime had a significantly reduced representation of Enterobacter and Klebsiella and instead had increased Bacteroidales and Gram-positive taxa and enhanced expression of tight junction proteins. Downstream positive effects of dietary kale were lack of granuloma in colon samples, no shortening of the colon and prevention of inflammation; the expression of F4/80, TLR4 and cytokines 1L-1b, IL-6, TNF-a and iNOS was not different from that of the control group. We conclude that through reducing the proliferation of P-LPS-producing bacteria and augmenting the integrity of the gut barrier, kale protects against DSS-induced inflammation.

Transgenic mice overexpressing human ALOX15 under the control of the aP2 promoter are partly protected in the complete Freund's adjuvant-induced paw inflammation model.

BACKGROUND, OBJECTIVES AND DESIGN: Arachidonic acid 15-lipoxygenase (ALOX15) has been implicated in the pathogenesis of inflammatory diseases but since pro- and anti-inflammatory roles have been suggested, the precise function of this enzyme is still a matter of discussion. To contribute to this discussion, we created transgenic mice, which express human ALOX15 under the control of the activating protein 2 promoter (aP2-ALOX15 mice) and compared the sensitivity of these gain-of-function animals in two independent mouse inflammation models with Alox15-deficient mice (loss-of-function animals) and wildtype control animals. MATERIALS AND METHODS: Transgenic aP2-ALOX15 mice were tested in comparison with Alox15 knockout mice (Alox15-/-) and corresponding wildtype control animals (C57BL/6J) in the complete Freund's adjuvant induced hind-paw edema model and in the dextran sulfate sodium induced colitis (DSS-colitis) model. In the paw edema model, the degree of paw swelling and the sensitivity of the inflamed hind-paw for mechanic (von Frey test) and thermal (Hargreaves test) stimulation were quantified as clinical readout parameters. In the dextran sodium sulfate induced colitis model the loss of body weight, the colon lengths and the disease activity index were determined. RESULTS: In the hind-paw edema model, systemic inactivation of the endogenous Alox15 gene intensified the inflammatory symptoms, whereas overexpression of human ALOX15 reduced the degree of hind-paw inflammation. These data suggest anti-inflammatory roles for endogenous and transgenic ALOX15 in this particular inflammation model. As mechanistic reason for the protective effect downregulation of the pro-inflammatory ALOX5 pathways was suggested. However, in the dextran sodium sulfate colitis model, in which systemic inactivation of the Alox15 gene protected female mice from DSS-induced colitis, transgenic overexpression of human ALOX15 did hardly impact the intensity of the inflammatory symptoms. CONCLUSION: The biological role of ALOX15 in the pathogenesis of inflammation is variable and depends on the kind of the animal inflammation model.

Effect of 3,3'-diselenodipropionic Acid on Dextran Sodium Sulfate-Induced Ulcerative Colitis in Mice.

3,3'-Diselenodipropionic acid (DSePA), a synthetic organoselenium compound, has received considerable attention because of its antioxidant properties and safety. Its protective effect against dextran sodium sulfate (DSS)-induced mouse ulcerative colitis (UC) and the role of T helper 17 (Th17) cell proliferation were investigated. Fifty C57BL/6 male mice were randomly assigned to one of five groups: control (Con), DSePA, DSS, low-dose DSePA (LSe), and high-dose DSePA (HSe). Mice in the DSS, LSe, and HSe groups drank 2% DSS to induce UC, and received normal saline, 1 and 2 mg/mL DSePA solution by intraperitoneal injection, respectively. The DSePA group only received 2 mg/mL DSePA solution. After 5 weeks, DSS challenge induced UC in the mice, which manifested as decreased body weight, shortened colon length, the loss of goblet cells, activated proliferating cells, and multiple signs of intestinal lesions by histological observation, all of which were reversed to varying degrees by DSePA administration. DSS upregulated the colonic protein expression of the macrophage marker F4/80 and proinflammatory cytokines (IL-1ß, IL-6, and TNFα), whereas DSePA administration downregulated the expression of these factors. DSS upregulated the mRNA expression of retinoic acid receptor-related orphan receptor γt (RORγt, mainly expressed in Th17 cells), IL-17A, and IL-17F and the levels of IL-17A and IL-17F in the colon, whereas DSePA administration decreased them. No difference was observed between the Con group and the DSePA group without DSS induction. Thus, DSePA administration ameliorated DSS-induced UC by regulating Th17-cell proliferation and the secretion of proinflammatory cytokines.

Lizhong Decoction Ameliorates Ulcerative Colitis in Mice via Regulation of Plasma and Urine Metabolic Profiling.

OBJECTIVE: To elucidate the mechanism of Lizhong Decoction (LZD) in treating dextran sodium sulfate (DSS)-induced colitis in mice based on metabonomics. METHODS: Thirty-six mice were randomly divided into 6 groups, including normal, model, low- (1.365 g/kg), medium- (4.095 g/kg) and high dose (12.285 g/kg) LZD and salazosulfadimidine (SASP) groups, 6 mice in each group. Colitis model mice were induced by DSS admistration for 7 days, and treated with low, medium and high dose LZD extract and positive drug SASP. Metabolic comparison of DSS-induced colitis and normal mice was investigated by using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass (UPLC-Q-TOF/MS) combined with Metabolynx™ software. RESULTS: The metabolic profiles of plasma and urine in colitis mice were distinctly ameliorated after LZD treatment (P<0.05). Potential biomarkers (9 in serum and 4 in urine) were screened and tentatively identified. The endogenous metabolites were mainly involved in primary bile acid, sphingolipid, linoleic acid, arachidonic acid, amino acids (alanine, aspartate, and glutamate), butanoate and glycerophospholipid metabolism in plasma, and terpenoid backbone biosynthesis, glycerophospholipid and tryptophan metabolism in urine. After LZD treatment, these markers notably restored to normal levels. CONCLUSIONS: The study revealed the underlying mechanism of LZD on amelioration of ulcerative colitis based on metabonomics, which laid a foundation for further exploring the pathological and physiological mechanism, early diagnosis, and corresponding drug development of colitis.

The Efficacy of Dextran-40 as a Venous Thromboembolism Prophylaxis Strategy in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

The incidence of venous thromboembolism (VTE) in peritoneal malignancies can approach 30 to 50 per cent without prophylaxis. Prophylaxis in cytoreductive surgeries (CRS) presents a challenge to preoperative heparin-based therapy because of an increased risk of coagulopathy and potential for bleeding. Herein, we report the large series of CRS and hyperthermic intraperitoneal chemotherapy receiving dextran-40 prophylaxis. Retrospective chart review of peritoneal malignancies patients undergoing CRS at University of Nebraska Medical Center identified 69 individuals who received dextran-40 between 2010 and 2013. The incidences of VTEs, perioperative bleeding, complications, morbidity, and mortality were determined in-hospital and at 90 days. Of the 69 patients treated, the 30-day VTE rate was 8.7 per cent, and no pulmonary embolisms, bleeding, anaphylactoid reaction, or mortality were observed with dextran usage. The specific VTE events included three upper extremity and three lower extremity VTEs. No additional VTE events were identified between 30 and 90 days. In conclusion, dextran-40 prophylaxis was not associated with any perioperative bleeding events, and the observed incidence of VTE was comparable to reported heparin-based prophylaxis in CRS/hyperthermic intraperitoneal chemotherapy patients. This data supports further exploration of dextran-40 as a VTE prophylactic agent in complex surgical oncology cases.

[STUDYING THE ACUTE TOXICITY OF DEXTRAN POLYALDEHYDE CONJUGATE WITH ISONICOTINIC ACID HYDRAZIDE.]

The acute toxicity of a new antubercular drug, dextran polyaldehyde conjugate with isonicotinic acid hydrazide (dextrazide), has been studied on animals, HepaRG cell line, and FRSN human skin fibroblasts. Average tolerable doses (LD(10), LD(16)), half-lethal doses (LD(50)), and lethal doses (LD(84)) of dextrazide have been determined for intraperitoneal introduction in mice and rats and intravenous injection in rabbits.

Efficacy and safety of antifungal additives in Optisol-GS corneal storage medium.

IMPORTANCE: Optisol-GS, the most common corneal storage medium in the United States, contains antibacterial but no antifungal supplementation. Most postkeratoplasty endophthalmitis and keratitis cases are now of a fungal origin. OBJECTIVE: To assess the efficacy and safety of voriconazole and amphotericin B in reducing Candida species contamination of Optisol-GS under normal storage conditions. DESIGN, SETTING, AND PARTICIPANTS: In vitro laboratory study using 15 pairs of research-grade donor corneas and 20-mL vials of Optisol-GS. INTERVENTIONS: Twenty vials of Optisol-GS were supplemented with either voriconazole at 1×, 10×, 25×, or 50× minimum inhibitory concentration (MIC) or amphotericin B at 0.25×, 0.5×, 1×, or 10× MIC. Known concentrations of Candida albicans and Candida glabrata were each added to a set of vials. Safety studies were performed by separating 15 pairs of donor corneas into unsupplemented Optisol-GS or Optisol-GS plus an antifungal. MAIN OUTCOMES AND MEASURES: Efficacy outcomes were viable fungal colony counts determined from samples taken on days 2, 7, and 14 immediately after removal from refrigeration and after warming to room temperature for 2 hours. Safety outcomes included percentage of intact epithelium and endothelial cell density on days 0, 7, and 14, as well as percentage of nonviable endothelial cells by vital dye staining on day 14. RESULTS: Growth of C albicans and C glabrata was observed in all voriconazole-supplemented vials. In contrast, there was no growth of either organism in amphotericin B-supplemented vials, except at 0.25× and 0.5× MIC on day 2, when viable counts of C glabrata were reduced by 99% and 96%, respectively. Compared with paired controls, with the exception of Optisol-GS plus amphotericin B at 10× MIC, donor corneas in supplemented Optisol-GS appeared to have no difference in endothelial cell density reduction, percentage of intact epithelium, or percentage of nonviable endothelial cells. CONCLUSIONS AND RELEVANCE: The addition of amphotericin B to Optisol-GS may significantly improve activity against contamination with Candida species, the primary cause of fungal infection after corneal transplantation. This study found significant endothelial toxic effects at the maximal concentration of amphotericin B.

Sphincter training or anal injections of dextranomer for treatment of anal incontinence: a randomized trial.

OBJECTIVE: The objective is to test if the injection of a bulking agent in the anal canal is superior to sphincter training with biofeedback in the treatment of anal incontinence. BACKGROUND: Anal incontinence is traditionally treated with conservative measures, such as pads and constipating medicine. If this fails, sphincter training with biofeedback is often offered before more advanced surgical procedures are considered. The injection of a bulking agent in the anal canal is a relatively new and promising treatment option. METHODS: In a randomized, controlled, evaluator-blinded trial, 126 adult patients with anal incontinence were randomly assigned to a transanal, submucosal injection of 4 x 1 mL of dextranomer in hyaluronic acid or to sphincter training with biofeedback. The primary outcome was severity of incontinence, evaluated by St Mark's score for incontinence (0 = continence to 24 = complete incontinence) assessed at 2 years after the start of treatment. A mixed models analysis was applied. RESULTS: Of the 126 participants, 64 patients were randomly assigned to anal injections, and among them the mean St Mark's score improved from 12.9 (95% CI: 11.8-14.0) at baseline to 8.3 (95% CI: 6.7-9.8) at the end of follow up. Among the 62 patients who were assigned to sphincter training with biofeedback, there was a corresponding improvement in St Mark's score from 12.6 (95% CI: 11.4-13.8) to 7.2 (95% CI: 7.2-8.8). Comparisons of St Mark's scores between the groups showed no differences in effect between treatments. CONCLUSION: The efficacy of anal injections and biofeedback in treating anal incontinence did not differ in this randomized, single-blinded, controlled trial.

Evaluation of dextran-flufenamic acid ester as a polymeric colon-specific prodrug of flufenamic acid, an anti-inflammatory drug, for chronotherapy.

Dextran-flufenamic acid ester (Dex-FFA) with varied degree of substitution (DS) was prepared by imidazolide method. Dex-FFA was stable in pH 1.2 or pH 6.8 buffer. The depolymerization degree of Dex-FFA by dextranase decreased as DS increased. Dex-FFA with DS of 13 or 20 released FFA up to 70% or 21% of the dose, respectively, on 24 h-incubation with the 10% cecal contents. FFA was liberated up to 29% of the dose on 24 h-incubation of dextranase pre-treated Dex-FFA with the homogenates of the upper intestine, whereas no FFA was detected devoid of dextranse-pretreatment. Upon oral administration of Dex-FFA (DS 13, 20 mg equivalent of FFA/kg) or FFA (10 mg/kg) to rats, t(max) for FFA with Dex-FFA administration delayed approximately 6 h compared with that of free FFA administration, while C(max) for FFA was similar. The plasma level for FFA became greater around 6 h after administration of Dex-FFA than free FFA and it was maintained throughout the period of 24 h-experiment. Dex-FFA markedly attenuated gastric ulcerogenicity of FFA. Taken together, Dex-FFA could be useful as a colon-specific prodrug which possesses anti-inflammatory properties and offers opportunities as a chronotherapeutic approach for the treatment of arthritis.

Cystoscopic injections of dextranomer hyaluronic acid into proximal urethra for urethral incompetence: efficacy and adverse outcomes.

OBJECTIVES: To determine whether dextranomer/hyaluronic acid would be more efficacious or would produce fewer complications when using the material in a standard proximal-urethra cystoscopically-directed injection technique. Injectable periurethral bulking agents are an alternative to stress incontinence surgery. Dextranomer, a highly hydrophilic dextran polymer, solubilized in a base of nonanimal stabilized hyaluronic acid, has been approved as an injectable agent for the treatment of childhood vesicoureteric reflux (Deflux, Q-Med AB, Uppsala, Sweden), and in Europe for women with stress urinary incontinence (SUI) (Zuidex, Q-Med AB, Uppsala, Sweden). A previous multicenter trial demonstrated nonequivalence compared with bovine glutaraldehyde cross-linked collagen with a high complication rate. We sought to determine whether the failure of the treatment lay in the material itself or the use of a blind, midurethral injection technique. METHODS: A retrospective case series of 56 patients undergoing cystoscopically guided bladder neck injections of dextranomer/hyaluronic acid with follow-up in 42, included 35 women with intrinsic sphincter deficiency (ISD), 4 men with postprostatectomy incontinence, 2 men with sphincteric denervation secondary to spinal cord injury, and 1 woman with sphincteric failure after a neobladder. Outcome assessment used gender-appropriate International Consultation on Incontinence Questionnaire, clinical records, and/or urodynamic assessment. RESULTS: Of 35 women with ISD, 4 developed pseudoabscess formation with outlet obstruction requiring multiple operative interventions. Patient-defined treatment failure occurred in all 4 carefully selected postprostatectomy incontinent men, and in 23 of 35 females with ISD. CONCLUSIONS: Complications with cystoscopically injected dextranomer hyaluronic acid at the bladder neck occurred at a high rate, and using a validated questionnaire, the efficacy of dextranomer hyaluronic acid applied in this manner for ISD was poor.

Traumatic axonal injury in the perisomatic domain triggers ultrarapid secondary axotomy and Wallerian degeneration.

Traumatic axonal injury (TAI) arising from diffuse brain injury (DBI) results in focally impaired axonal transport with progressive swelling and delayed disconnection over several hours within brainstem axons. Neocortical DBI-mediated perisomatic axotomy does not result in neuronal death, suggesting that a comparably delayed axotomy progression was responsible for this unanticipated response. To evaluate delayed perisomatic axotomy, the current study was initiated. Rats received intracerebroventricular 10-kDa dextran followed by moderate midline/central fluid percussion injury (FPI) or FPI alone. At 15, 30, 60, and 180 min post-injury, light and transmission electron microscopy identified impaired axonal transport via antibodies targeting amyloid precursor protein (APP), while double-label fluorescent microscopy explored concomitant focal axolemmal alterations via dextran-APP co-localization. At 15 min post-injury, perisomatic TAI was identified with LM within dorsolateral and ventral posterior thalamic nuclei. Using TEM, many sustaining somata and related proximal/distal axonal segments revealed normal ultrastructural detail that was continuous with focal axonal swellings characterized by cytoskeletal and organelle pathology. In other cases, axotomy was confirmed by loss of axonal continuity distal to the swelling. By 30 min post-injury, perisomatic axotomy predominated. By 60-180 min, somatic, proximal axonal segment, and swelling ultrastructure were comparable to earlier time points although swelling diameter increased. Distal axonal segment ultrastructure now revealed the initial stages of Wallerian degeneration. The site of perisomatic axotomy did not internalize dextran, suggesting that its pathogenesis occurred independent of altered axolemmal permeability. Collectively, this DBI-mediated ultrarapid perisomatic axotomy and its sequelae further illustrate the varied axonal responses to trauma.

Preclinical studies of [(99m)Tc]DTPA-mannosyl-dextran .

We report the preclinical testing of a synthetic receptor-binding macromolecule, [(99m)Tc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, K(D) = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration, and perivascular irritation studies in rabbits following intra-muscular administration at 100 and 1000 times the scaled human dose. Biodistribution studies in rabbits at 15 m, 1 h, and 3 h indicated that [(99m)Tc]DTPA-mannosyl-dextran cleared the hind foot pad with a biological half-life of 2.21 +/- 0.27 h. Other than mild hepatocyte hypertrophy in rabbits, no abnormalities in toxicology or pathology were found. Intravenous administration had no effect on survival, any clinical observations, electrocardiograms, or blood pressures. Intramuscular injection had no effect on survival, clinical observations, injection site observations, or injection site histopathology. The estimated absorbed radiation dose to the affected breast was 0.15 mGy/MBq and the effective dose was 1.06 x 10(-2) mSv/MBq. This preclinical study demonstrates that [(99m)Tc]DTPA-mannosyl-dextran has no toxicities and has an acceptable biodistribution and radiation dose.

Combined drug therapy with diltiazem, dextran, and hydrocortisone (DDH therapy) for late cerebral vasospasm after aneurysmal subarachnoid hemorrhage: assessment of efficacy and safety in an open clinical study.

Late cerebral vasospasm after subarachnoid hemorrhage (SAH) is a disastrous phenomenon for the patients and a definite treatment has not been established. We studied 48 consecutive patients receiving high-dose diltiazem (5 micrograms/kg/min) injection combined with dextran and hydrocortisone to late cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). All but 2 patients underwent surgery within 72 hours after SAH. Diltiazem was continuously given via a central venous line for up to 2 weeks in conjunction with simple cisternal drainage. 5% of dextran solution (500 ml/day) was infused for 7-10 days. Hydrocortisone was given 1,600 mg on the first day, then the dose was gradually decreased over 14 days. Symptomatic vasospasm (SVS) occurred in 5 patients (10.4%), 4 patients recovered, but 1 had severe neurological deficit. A low density area on CT-scan was observed in 2 patients. Thirty patients (62.5%) had good recovery, 10 patients (20.8%) had moderate disability, 3 (6.3%) had severe disability and 3 (6.3%) had vegetative survival. Two patients died of the initial brain damage. There were no severely hypotensive side effects. However, 3 patients showed atrioventricular blockage on electrocardiogram. These side effects subsided after the dose of the drug was decreased or administration was stopped altogether. These findings show that high-dose calcium antagonist diltiazem therapy combined with dextran and hydrocortisone injection is safe and effective for prevention of late cerebral symptomatic vasospasm after SAH.

Controversies in shock research: hypertonic resuscitation--pros and cons.

The proper fluid resuscitation of hemorrhagic shock is still controversial. Hypertonic saline has been suggested for prehospital resuscitation of hemorrhagic shock, because of its superior ability to expand blood volume and elevate systemic blood pressure and cardiac output in a small volume and during a short time period. We have defined two types of hemorrhagic shock: controlled hemorrhagic shock (CHS), where the bleeding source is immediately occluded following hemorrhage, and uncontrolled hemorrhagic shock (UCHS), where bleeding is induced by injury to blood vessels that are left unoccluded. It was observed that hypertonic saline (HTS) treatment of controlled hemorrhagic shock leads to an increase in blood pressure and cardiac output, while HTS treatment of UCHS leads to increased bleeding from injured blood vessels, hemodynamic deterioration, and increased mortality. Conversion of UCHS to CHS by tourniquet, military antishock trousers, or surgical hemostasis prevented excessive bleeding and mortality following HTS. Several clinical studies have used hypertonic saline dextran (HSD) or hypertonic saline (HS) for treatment of trauma casualties, but to date no significant improvement in mortality has been demonstrated by either HS or HSD. A more favorable effect but still not statistically significant effect has been demonstrated in patients with a Glasgow Coma Scale of 8 or less. The efficacy of HS has not clearly been established in clinical trials, in all of which HS was used in combination with conventional crystalloid therapy. Further human trials are required to better define the patient population that would benefit most from the prehospital administration of HS.

Anaesthetic implications of 32% Dextran-70 (Hyskon) during hysteroscopy: hysteroscopy syndrome.

This review describes the properties and side effects of Hyskon and the implications for the patient and anaesthetist during hysteroscopy. The amount of Hyskon absorbed is dependent on the injection pressure, the extent of tissue trauma, the seal of the hysteroscope around the cervix, and the duration of infusion. The mechanism of pulmonary oedema after absorbtion of Hyskon is fluid overload, and not injury to pulmonary capillary endothelium. The haematological effects are primarily due to haemodilution. However, case reports suggest that Dextran 70 may cause a syndrome resembling disseminated intravascular coagulation. The allergic response to Hyskon consists of both an anaphylactic and an anaphylactoid component. It is recommended that hysteroscopy with Hyskon be limited to 45 min, and that all possible measures be taken to minimize tissue trauma and bleeding. The volume of Hyskon should be limited to less than 500 ml, since pulmonary oedema and coagulopathy have been described with even lesser amounts. The cumulative volume of Hyskon should be monitored frequently and the patient should be closely monitored for signs of impending pulmonary oedema.

Dextran 70--encouraging early clinical studies.

There appears to be significant data both in animal and human studies to support the contention that 32% high molecular weight dextran-70 is of significant benefit in the minimization of surgical adhesion formation--and reformation after lysis. The data would suggest that it is more valuable in more severe cases, and that it tends to be more efficacious in dependent portions of the pelvis supporting, at least in part, the "hydroflotation" theory of its mechanism of action. Allergic reaction is possible but quite rare, and concern about the possible role of dextran-70 in support of clinical bacterial infection appears to be unsubstantiated by both clinical and experimental data.