The Comparison of Biodistribution, Efficacy and Toxicity of Two PEGylated Liposomal Doxorubicin Formulations in Mice Bearing C-26 Colon Carcinoma: a Preclinical Study.

BACKGROUND: Over the past several years, the considerable attention has been progressively given to liposomal formulations of anthracyclines. SinaDoxosome(®) (Exir Nano Sina Company, Iran) is a pegylated liposomal doxorubicin (DOX) which approved by Food and Drug Administration of IRAN for treatment of some types of cancer. The aim of this study was to compare the biodistribution, efficacy, cardiotoxicity and hepatotoxicity of SinaDoxosome(®) with Caelyx(®) in mice bearing C-26 colon carcinoma. METHODS AND RESULTS: Mice tumor size evaluation during the experimental period (28 days) showed comparable therapeutic efficacy of nano-formulations. The biodistribution studies showed no significant difference in DOX tissue concentration between Caelyx(®) and SinaDoxosome(®). DOX induced-ECG changes were not detected in nano-formulations. No significant alteration was found in biochemical indexes of myocardial injury in mice exposed to nano-formulations in comparison with control mice. The tissue oxidative parameters such as lipid peroxidation, glutathione, catalase and superoxide dismutase was significantly changed as the results of free DOX treatment. However, the oxidative status of Caelyx(®) and SinaDoxosome(®) treated animals did not showed any changes. The experiment also revealed that apoptotic pathway was not activated in the heart of mice exposed to nano-formulations. CONCLUSIONS: Although this investigation showed that Caelyx(®) and SinaDoxosome(®) are similar in terms of biodistribution, efficacy and toxicity, appropriate clinical evaluations in patients should be considered.

Synthesis of a microhydrogel composite from cellulose nanowhiskers and starch for drug delivery.

This work describes the preparation of a microhydrogel composite from cellulose nanowhiskers (CNW) and starch in an ultrasound assisted-emulsion. CNW, which showed rod-like morphology, was obtained by acid hydrolysis of cane-based cellulose. The introduction of vinyl bonds to both CNW and starch enabled us to create the microhydrogel composite in which CNW played a role as a covalent cross-linker. Furthermore, CNW may act as an emulsifying agent for emulsion, improving both sphericity and homogeneity of the microparticles. The drug release was regulated in response to changes in the CNW amounts. The modeling of the release kinetics indicated that the drug release is driven by an anomalous mechanism and that the addition of CNW to starch microparticles led to differences in that mechanism. The release rate became ca. 2.9 times slower when CNW is added. When combined with starch, CNW played a role as a retardant factor for drug release.

Antitrypanasomal activity of novel benzaldehyde-thiosemicarbazone derivatives from kaurenoic acid.

A series of new thiosemicarbazones derived from natural diterpene kaurenoic acid were synthesized and tested against the epimastigote forms of Trypanosoma cruzi to evaluate their antitrypanosomal potential. Seven of the synthesized thiosemicarbazones were more active than kaurenoic acid with IC50 values between 2-24.0 mM. The o-nitro-benzaldehyde-thiosemicarbazone derivative was the most active compound with IC50 of 2.0 mM. The results show that the structural modifications accomplished enhanced the antitrypanosomal activity of these compounds. Besides, the thiocyanate, thiosemicarbazide and the p- methyl, p-methoxy, p-dimethylamine, m-nitro and o-chlorobenzaldehyde-thiosemicarbazone derivatives displayed lower toxicity for LLMCK2 cells than kaurenoic acid, exhibing an IC50 of 59.5 mM.

Evaluation of the molluscicidal and Schistosoma mansoni cercariae activity of Croton floribundus extracts and kaurenoic acid / Avaliação das atividades moluscicida e cercaricida (Schistosoma mansoni) dos extratos de Croton floribundus e do ácido caurenóico

Extratos de Croton fluribundus (Euphorbiaceae), ácido caurenóico e dois derivados do ácido caurenóico foram avaliados como moluscicida, cercaricida e também foi verificada a letalidade destas amostras frente a larvas de Artemia salina Leach. Nestes ensaios foram observadas significantes atividades moluscicida e cercaricida associadas a uma reduzida toxicidade frente ao camarão de água salgada.

Lethality of the extracts of Croton floribundus (Euphorbiaceae), a medicinal plant from south Brazil, and of the kaurenoic acid, an isolated compound, and two of its derivatives against adult Biomphalaria glabrata snails, Schistosoma mansoni cercariae and Artemia salina Leach. brine shrimp larvae are reported. Both extracts and the isolated compound showed significant molluscicidal and cercaricidal activities and reduced toxicity in brine shrimp assays.

Changes in the tissue and plasma superoxide dismutase (SOD) levels in a burned rat model.

To examine whether thermal injury alters the superoxide dismutase (SOD) concentrations in various types of tissue or plasma, we studied the plasma and tissue Mn- and Cu/Zn-SOD levels in a rodent burn model. The animals were resuscitated with saline (50 mg/kg, i.p.) immediately following thermal injury and thereafter were sacrificed at either 6 or 24 hours post-burn. The Mn- and Cu/Zn-SOD levels were measured using an enzyme-linked immunosorbent assay (ELISA). The plasma Mn- and Cu/Zn-SOD concentrations significantly increased 6 hours after the injury and positively correlated with the burn size. The kidney Mn-SOD concentrations were significantly higher 24 hours after the injury in the animals with 30% burns than in those with either sham or 50% burn injuries. The lung Cu/Zn-SOD concentrations were also significantly higher 6 hours after the injury in animals with 30% burns than in the other two types above. These findings suggest that the changes in the SOD concentrations after burn injury vary according to the type of SOD and also the type of tissue. As a result, the SOD concentrations may play some role in the early response to thermal trauma.

Burns caused by medical therapy.

A burn injury may occur as an unexpected consequence of medical treatment. We examined the burn prevention implications of injuries received in a medical treatment facility or as a direct result of medical care. The records of 4510 consecutive admissions to 1 burn center between January 1978 and July 1997 were retrospectively reviewed. A cohort of 54 patients burned as a result of medical therapy was identified and stratified by location (home vs medical facility) and by mechanism of injury. Twenty-two patients were burned in a medical treatment facility, including 12 patients who were burned as a result of careless or unsupervised use of tobacco products. Thirty-two patients were burned as a result of home medical therapy, including 9 patients who had scald injuries from vaporizers, 8 patients who were burned by simultaneous use of cigarettes and home nasal oxygen therapy, and 11 patients who were burned by therapeutic application of heat. In contrast to previous studies, no patient was burned by the use of medical laser devices. To further decrease burn risk from medical therapy we advocate the prohibition of cigarette smoking in any medical facility. Continued tobacco use may represent a contraindication to home oxygen therapy. Given the lack of proof of efficacy combined with the potential for burn injury, the use of vaporizers to treat upper respiratory symptoms should be discouraged. Patients with diminished sensation or altered mental status are at increased risk of burn injury from bathing or topical heat application and merit closer monitoring during these activities.

Acute respiratory failure that complicates the resuscitation of pediatric patients with scald injuries.

Respiratory failure that requires endotracheal intubation is an uncommon but potentially fatal complication of scald burns in children. Because scalds are rarely associated with a direct pulmonary injury, the pathophysiology of respiratory failure is unclear. A possible mechanism may be upper airway edema, diminished pulmonary compliance secondary to fluid resuscitation, or both. To identify an at-risk population for intubation after a scald injury, the hospital courses of 174 consecutive patients under the age of 14 years who were admitted after a scald injury to a single burn center during a 6-year period were examined. Seven of these patients (4%) required endotracheal intubation. No patient older than 2.8 years or who had a scald injury that covered less than 19% of the total body surface area required intubation. Patients who required intubation were younger (mean age, 1.4 vs. 2.8 years, P<.001), had a larger mean burn size (29.9% vs. 12.3% total body surface area, P<.001), and required more fluid resuscitation (7.66 vs. 4.07 cc/kg per percentage of total body surface area burned, P<.001) than patients who did not require intubation. Examination of the adequacy of resuscitation revealed that the intubated patients had an average hourly urine output of 0.84 cc/kg during the first 24 hours, suggesting that resuscitation was not excessive. Multivariate analysis demonstrated that both larger burn size (P = .041) and younger age (P = .049) were independent predictors of the need for intubation. Young patients with large body surface area burns that required large volumes of resuscitation comprise an at-risk group for respiratory failure after a scald injury. Increased vigilance is merited during the resuscitation of these patients.

Elder abuse: a call to action.

An estimated 2 million people a year are victims of elder abuse, which ranges from neglect and mistreatment to physical abuse. By the year 2020, a full 22% of the population will be aged 65 or older. This demographic explosion demands that we identify and protect those at risk. To investigate the incidence of elder abuse or neglect (EAN) and to determine clinician awareness of associated risk factors, we conducted a 1-year retrospective review of thermally injured patients aged 60 or older. Data included age, total body surface area burned, mechanism of injury, length of hospital stay, mortality, abuse or neglect risk factors, and referral to the appropriate social agency. We found that our elderly patients (n = 28) were poorly screened for EAN. While 64% to 96% of patients were screened for cognitive impairment, overall health, and financial resources, none were screened for risk factors of emotional isolation. None of the patient's caregivers, including any spouses, roommates, or guardians, were screened for risk factors of substance abuse, familial violence, dependency needs, or external stresses. With the use of available data, we were able to place 11 patients on the following levels of abuse or neglect: 1) low risk for abuse; 2) self-neglect; 3) neglect; and 4) abuse. By this scale, 7 patients (64%) were victims of self-neglect, 3 patients (27%) were victims of neglect, and 1 patient (9%) was a victim of abuse. Adult Protective Services intervened in 2 cases. Recognizing that all cases of EAN should be preventable, we cannot accept the socioeconomic impact of this entity. The 11 patients identified as victims of neglect, self-neglect, or abuse accounted for 135 hospital days and 8 fatalities. Before we can address EAN, health care personnel must be made aware of the problem and routine screening for risk factors must be implemented. The true incidence of EAN is likely underestimated because health care providers have difficulty recognizing its features. A standard assessment tool to screen for neglect or abuse should be used for each older adult admission.

Preventable burns associated with the misuse of gasoline.

Gasoline is intended for use as a motor fuel, but the universal availability of gasoline in the home encourages misuse as a solvent, insecticide, accelerant or cleaning solution. The careless or inappropriate use of gasoline may result in burn injury. We examined the circumstance of gasoline-related injury in a population admitted to one burn centre to determine the potential for burn prevention efforts. A retrospective review of all burn admissions to one centre for the years 1978 to 1996 demonstrated hat 1011 of 4339 acute admissions (23.3%) were gasoline-related. This group had an average total burn size of 29.8% total body surface (TBSA) and an average full thickness injury of 14.4% TBSA. There were 144 fatalities resulting from gasoline-associated burn injury. Where such determination could be made, the use of gasoline was judged to be inappropriate or unsafe in 687 of 788 cases (87.1%). Ninety of 144 fatalities (62.5%) were associated with inappropriate or unsafe use of gasoline. The careless or inappropriate use of gasoline poses significant risk of burn injury. The indoor use of gasoline, as well as use of gasoline for purposes other than as a motor fuel, should be strongly discouraged.

Fatal and near-fatal complications of liposuction.

Cosmetic liposuction is considered to be safe and effective in properly selected patients and is widely done as an outpatient or office procedure. When major complications occur, office-based practitioners may refer patients to a hospital emergency department, where medical personnel unfamiliar with this procedure may underestimate the risk of serious infection or other major complications. We present two cases of massive necrotizing fasciitis treated in a burn center after liposuction surgery. One patient died, and the second required lengthy hospitalization, extensive debridement, and split-thickness skin grafting of 22% of the total body surface area. Pain out of proportion to clinical findings is a hallmark of necrotizing fasciitis and should prompt consideration of this entity even in the absence of cutaneous signs of infection. Definitive diagnosis is made by biopsy and rapid section histologic analysis. Liposuction may result in major complications or death. Emergency department physicians or general surgeons may be called upon to manage such complications and should be aware of these risks.

Body habitus as a predictor of burn risk in children: do fat boys still get burned?

Previous research at this institute has demonstrated that heavy-for-age boys are more burn prone than their normal sized counterparts. As this study is now 26 years old, we reexamined the anthropomorphic indices of 372 children admitted to one burn center between January 1991 and July 1997 to determine if this trend was still evident. Male children were over-represented in the < or =5th and >95th percentiles for both height (p < 0.001, p < 0.05) and weight (p < 0.01, p < 0.001). Female children were over-represented in the < or =5th and > 95th percentiles for height (p < 0.01, p < 0.05). Twenty-eight percent of boys at or below the 5th percentile for weight were burned as a result of known or suspected intentional injury, compared to 5.9% of the entire pediatric burn population. (p < 0.0004). 'Fat boys' continue to be over-represented in the pediatric burn population. Additionally, in the more recent time period, boys at or below the 5th percentile for height or weight and girls= < 5th percentile or >95th percentile for height are also over-represented. The increased frequency of burn injury in small-for-age children may reflect an increased risk of burn injury secondary to neglect or nonaccidental trauma.

Update on current therapeutic approaches in burns.

Burn injury results in a rapid loss of intravascular volume as wound edema forms, which reduces the circulating blood volume and generates the need for fluid therapy to combat hypovolemia. Fluid resuscitation of a burn patient is usually carried out with isotonic, sodium- and chloride-containing fluids, such as lactated Ringer's solution. The initial 24 h resuscitation volume is based on the burn size and body weight of the patient. Following a successful resuscitation, the burn patient develops stereotypic neurohormonal and metabolic responses that, depending on the extent of injury, last for several weeks or months. Breathing of incomplete products of combustion by the fire victim produces inhalation injury, the incidence of which rises with increasing burn size and the severity of which is proportional to the duration of exposure. Systemic hypoxia from carbon monoxide toxicity causes early death; chemical airway injury increases mortality and predisposes to subsequent pneumonia that further reduces survival. The diagnosis of inhalation injury is made by bronchoscopy and/or xenon scan and therapy involves support of ventilation. Thermal destruction of the cutaneous mechanical barrier and the presence of nonviable avascular burn eschar as well as impairment of other host defenses render the burn patient susceptible to local as well as systemic infections. Care following resuscitation is focused on topical antimicrobial therapy, burn wound excision, and wound closure by grafting. Nutritional support and the prevention and control of infection are constant themes in burn patient management. A progressive improvement in general care of the acutely injured patient, prevention of shock, effective means of maintaining organ function, prevention and control of burn wound and other infections, and physiologically based metabolic support have significantly increased burn patient survival in recent decades.

The influence of inhalation injury and pneumonia on burn mortality.

In order to assess the specific effects of inhalation injury and pneumonia on mortality in burn patients, the records of 1058 patients treated at a single institution over a five-year period, 1980-1984, were reviewed. Of these patients, 373 (35%) had inhalation injury diagnosed by bronchoscopy and/or ventilation perfusion lung scan. Of the 373 patients, 141 (38%) had subsequent pneumonia. Among the patients without inhalation injury, pneumonia occurred in 60 of 685 (8.8%). A multiple logistic equation was developed to estimate expected mortality at any age and burn size for patients without either inhalation injury or pneumonia, with either alone, or with both. Subtraction of the expected mortality without either inhalation injury or pneumonia from the expected mortality in the presence of either or both permitted the estimation of additional mortality attributable to these complications. Inhalation injury alone increased mortality by a maximum of 20% and pneumonia by a maximum of 40%, with a maximum increase of approximately 60% when both were present. The influence on mortality was maximal in the midrange of expected mortality without these complications for any age group. These data indicate that inhalation injury and pneumonia have significant, independent, additive effects on burn mortality and that these effects vary with age and burn size in a predictable manner.

Effects of environment on infection in burn patients.

Burn patients in an early cohort (n = 173) treated in an intensive care ward without separate enclosures were compared with a later cohort (n = 213) treated in a renovated unit with separate bed enclosures. The number of patients developing infection was significantly reduced in the late group. Observed mortality was compared with mortality predicted on the basis of burn size and age alone. Reduction in observed compared with predicted mortality, inapparent in the early group, was seen in the late group and was restricted to the subgroup of patients with predicted mortality of 25% to 75%, in which the observed mortality of 28.3% was less than the predicted mortality of 48.7%. The incidence of infected patients was reduced from 58.1% in the early cohort to 30.4% in the late cohort. In comparison of the early cohort with the late cohort, the overall proportion of patients with bacteremia was reduced from 20.1% to 9.4%, while the incidences of both pneumonia and burn wound invasion remained unchanged. Providencia and Pseudomonas species, endemic in the early cohort, were eliminated in the late cohort. Reduction of infection by environmental manipulation in burn patients was possible and was associated with improved survival.

Reduced serum T4 and T3 and their altered serum binding after burn injury in rats.

Total T4 and T3 concentrations are often suppressed in burned patients. To investigate the significance of such changes, we have characterized serum T4 and T3 after full-thickness scald burns (60% body surface under anesthesia) of 270-gm male Sprague-Dawley rats housed in a light:dark cycle of 14:10 hr. Groups (N = 9-15) of BURN, SHAM (anesthesia, fur clipped, no burn) and CON (controls) were sacrificed on postburn days 8 and 14. T4 and T3 (radioimmunoassay), free indices (FT4I and FT3I = respective total T4 or T3 X in vitro charcoal T3 uptake, T3U), and free concentrations (FT4 and FT3 = total T4 or T3 X respective equilibrium dialyzable fraction, T4DF or T3DF) were not different between CON and SHAM. Compared to SHAM, mean T4 and FT4I (by about 48% of respective SHAM means on both days), TT3 (by 36, 43%), and FT3I (by 38, 45%) (days 8, 14) were suppressed in BURN (all p less than 0.001). T4DF (both days) and T3DF (day 14) were significantly elevated in BURN, demonstrating a deficit in serum binding, but T3U was not. FT4 (by 26, 22%) and FT3 (by 33, 34%) (day 8, 14) were significantly lower in BURN. On either day, covariance analyses (BURN vs. combined CON + SHAM) correlated FT4I or FT3I with respective FT4 or FT3 (all p less than 0.001, slopes not different in BURN vs. CON + SHAM), but the lower FT4I and FT3I in BURN significantly overestimated (all p less than 0.001) the depression of respective FT4 and FT3 in BURN.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal changes in burned hamsters.

Burned male Syrian hamsters (burn size 23% of body surface) exhibited reduced total (T4) and free (FT4) serum concentrations, a defect in T4 binding to serum proteins manifested by the T4 dialyzable fraction but not the in vitro T3 charcoal uptake, and reduced serum testosterone concentration. These changes are similar to those noted previously in burned humans. Unlike such patients, burned hamsters did not exhibit reduced serum T3 nor elevated rT3 concentrations in a reproducible manner. Pinealectomy performed before burning in hamsters did not prevent the burn-induced depression in serum T4 and testosterone.

Upper airway sequelae in burn patients requiring endotracheal intubation or tracheostomy.

During a period of 11 1/2 months, 41 of 217 adult burn patients admitted to the U.S. Army Institute of Surgical Research Burn Center required endotracheal intubation or tracheostomy for management of the airway and/or ventilatory assistance. Permanent upper airway sequelae were recorded and related to presence of inhalation injury, duration of tube placement, cuff pressure, and pulmonary compliance. An "inhalation injury scoring system" based upon history, physical examination, bronchoscopic findings, and abnormalities at 133xenon lung scan correlated well with postinjury alteration in compliance and subsequent sequelae. Significant inhalation injury was found in 35 patients. Seventeen of the study patients survived (Group I) and 24 patients expired (Group II). Group I patients were screened for permanent airway sequelae by fiberoptic bronchoscopy, xeroradiograms, and spirometry undertaken an average of 11 weeks after extubation or decannulation. Four patients developed tracheal stenosis and five patients had significant tracheal scar granuloma formation. Sequelae were generally more frequent and more severe after tracheostomy than after translaryngeal intubation, and duration of tube placement and presence of a tracheal stoma were the most important etiological factors in permanent damage. For initial respiratory support, we favor the use of translaryngeal (nasotracheal) tubes for periods up to 3 weeks. Fiberoptic bronchoscopic examination is the most reliable follow-up method for detecting anatomic damage in such patients. Spirometry can be used as a noninvasive screening test and xeroradiograms are helpful in assessing the degree of tracheal stenosis.

Replacement therapy with modified immunoglobulin G in burn patients: preliminary kinetic studies.

Suppression of serum immunoglobulin G for periods ranging from days to weeks following thermal injury may enhance the risk of infection in burn patients. In an initial trial, we attempted to determine whether intravenous pulses of Immunoglobulin G (IgG) will establish and maintain normal serum IgG concentrations in this interval. The levels of endogeneous serum IgG in eight control patients, mean total burn size 45 percent body surface area (no IgG infusions), were measured by radial immunodiffusion on various postburn days. Commercially available reduced alkylated IgG (5 percent Gamimune, Cutter Biological, Berkeley, California) was infused in doses of 500 mg/kg twice per week in four patients (total burn size 32 percent) and once per week in five patients (total burn size 47 percent), beginning during the first postburn week. Circulating IgG was measured prior to each infusion and at three postinfusion times: (1) 15 minutes (peak), (2) one day, and (3) either day 3, 4, or 6. Surgery or blood transfusions prior to one of these time points invalidated kinetic analysis of some infusions. Exponential two-point decay constants for total serum IgG after each of 24 infusions were calculated separately for early (day 0-1) and later (day 1-3 or 1-4) postinfusion intervals and assessed by stepwise regression analysis to determine sources of variation in decay. Early decay was seen to be faster with larger burn size after accounting for variation of decay with preinfusion and peak IgG values. Later decay was not related to burn size. Maltose, a constituent of the IgG preparation, was detectable in serum for only four to eight hours after each infusion and may have contributed to a 20 percent increase in total serum glucose between four and eight hours postinfusion. Mean serum IgG in patients given infusions twice weekly was in the normal range after one infusion, about a week earlier than in untreated patients. Such infusions maintained normal IgG levels.