Impact of cirrhosis in patients undergoing laparoscopic liver resection in a nationwide multicentre survey.

BACKGROUND: The aim was to analyse the impact of cirrhosis on short-term outcomes after laparoscopic liver resection (LLR) in a multicentre national cohort study. METHODS: This retrospective study included all patients undergoing LLR in 27 centres between 2000 and 2017. Cirrhosis was defined as F4 fibrosis on pathological examination. Short-term outcomes of patients with and without liver cirrhosis were compared after propensity score matching by centre volume, demographic and tumour characteristics, and extent of resection. RESULTS: Among 3150 patients included, LLR was performed in 774 patients with (24·6 per cent) and 2376 (75·4 per cent) without cirrhosis. Severe complication and mortality rates in patients with cirrhosis were 10·6 and 2·6 per cent respectively. Posthepatectomy liver failure (PHLF) developed in 3·6 per cent of patients with cirrhosis and was the major cause of death (11 of 20 patients). After matching, patients with cirrhosis tended to have higher rates of severe complications (odds ratio (OR) 1·74, 95 per cent c.i. 0·92 to 3·41; P = 0·096) and PHLF (OR 7·13, 0·91 to 323·10; P = 0·068) than those without cirrhosis. They also had a higher risk of death (OR 5·13, 1·08 to 48·61; P = 0·039). Rates of cardiorespiratory complications (P = 0·338), bile leakage (P = 0·286) and reoperation (P = 0·352) were similar in the two groups. Patients with cirrhosis had a longer hospital stay than those without (11 versus 8 days; P = 0·018). Centre expertise was an independent protective factor against PHLF in patients with cirrhosis (OR 0·33, 0·14 to 0·76; P = 0·010). CONCLUSION: Underlying cirrhosis remains an independent risk factor for impaired outcomes in patients undergoing LLR, even in expert centres.

ANTECEDENTES: El objetivo de este estudio fue analizar el impacto de la cirrosis en los resultados a corto plazo después de la resección hepática laparoscópica (laparoscopic liver resection, LLR) en un estudio de cohortes multicéntrico nacional. MÉTODOS: Este estudio retrospectivo incluyó todos los pacientes sometidos a LLR en 27 centros entre 2000 y 2017. La cirrosis se definió como fibrosis F4 en el examen histopatológico. Los resultados a corto plazo de los pacientes con hígado cirrótico (cirrhotic liver CL) (pacientes CL) y los pacientes con hígado no cirrótico (non-cirrhotic liver, NCL) (pacientes NCL) se compararon después de realizar un emparejamiento por puntaje de propension del volumen del centro, las características demográficas y del tumor, y la extensión de la resección. RESULTADOS: Del total de 3.150 pacientes incluidos, se realizó LLR en 774 (24,6%) pacientes CL y en 2.376 (75,4%) pacientes NCL. Las tasas de complicaciones graves y mortalidad en el grupo de pacientes CL fueron del 10,6% y 2,6%, respectivamente. La insuficiencia hepática posterior a la hepatectomía (post-hepatectomy liver failure, PHLF) fue la principal causa de mortalidad (55% de los casos) y se produjo en el 3,6% de los casos en pacientes CL. Después del emparejamiento, los pacientes CL tendieron a tener tasas más altas de complicaciones graves (razón de oportunidades, odds ratio, OR 1,74; i.c. del 95% 0,92-0,41; P = 0,096) y de PHLF (OR 7,13; i.c. del 95% 0,91-323,10; P = 0,068) en comparación con los pacientes NCL. Los pacientes CL estuvieron expuestos a un mayor riesgo de mortalidad (OR 5,13; i.c. del 95% 1,08-48,6; P = 0,039) en comparación con los pacientes NCL. Los pacientes CL presentaron tasas similares de complicaciones cardiorrespiratorias graves (P = 0,338), de fuga biliar (P = 0,286) y de reintervenciones (P = 0,352) que los pacientes NCL. Los pacientes CL tuvieron una estancia hospitalaria más larga (11 versus 8 días; P = 0,018) que los pacientes NCL. La experiencia del centro fue un factor protector independiente de PHLF (OR 0,33; i.c. del 95% 0,14-0,76; P = 0,010) pacientes CL. CONCLUSIÓN: La presencia de cirrosis subyacente sigue siendo un factor de riesgo independiente de peores resultados en pacientes sometidos a resección hepática laparoscópica, incluso en centros con experiencia.

Primum Non Nocere: Organ Donation After Electrocution and Transplantation of Electricity-Damaged Livers: Report of 2 Cases.

Liver transplantation remains the treatment of choice for patients with end-stage liver disease. However, allograft availability continues to be a problem, and extending the criteria for organ acceptance is key. Deceased donors after electrical accidents, as well as electricity-traumatized allografts, are not common but should be considered suitable. This study describes 2 cases of heart-beating organ donors with electrical injury to the liver. In 1 case, the electric shock was the cause of death; in the second case, the injury was caused by defibrillation at organ procurement. Both allografts had sustained sizeable electrical injury, and both resulted in excellent early posttransplant outcomes. These cases demonstrate that electrocution is not a contraindication to donation and that electricity-traumatized allografts may remain transplantable after careful assessment. Education of all staff in the management of such donors can optimize utility of such allografts.

Aflibercept in persistent neovascular AMD: comparison of different treatment strategies in switching therapy.

PurposeTo evaluate the effects of aflibercept administered according to a pro re nata (PRN) or Fixed Regimen to patients with neovascular AMD and persistent intraretinal/subretinal fluid (IRF/SRF) despite three consecutive ranibizumab injections.MethodsPatients were switched to aflibercept injection (IVA) administered according to a PRN or to a fixed regimen for 1 year in two different retina centers. At baseline each patient underwent a complete ophthalmologic evaluation, including best-corrected visual acuity assessment (BCVA ETDRS chart), fluorescein, and indocyanine green angiography and OCT.ResultsEach group included 36 eyes. After 1 year the PRN group showed BCVA stabilization (63 vs 60 letters, P=0.33), whereas fixed regimen group showed significant BCVA improvement (68 vs 71, P=0.008). The median central retinal thickness decreased by 94 µm in the PRN (P=0.002) and by 148 µm in the fixed regimen group (P≤0.001). Complete IRF/SRF reabsorption was found in 58% of eyes in the PRN and in 42% of eyes in the fixed regimen group. At 1-year visit, the percentage of eyes with pigment epithelium detachment did not significantly decrease, but a height reduction was recorded in both groups. The median number of IVA was 3.5 in the PRN and 7 in the fixed regimen group.ConclusionThe switch to aflibercept with both treatment strategies enabled improvement in morphological parameters and stabilization of visual acuity. BCVA improvement and reduction in vision loss with reduction in retinal thickness, fluid and PED height was achieved with the fixed regimen in previously treated nAMD after 1 year.

Surgical management of the pancreatic stump following pancreato-duodenectomy.

Pancreato-duodenectomy (PD) is the treatment of choice for periampullary tumors, and currently, indications have been extended to benign disease, including symptomatic chronic pancreatitis, paraduodenal pancreatitis, and benign periampullary tumors that are not amenable to conservative surgery. In spite of a significant decrease in mortality in high volume centers over the last three decades (from>20% in the 1980s to<5% today), morbidity remains high, ranging from 30% to 50%. The most common complications are related to the pancreatic remnant, such as postoperative pancreatic fistula, anastomotic dehiscence, abscess, and hemorrhage, and are among the highest of all surgical complications following intra-abdominal gastro-intestinal anastomoses. Moreover, pancreatico-enteric anastomotic breakdown remains a life-threatening complication. For these reasons, the management of the pancreatic stump following resection is still one of the most hotly debated issues in digestive surgery; more than 80 different methods of pancreatico-enteric reconstructions having been described, and no gold standard has yet been defined. In this review, we analyzed the current trends in the surgical management of the pancreatic remnant after PD.

A (single case) rehabilitation program based on cueing for freezing of speech.

BACKGROUND: Freezing of speech (FoS) and other repetitive speech behaviours can frequently occur in parkinsonian syndromes, worsening the efficacy of language functioning, hampering social interactions, and thus reducing quality of life. Pharmacological treatment are ineffective and other interventions have not specifically developed so far. AIM: The aim of this paper was to test the efficacy on a pilot rehabilitation program for freezing of speech based on cueing. SETTING: Outpatient clinic. POPULATION: Single-case. METHODS: We developed a pilot rehabilitation program based on visual, auditory and sensory cueing. The patient underwent the protocol for a 6-month period (1-hour sessions, 3 times weekly). Perceptual analyses of his speech were performed before and after the rehabilitation program by to different blinded reviewers. RESULTS: There has been a reduction of FoS and other iterative speech episodes. Intelligibility also improved according to both the patient and his relatives. CONCLUSION: Our preliminary results show that visual, auditory and sensory cueing can be effective to prevent and overcome FoS episodes. Possible underlying mechanisms of the improvement are discussed. CLINICAL REHABILITATION IMPACT: Rehabilitation programs based on cueing should be considered and offered in Parkinsonian patients exhibiting FoS or other iterative speech phenomena.

Allograft nephrectomy: what is the best surgical technique?

BACKGROUND: The objective of this study was to evaluate differences in outcomes of allograft nephrectomies performed by extracapsular versus intracapsular techniques. METHODS: From 1993 to 2010, we performed 89 allograft nephrectomies, including 57 by extracapsular techniques and 32 by intracapsular, chosen according to feasibility at the beginning of the surgery. Fisher exact test and logistic regression were used for statistical analysis. Survival estimates after allograft nephrectomy were calculated according to the Kaplan-Meier method. RESULTS: After a mean graft survival of 49.7 months, the indications for transplant nephrectomy were chronic rejection (39.3%), acute rejection (22.5%), infection/sepsis (19.1%), gross hematuria (6.7%), renal vein thrombosis (6.7%), renal artery thrombosis (3.4%), and graft rupture (2.3%). Mean operative time, blood loss, transfusions, and complications were similar between the extracapsular and intracapsular groups. The only difference in surgical aspects between the 2 groups was the mean hospital stay, which was longer for the extracapsular group (13.8 vs 7.6 days; P = .01), a result that was confirmed by multivariate analysis (odds ratio, 1.05; 95% confidence interval, 1.0-1.1; P = .03). CONCLUSIONS: Our experience showed no significant advantages in favor of the intracapsular technique except for a shorter length of hospital stay than after the extracapsular procedure.

The effects of weight loss due to gastric banding and lifestyle modification on red blood cell aggregation and deformability in severe obese subjects.

OBJECTIVE: To investigate the changes in the aggregation index (AI) and the elongation index (EI), in severe obese subjects (MbObS) undergoing laparoscopic adjustable gastric banding (LAGB). AI and EI are measured by Laser assisted Optical Rotational Red Cell Analyzer (LORCA) and are markers of erythrocyte aggregation and deformability, respectively. DESIGN AND SUBJECTS: Before, 3 and 6 months after LAGB plus lifestyle changes (Mediterranean diet plus daily moderate exercise), we evaluated AI, EI, body mass index (BMI), total (ToT) cholesterol (Chol), high-density lipoprotein (HDL)-Chol, low-density lipoprotein (LDL)-Chol, triglycerides and fasting glucose and insulin levels in 20 MbObS. The Student's t-test was used for comparisons between independent groups and the analysis of variance to assess differences in AI and EI at the 3 time points. Pearson's correlation coefficient was used to assess correlation among continuous variables and multiple linear regression analysis to assess predictive factors for AI and EI changes. RESULTS: BMI and all blood parameters showed a statistically significant decline 3 and 6 months after LAGB as compared with basal, except for EI and HDL-Chol that significantly increased. Stepwise selection of predictors shows that at 3 and 6 months, EI values depended on HDL-Chol values at the same time point. In the EI model, blood glucose was also statistically significant at 6 months. CONCLUSION: Our data show a significant improvement in EI after LAGB-induced weight loss, which correlates with an improved lipid pattern and support the idea that the rapid weight loss induced by LAGB plus lifestyle changes might reduce the thromboembolic risk and the high mortality risk found in MbObS.

Abdominal nodal localization of Castleman's disease: report of a case.

INTRODUCTION: Castleman's disease (CD) is a rare benign disorder that may grow in any area where lymphoid tissue is normally present but the most frequent site is mediastinum (67%); the abdomen is rarely affected by this pathology. In the pathogenesis of CD an important role could be played by HHV-8. Diagnosis is difficult and the diagnostic certainty is obtained only by histological examination. For this disease there is no gold-standard treatment. CASE REPORT: We report the case of a woman of 33 years of age affected by a rare form of abdominal nodal localization of Castleman's Disease for which the patient underwent surgery. CONCLUSION: CD must be included in the differential diagnosis of retroperitoneal tumors even though the definitive diagnosis can only be achieved by histological and immunohistochemical examination. In the case of single location, the treatment of choice is surgical removal.

Photodynamic therapy outcomes in a case of macular choroidal neovascularization secondary to Candida endophthalmitis.

PURPOSE: To evaluate the effects on visual function and choroidal neovascularization (CNV) progression in a case of subretinal CNV due to Candida endophthalmitis treated with a combination of photodynamic therapy (PDT) and drugs. METHODS: A 28-year-old one-eyed woman with CNV in the right eye came to our observation. The CNV developed as a consequence of Candida endophthalmitis. The CNV was treated with six PDT treatments with verteporfin in association with systemic steroid therapy with prednisone (100 mg/day to reduce) and fluconazole (800 mg/day to reduce). Visual acuity (VA) was assessed in pre-PDT conditions and after six PDT treatments (24 months of follow-up). RESULTS: Pre-PDT VA was 20/125; after 24 months of follow-up, six PDT re-treatments, and pharmacologic therapy, VA was stabilized at 20/100. CONCLUSIONS: In our case, associated PDT and drug therapies were safe and useful to maintain VA and to arrest CNV progression in the foveal region after 2 years of follow-up.

Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life and work productivity.

BACKGROUND: Effects of frequent nocturnal symptoms of gastro-oesophageal reflux disease (GERD-FNS) on health-related quality of life (HRQOL) and work productivity are not well documented. AIM: To assess symptom severity, production loss, and HRQOL among employed adults with and without GERD-FNS. METHODS: Using several validated outcome measures in a web survey design, GERD was pre-specified as GERD Symptom and Medication Questionnaire score >9, and > or =1 episode of heartburn or acid regurgitation during the preceding week. GERD-FNS patients were those reporting > or =2 symptom-nights during the previous week; their outcomes were compared with those of patients having minimal or no nocturnal symptoms (GERD-NNS) and vs. non-GERD controls. RESULTS: Data were collected from 1002 GERD patients (476 GERD-FNS, 526 GERD-NNS) and 513 controls. Severe symptoms were more common, sleep abnormalities were more frequent (P < 0.0001) and SF-36 scores lower (P < 0.05, all scores) among GERD-FNS patients vs. GERD-NNS patients. GERD-related work loss was greater among those with GERD-FNS vs. GERD-NNS (P < 0.0001). Work loss and functional limitations were more pronounced when comparing GERD-FNS cases vs. non-GERD controls. CONCLUSION: Employed adults with frequent nocturnal GERD report more severe symptoms, and are associated with impaired sleep, HRQOL and work productivity compared with controls and patients with minimal or no nocturnal symptoms.

Lipid microencapsulation allows slow release of organic acids and natural identical flavors along the swine intestine.

The purpose of the present work was to investigate the in vivo concentrations of sorbic acid and vanillin as markers of the fate of organic acids (OA) and natural identical flavors (NIF) from a microencapsulated mixture and from the same mixture non-microencapsulated, and the possible consequences on the intestinal microbial fermentation. Fifteen weaned pigs were selected from 3 dietary groups and were slaughtered at 29.5 +/- 0.27 kg of BW. Diets were (1) control; (2) control supplemented with a blend of OA and NIF microencapsulated with hydrogenated vegetable lipids (protected blend, PB); and (3) control supplemented with the same blend of OA and NIF mixed with the same protective matrix in powdered form but without the active ingredient coating (non-protected blend, NPB). Stomach, cranial jejunum, caudal jejunum, ileum, cecum, and colon were sampled to determine the concentrations of sorbic acid and vanillin contained in the blend and used as tracers. Sorbic acid and vanillin were not detectable in pigs fed the control, and their concentrations were not different in the stomach of PB and NPB treatments. Pigs fed PB showed a gradual decrease of the tracer concentrations along the intestinal tract, whereas pigs fed NPB showed a decline of tracer concentration in the cranial jejunum and onwards, compared with the stomach concentrations. Sorbic acid and vanillin concentrations along the intestinal tract were greater (P = 0.02) in pigs fed PB compared with pigs fed NPB. Pigs fed PB had lower (P = 0.03) coliforms in the caudal jejunum and the cecum than pigs fed the control or NPB. Pigs fed the control or PB had a greater (P = 0.03) lactic acid bacteria plate count in the cecum than pigs fed NPB, which showed a reduction (P = 0.02) of lactic acid concentrations and greater (P = 0.02) pH values in the caudal jejunum. The protective lipid matrix used for microencapsulation of the OA and NIF blend allowed slow-release of both active ingredients and prevented the immediate disappearance of such compounds upon exiting the stomach.

Quality of vision: A consensus building initiative for a new ophthalmologic concept.

PURPOSE: Many studies have addressed the quantification of visual acuity, and the conventional method of measuring it has so far demonstrated serious limitations. Vision testing requires new methods that can more precisely express the quality of vision as perceived by the patient. METHODS: This study employed the Delphi method of consensus building. Concepts associated with quality of vision (QoV) were identified by a board of experts and proposed to participating specialists in two subsequent questionnaires. Upon receipt of the completed questionnaires, the replies were classified to determine the building blocks of a consensus. RESULTS: By analyzing the replies to the two questionnaires, the authors determined the key elements of QoV on which a consensus was found among the respondents. CONCLUSIONS: A consensus was reached on the opinion that the quantification of visual acuity by traditional means is inadequate for investigating QoV. Although visual acuity is still a basic element for testing, the experts believe that contrast sensitivity, reading speed, and microperimetry are additional parameters necessary for quantifying QoV. The use of a psychometric questionnaire on visual function could allow a better interpretation of visual impairment.

Naltrexone and acamprosate. Using new drugs for alcohol dependence.

BACKGROUND: Two new drugs for the treatment of alcohol dependence have recently become available in Australia. Both naltrexone and acamprosate have an 'anticraving' action, but act on different pathways and have different properties. OBJECTIVE: This article aims to give an outline of the major pharmacological features of the two new drugs and some guidelines on their use for general practitioners. DISCUSSION: The past 50 years have seen major advances in almost all medical disciplines. A notable exception has been the alcohol and drug field. The arrival of methadone to Australia in the 1960s was, until lately, the most recent advance in the field. Over the past 18 months, several new drugs have become available for use in alcohol and drug (A&D) clinics. These drugs have also become available to the GP, but their use by this group remains relatively small.

[Phantom rectum after Miles' operation]. / Il retto fantasma dopo intervento di Miles.

The authors observed symptoms relating to the existence of a phantom rectum, a phenomenon about which little is still known, in 233 cases (32.1%) in a series of 724 patients undergoing amputation of the abdomino perineal rectum due to malignant neoplasm. The genesis of this phenomenon is attributed to an abnormal reactivity of the cortical and thalamic projection areas with greater response to stimuli from the stump or aspecific visceral stimuli, or even stimuli from the adjacent cortical regions. The psychodynamic aspects linked to the patient's need to develop a different body awareness should not be underestimated; this has to integrate a new anatomic reality, such as colostomy in the place of the anorectum, entailing the relinquishment of the previous body scheme. Prevention and treatment of phantom rectum, which is painful in 27% of cases, is essential for a correct operating technique, adequate psychotherapeutic support, the patient's active participation in a reeducation programme for colostomy management. It should not be forgotten that painful phantom rectum, especially with late onset, may be diagnostically significant as an indicator of the recurrence of neoplastic pathology, sometimes allowing diagnosis to be anticipated by several months. This underlines the importance of carrying out a careful postoperative clinical, biohumoral and radiological control in these patients, including pelvic CT. In the authors' experience of 233 patients suffering from phantom rectum, it was possible to document the presence of neoplastic recidivation in 30 cases (12.8%) using pelvic CT. In these cases, symptoms appeared after a disease-free interval of 26.3 months (range 3-75 months), whereas the presence of phantom rectum without recidivation is usually described in the first 2 months after surgery.

Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial.

BACKGROUND: Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. PATIENTS AND METHODS: One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) +/- glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. RESULTS: When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control--58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control--74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). CONCLUSIONS: The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.

Neuroprotectant drugs in cisplatin neurotoxicity.

Cisplatin (CDDP) is one among the most effective and widely used anticancer drugs. Its use is, however, often limited by its peripheral neurotoxicity, which may be severely disabling and sometimes not reversible. To prevent or reduce CDDP peripheral neurotoxicity several "neuroprotective" drugs have been proposed. This goal is of extreme importance in the treatment of cancer patients, especially in view of the better results obtained by anticancer chemotherapy in terms of longer disease-free survival which has made even more crucial than in the past the point of the quality of life of the long-surviving patients. The data of pre-clinical and clinical studies with neuroprotectant agents are often conflicting, in some cases because of inadequate methods of evaluation and/or study design used to examine their effectiveness. The aims of this review will be 1) to discuss and describe the most appropriate methods of evaluation of CDDP and neuro-protectant drugs in experimental in vitro and in vivo pre-clinical studies 2) to evaluate critically the results of the clinical trials reported so far with the combined treatment and 3) to explore the possible future strategies to achieve neuroprotection during high-dose CDDP treatment in humans.

Weekly cisplatin +/- glutathione in relapsed ovarian carcinoma.

On the basis of experimental data showing the efficacy of glutathione (GSH) as a protective agent on cisplatin-induced neurotoxicity and the clinical evidence of the low incidence of neurotoxicity in high-dose cisplatin + GSH treated patients we evaluated the neuroprotective effect of GSH in a randomized phase II study. Thirty-three patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging 450-650 mg m-2 were randomized to receive cisplatin 50 mg m-2 weekly +/- 2.5 g GSH for 9 consecutive weeks. Clinical and instrumental neurologic and otologic evaluations were made at the baseline and at the end of the study. Overall response rate in 31 evaluable patients was: 9/15 in group A and 12/16 in group B, including 4/15 vs 7/16 complete responses. The administered dose intensity of cisplatin was higher in the GSH treated patients (100% dose intensity was received by 56% vs 27%). A trend in terms of neuroprotection was detected in the GSH treated group, and no major difference was observed in the other toxicities between the two groups. It is concluded that possible benefit can be expected from the concomitant administration of GSH and cisplatin in patients at high risk of developing neurotoxicity, without decreasing the anti-tumor activity.

Pharmacokinetic evaluation of two different formulations of megestrol acetate in patients with advanced malignancies.

The bioequivalence of two megestrol acetate formulations, 160-mg "tablets" and 160-mg "sachets," was investigated in a single-dose, open-label, balanced-for-sequence cross-over study involving 12 advanced-cancer patients. The observed plasma megestrol-acetate time course obtained with both formulations was consistent with the literature data. The main source of variability in the pharmacokinetic parameters was intersubject variability; drug formulation played only a minor (and nonsignificant) role. The width of the 90% confidence interval of the area-under-the-curve (AUC) ratio (sachets: tablets) computed according to Schuirmann (0.9-1.4) was mainly due to the presence of a single outlier, showing an AUC ratio of 2.7. The trend to higher bioavailability of the new formulation was not significant, especially as compared with the dose-response data reported in the literature.