Laparoscopic versus open extended radical left pancreatectomy for pancreatic ductal adenocarcinoma: an international propensity-score matched study.

BACKGROUND: A radical left pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC) may require extended, multivisceral resections. The role of a laparoscopic approach in extended radical left pancreatectomy (ERLP) is unclear since comparative studies are lacking. The aim of this study was to compare outcomes after laparoscopic vs open ERLP in patients with PDAC. METHODS: An international multicenter propensity-score matched study including patients who underwent either laparoscopic or open ERLP (L-ERLP; O-ERLP) for PDAC was performed (2007-2015). The ISGPS definition for extended resection was used. Primary outcomes were overall survival, margin negative rate (R0), and lymph node retrieval. RESULTS: Between 2007 and 2015, 320 patients underwent ERLP in 34 centers from 12 countries (65 L-ERLP vs. 255 O-ERLP). After propensity-score matching, 44 L-ERLP could be matched to 44 O-ERLP. In the matched cohort, the conversion rate in L-ERLP group was 35%. The L-ERLP R0 resection rate (matched cohort) was comparable to O-ERLP (67% vs 48%; P = 0.063) but the lymph node yield was lower for L-ERLP than O-ERLP (median 11 vs 19, P = 0.023). L-ERLP was associated with less delayed gastric emptying (0% vs 16%, P = 0.006) and shorter hospital stay (median 9 vs 13 days, P = 0.005), as compared to O-ERLP. Outcomes were comparable for additional organ resections, vascular resections (besides splenic vessels), Clavien-Dindo grade ≥ III complications, or 90-day mortality (2% vs 2%, P = 0.973). The median overall survival was comparable between both groups (19 vs 20 months, P = 0.571). Conversion did not worsen outcomes in L-ERLP. CONCLUSION: The laparoscopic approach may be used safely in selected patients requiring ERLP for PDAC, since morbidity, mortality, and overall survival seem comparable, as compared to O-ERLP. L-ERLP is associated with a high conversion rate and reduced lymph node yield but also with less delayed gastric emptying and a shorter hospital stay, as compared to O-ERLP.

A novel method for near-infrared fluorescence imaging of the urethra during perineal and transanal surgery: demonstration in a cadaveric model.

AIM: Transanal total mesorectal excision is a promising novel sphincter-saving procedure for low rectal cancer. However, the transanal bottom-up dissection is associated with increased rates of iatrogenic urethral injuries. Near-infrared fluorescence (NIRF) imaging, given its deeper tissue penetration, has been explored in a limited number of studies for enhanced intra-operative urethral visualization. In this study, we explored the feasibility of a novel, ultrabright, biocompatible fluorescent polymer to coat urinary catheters for the purpose of intra-operative urethral visualization. METHODS: In an ex vivo experiment, using a near-infrared laparoscope, the fluorescent signal of a coated catheter (near-infrared coating of equipment, NICE) was qualitatively and quantitatively compared to the signal of indocyanine green (ICG)/Instillagel® mixtures and ICG-filled catheters at several concentrations. Also, in three male human torsos, using fluorescent urinary catheters, NIRF-guided perineal dissections and a transanal total mesorectal excision were performed. Intra-operative NIRF-based urethral visualization was performed systematically. RESULTS: During the qualitative and quantitative fluorescence signal assessment, NICE-coated catheters were clearly superior to the ICG-based solutions. In the cadaveric experiments, enhanced urethral visualization was possible even at early stages of dissection, when the organ was covered by several tissue layers. CONCLUSIONS: NICE-coated catheters represent a promising potential to allow for NIRF-based intra-operative urethral visualization.

Asthma and gender: The female lung.

Asthma is a common chronic disease that affects over 300 million people worldwide, resulting in a considerable socio-economic burden. Literature data suggest that asthma has a higher incidence in females, particularly at certain stages of pubertal development. Moreover, women seem to experience more asthma symptoms than men and to use more rescue medications, resulting in a reduced quality of life. Although several mechanisms have been proposed to explain these differences, there are not yet final data available in the literature on the role of gender in the pathogenesis of asthma and different behavior in females. Some study suggested a more prevalent hyper-responsiveness in women than in men. Nevertheless, in the literature definitive data on a possible different response to drugs used for asthma between males and females are not described. Understanding the mechanisms that underlie these gender differences in clinical history of asthma patients could give inspiration to new areas of research to obtain a more specific diagnostic and therapeutic approach gender-oriented.

Robotic platforms in gynaecological surgery: past, present, and future.

Background: More than two decades ago, the advent of robotic laparoscopic surgery marked a significant milestone, featuring the introduction of the AESOP robotic endoscope control system and the ZEUS robotic surgery system. The latter, equipped with distinct arms for the laparoscope and surgical instruments, was designed to accommodate remote connections, enabling the practice of remote telesurgery as early as 2001. Subsequent technological progress has given rise to a range of options in today's market, encompassing multi-port and single-port systems, both rigid and flexible, across various price points, with further growth anticipated. Objective: This article serves as an indispensable guide for gynaecological surgeons with an interest in embracing robotic surgery. Materials and methods: Drawing insights from the experience of the Strasbourg training centre for minimally invasive surgery (IRCAD), this article offers a comprehensive overview of existing robotic platforms in the market, as well as those in development. Results: Robotic surgical systems not only streamline established operative methods but also broaden the scope of procedures, including intra- and transluminal surgeries. As integral components of the digital surgery ecosystem, these robotic systems actively contribute to the increasing integration and adoption of advanced technologies, such as artificial intelligence-based data analysis and support systems. Conclusion: Robotic surgery is increasingly being adopted in clinical practice. With the growing number of systems available on the marketplace, the primary challenge lies in identifying the optimal platform for each specific procedure and patient. The seamless integration of robotic systems with artificial intelligence, image-guided surgery, and telesurgery presents undeniable advantages, enhancing the precision and effectiveness of surgical interventions. What is new?: This article provides a guide to the robotic platforms available on the market and those in development for gynaecologists interested in robotic surgery.

An update on atezolizumab for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a worldwide problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Its close association with chronic liver diseases and liver cirrhosis represents a significant challenge in its treatment. Sorafenib, the first front-line systemic treatment for unresectable HCC cases, was approved only in 2007. The role of sorafenib remained largely unchallenged until very recently, with the sole exception of a trial demonstrating the noninferiority of lenvatinib, another tyrosine kinase inhibitor. The therapeutic scenario changed dramatically in 2020, when the combination of atezolizumab and bevacizumab proved to be significantly superior to sorafenib and, thus, establishing a new standard of care. In this monograph we provide an update about the safety and efficacy of atezolizumab reported in the clinical trials of HCC, as monotherapy or in combination with other agents.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Multimedia article. Combined sentinel node biopsy and localized sigmoid resection entirely by natural orifice transluminal endoscopic surgery: a new challenge to the old paradigm.

INTRODUCTION: We demonstrate localized sigmoidectomy with sentinel node biopsy performed entirely via natural orifice transluminal endoscopic surgery in a porcine model (see Video, Supplemental Digital Content 1, http://links.lww.com/A1170). METHODS: To perform transluminal endoscopic sentinel node biopsy in the sigmoid mesocolon, a conventional double-channel gastroscope created both the gastrotomy and pneumoperitoneum enabling peritoneoscopy. The sigmoid colon was exposed by an intracolonic magnet under extracorporeal control while intraluminal colonoscopy performed lymphatic mapping via submucosal injection of methylene blue dye. After searching the mesocolon for blue-stained lymph channels, the sentinel nodes were resected and retrieved by the intraperitoneal fiberscope. Immediate thereafter localized sigmoidectomy was performed via an additional transcolonic access just above the rectosigmoid junction. With the circular stapler anvil placed early into the proximal colon, mesenteric dissection and proximal transection were performed using conventional laparoscopic instruments worked through a long standard trocar passed transanally through the colotomy. The specimen was delivered per ano (pull-through technique) and the distal margin cross-stapled extracorporeally, including the colotomy within the specimen. Stapled intestinal anastomosis was fashioned by passing a circular stapler transanally (thus returning the rectal stump to its anatomic position) and mating it with the in situ anvil. The gastrotomy was closed as previously described. RESULTS: The operative duration was 31.4 minutes and technical success was readily achieved. Patency and integrity of the anastomosis was confirmed by sigmoidoscopy. CONCLUSION: Oncologically propitious surgery for germinal colonic neoplasia may be encompassed by natural orifice transluminal endoscopic surgery. This provocative proposal challenges the conventional treatment paradigm for early stage colonic neoplasia although much further validation of the concepts involved is required.

Natural Orifice Surgery: the next step in minimal invasiveness towards no scar surgery.

The possibility to operate into the abdominal cavity by means of flexible endoscopes introduced through natural orifices represents a major step forward in the continuous research for minimal invasive treatment attaining the unimaginable goal of no scar surgery. After several years of investigation in experimental settings, natural orifice surgery is becoming a valuable therapeutic option both as totally transluminal endoscopic approach or with the support of minimal transabdominal assistance. The promising operative results and the great interest determined among the patients always looking for effective treatment associated with less bodily trauma, postoperative pain and faster recovery, are pushing the development of dedicated technological solutions that will make natural orifice - no scar surgery more easy and reproducible to perform and applicable also to more advanced diseases. Natural orifice surgery has the potential to abolish the historical association of surgery to that of scar and pain representing a very appealing surgical option for the patients highly respectful of their body and psychological integrity.

Mild hepatitis at recommended doses of acetaminophen in patients with evidence of constitutionally enhanced cytochrome P450 system activity.

Acetaminophen (paracetamol) is used throughout the world for pain relief and antipyresis in both children and adults. In many countries, it can be purchased without a medical prescription and it is also a common component of a number of over-the-counter remedies for colds, influenza and the like. Fasting, malnutrition and use of alcohol and/or other drugs are thought to play causal roles in hepatotoxicity associated with recommended doses of acetaminophen although liver injury provoked by therapeutic doses has also been observed in the absence of these factors. We describe two patients who experienced subclinical hepatotoxic reactions after taking acetaminophen at therapeutic doses. The results of an antipyrine metabolism test suggest the presence of constitutional hyperactivity of the cytochrome P450-dependent mixed function oxidative system in both patients. We hypothesize that the latter contributed to the hepatotoxicity and that it may play a role in idiosyncratic reactions to this drug.

Alcoholic and nonalcoholic forms of fatty liver disease.

Fatty liver (or steatosis) is an increasingly common finding in histolgical evaluation of liver biopsies. It is frequently associated with obesity, diabetes, metabolic syndromes, and/or alcohol abuse. When the steatosis is accompanied by inflammation and fibrosis, the risk of progression to severe liver disease is high. The aim of this paper is to review the clinical features, pathophysiology, natural history, and options for the treatment of nonalcoholic and alcoholic forms of fatty liver disease.

A case of acute fulminant multiple sclerosis treated with alemtuzumab.

We describe the case of a woman who came to our attention for acute onset and very rapidly worsening left hemiplegia, vision loss and cognitive impairment. MRI, laboratory and clinical investigations were highly suggestive of an active inflammatory demyelinating disease. Following exclusion of other possible etiologies, a diagnosis of Marburg's variant multiple sclerosis was made. After repeated high-dose steroids and plasma-exchange, the patient was treated with a first course of alemtuzumab followed by improvement of the clinical and MRI picture. This is the first reported case of Marburg type multiple sclerosis treated with alemtuzumab.

The new 4DDome prosthesis: an original light and partially absorbable composite mesh for hernia repair.

INTRODUCTION: The use of non-absorbable meshes for the repair of inguinal hernias has become standard; however, these meshes have been associated with complications including long-term postoperative pain. To this end, a new partially absorbable composite mesh has been developed, and the aim of this study was to investigate its efficacy in animal and human trials. MATERIALS AND METHODS: Sixty male Wistar rats were used to evaluate the behavior of the newly designed composite mesh. Composite meshes were implanted in the extra-peritoneal plane for 2, 4 and 8 weeks and compared to a standard polypropylene mesh. Forty patients with symptomatic inguinal hernias were treated using a new 4DDome designed prosthesis. Follow-up was by clinical and ultrasound examination at 1, 6 and 12 months. RESULTS: The animal study demonstrated that the inflammatory reaction associated with the new composite mesh was significantly lower than a standard polypropylene mesh, characterized by a lower macrophage infiltrate (P < 0.001). The mesh did not shrink over the 8-week period, unlike the polypropylene mesh (P < 0.05). The human study showed that there were three minor postoperative complications, no recurrences and the mesh was well tolerated. Follow-up with serial ultrasound showed that at 10 days and 1 month the dome was clearly visible in position; however, by 6 months it had flattened out, been partially absorbed and become incorporated into the repair. CONCLUSION: These experimental and clinical studies have validated the concept of the new 4DDome composite mesh. It was well tolerated and was associated with good short-term results. The combination of the dome shape and the new composite mesh means that less polypropylene is required and represents a significant advance in anterior hernia repair.

Fatty liver and drugs.

Drug-induced liver diseases (DILD) are clinico-pathologic patterns of liver injury caused by drugs or other foreign compounds. Steatohepatitis is a rare form of DILD, and drugs account for fewer than 2% of non-alcoholic steatohepatitis (NASH). Drugs known to be capable of inducing steatosis and steatohepatitis can be divided into three broad groups: those that cause steatosis and steatohepatitis independently (e.g., amiodarone, perhexiline maleate); drugs which can precipitate latent NASH (e.g., tamoxifen); drugs whic duce sporadic events of steatosis/steatohepatitis (e.g., carbamazepine). Clinical DILD syndromes include acute viral hepatitis-like injury, acute liver failure, cholestatic hepatitis,liver disease with signs of hypersensitivity, autoimmune hepatitis-like injury, acute venous-Outflow obstruction, chronic cholestasis, ciirrhosis, steatosis and steatohepatitis. The clinical picture is by no means dependent on the mechanism of injury (direct hepatotoxicity, idiosyncratic reactions, hypersensitivity reactions). Reliable diagnosis of drug-induced liver disease requires demonstration of close correlation between the patient history and clinical, laboratory, and histological data.

Nutritional aspects in patients with non-alcoholic steatohepatitis (NASH).

BACKGROUND AND OBJECTIVES: Metabolic alterations are a common feature in patients affected by non-alcoholic steato-hepatitis (NASH). A strong correlation exists between overweight, in particular visceral fat accumulation, and prevalence of NASH, especially in men. Thus, diet-induced weight loss represents a fundamental tool in disease management of these patients. The aim of the present study was to evaluate body composition and nutrient utilisation in patients with NASH, comparing them with patients affected by chronic hepatitis related to hepatitis C virus (HCV) infection and with healthy subjects. MATERIALS AND METHODS: Twenty male outpatients with NASH (age: 41 +/- 11 yr; BMI: 26.2 +/- 2.1 kg/m2) and 14 HCV male patients (age 44.6 +/- 13 yr; BMI: 24.8 +/- 2.8 kg/m2) were enrolled in the study. A group of 20 healthy male subjects (age: 39 +/- 10 yr; BMI: 23.3 +/- 1.1 kg/m2) were studied as controls. Body composition was assessed by anthropometry and dual-energy X-ray absorptiometry; resting metabolic rate and nutrient oxidation by indirect calorimetry. A 7-day food diary was collected. The main biochemical parameters were measured using standardised laboratory techniques. RESULTS: Body weight was higher in NASH patients with respect to HCV patients and control subjects (respectively 75.2 +/- 8.9 vs 68.5 +/- 9.4 and vs 67.0 +/- 8.0 kg; P < 0.01) and this was essentially due to fat mass increase. Fat-free mass reduction was found in HCV patients with respect to both NASH and control subjects. Patients with NASH had a significantly higher waist circumference (P < 0.01) and a lower resting metabolic rate (RMR) with respect to HCV and control subjects. Energy intake was significantly higher in NASH patients (P < 0.01) compared to the other two groups. CONCLUSIONS: NASH patients showed an increase in body weight, fat mass and visceral fat accumulation with respect to HCV and control subjects. The reduction in RMR, coupled with increase energy intake may explain the body composition alterations found in these patients.

Nonalcoholic fatty liver disease: defining a common problem.

Non Alcoholic Fatty Liver Disease (NAFLD), with prevalence of 10-51% in general population involving all ages, is the major cause of elevation of ALT and a common finding by ultrasound screening and may range from simple steatosis, to Non Alcoholic Steatohepatitis (NASH) and its clinical consequences as cirrhosis and hepatocellular carcinoma. In this review will be analyse factors influencing the onset of the disease. NAFLD, primarly associated with insulin resistance, is in fact considered the hepatic manifestation of the metabolic syndrome: a cluster of disorder that includes obesity, diabetes mellitus, dyslipidaemia, arteriosclerosis and hypertension. The increased incidence and prevalence of obesity and diabetes may explain growing interest in NAFLD. Racial, ethnic, enviromental and behaviour models are also reviewed.

The natural history and risk factors for progression of non-alcoholic fatty liver disease and steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is a condition of increasing incidence in western Countries seldom associated to other diseases of high prevalence in general population (i.e. diabetes and obesity). NAFLD ranges from simple fatty liver to steatohepatitis (NASH), which may lead to cryptogenic cirrhosis and in some cases hepatocellular carcinoma (HCC). Natural history of NAFLD in humans is poorly understood and progression of liver disease seems to be due to interaction between hosting (i.e. genetic, gut flora, insulin resistance) and environmental factors (social and eating behaviours) that should be responsible of increased oxidative stress within hepatocytes. Even if we need non-invasive markers able to describe the progression of liver disease, only meaning of liver biopsy is useful to characterize the stigmata of worsening such as inflammation and fibrosis.

Hepatic steatosis and vascular disease.

Nonalcoholic fatty liver disease (NAFLD) refers to a wide picture of liver damage, ranging from steatosis to steatohepatitis, fibrosis and cirrhosis. The epidemiological studies demonstrated an association of NAFLD with obesity, type 2 diabetes and hyperlipidemia. Under this light the metabolic syndrome (MS), including NAFLD, obesity, central fat distribution, diabetes, dyslipidemia, hypertension and atherosclerotic cardiovascular disease (CVD) can be considered the link to explain the presence of vascular diseases in patients with NAFLD. In NHANES III, the authors demonstrated that the presence of MS was associated with increased risk of myocardial infarction, stroke or both. In a prospective study on 1209 Finnish middle-aged men without CVD or diabetes at baseline, Lakka showed that MS per se is associated with an increased risk of CVD and all-cause mortality. Finally the Atherosclerosis Risk in Communities (ARIC) confirmed that subjects with MS were 2 times more likely to have prevalent coronary heart disease. From a pathophysiological point of view, growing evidences implicate the oxidative stress as the unifying mechanism for many CVD risk factors. Under this light there is emerging evidence suggesting that there is a significant increase in vascular oxidative stress in patients with MS, with the presence of endothelial dysfunction in the early stage of the syndrome. Indeed, the inflammation process evidentiated in these patients is initiated at the endothelial level, stressing the key role of this active and dynamic tissue in the pathophysiological pathways. Under this light the endothelium can be considered as the last effector of a multi-syndrome and the main target of all the future studies focused on the underlying mechamisms of this complex network. Because of the potential serious public health impact, the comprehension of these patophysiological pathways will be crucial to design new preventive measures and therapeutic strategies.

Pharmacokinetics of a new extended-release nifedipine formulation following a single oral dose, in human volunteers.

This study aimed to define the pharmacokinetics of nifedipine following oral administration of a new extended-release formulation. Twelve healthy volunteers of both sexes, aged 39 +/- 4 years, were treated with a single oral tablet of a new extended-release formulation containing 40 mg of nifedipine. Samples of venous blood were taken before dosing, after 30 min and at 1, 2, 4, 8, 12, 16, 20 and 24 h after administration. Nifedipine concentration was measured by means of a high-performance liquid chromatography method. Noncompartmental pharmacokinetics parameters were then calculated. The plasma concentration of nifedipine increased slowly and in seven subjects biphasic peaks occurred. The mean values were as follows: t(max): 8.5 +/- 1.2 h; C(max): 36.55 +/- 6.76 ng/ml; AUC: 347.06 +/- 51.61 ng/h/ml; AUC 409.99 +/- 61.08 ng/h/ml; A(half-life): 2.26 +/- 0.36 h; D(half-life): 2.43 +/- 0.44 h; E(half-life): 4.62 +/- 0.79 h. Twenty-four hours after administration nifedipine was still detectable (3.17 +/- 0.67 ng/ml). Arterial blood pressure decreased and heart rate increased concurrently and proportionally to the increase in nifedipine concentration. Extended-release nifedipine formulations have better tolerability profiles than immediate-release formulations, which are at present not recommended in the treatment of hypertension, hypertensive crises or myocardial infarction. This new extended-release formulation has interesting pharmacokinetic parameters and may be effective in conditions in which dihydropyridine calcium channel blockers are indicated.

Chronic administration of l-sulpiride at non-neuroleptic doses reduces the duration of immobility in experimental models of "depression-like" behavior.

It has been shown that long-term administration of l-sulpiride induces a down-regulation of beta receptor-associated adenylate cyclase activity in the frontal cortex of rats, and adaptive response that is typically associated with the chronic administration of antidepressants. Here we show that in two animal models of "depression-like" behavior (forced swim in rats and tail suspension in mice), the long-term (21 days) administration of l-sulpiride at a non-neuroleptic dose (2 mg/kg IP twice a day) significantly decreases the duration of immobility, the effect being similar to that of desipramine (20 mg/kg IP). The same dose (2 mg/kg) of l-sulpiride, acutely administered, has no effect at all. On the other hand, either chronic (21 days) or acute administration of neuroleptic doses of l-sulpiride have an opposite effect, and indeed increase the duration of immobility. These results are an in vivo support to the in vitro findings suggesting that low doses of l-sulpiride may have antidepressant-like activity.

l-Sulpiride, at a low, non-neuroleptic dose, prevents conditioned fear stress-induced freezing behavior in rats.

Antidepressant drugs are effective in anxiety states, including panic disorder. Both clinical and animal studies indicate that l-sulpiride, at low, non-neuroleptic doses, has antidepressant activity. The present study examined the effect of an antidepressant dose of l-sulpiride (4 mg/kg per day SC), compared with a well-established antidepressant drug (fluoxetine, 3 mg/kg per day SC), in a rat model of anticipatory anxiety/panic behavior: conditioned fear stress-induced freezing behavior. Long-term (26 days) administration of l-sulpiride almost completely abolished freezing, a similar effect being produced by fluoxetine (freezing duration, in seconds: controls, 148.1 +/- 29.6; l-sulpiride, 27.5 +/- 8.3; fluoxetine, 72.0 +/- 15.2). The same doses of l-sulpiride (4 mg/kg SC) and fluoxetine (3 mg/kg SC) had no effect when administered for shorter periods (1, 5, or 12 days). No effect was produced by the long-term (26 days) administration of a neuroleptic dose of l-sulpiride (20 mg/kg per day SC). These results demonstrate that long-term administration of low, non-neuroleptic doses of l-sulpiride, is highly effective in an animal model of anticipatory anxiety/panic behavior.