HP 818: A centrally acting analgesic with neuroleptic properties

HP 818 (1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED₅₀ values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar > fentanyl > HP 818 > codeine > droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self-stimulation assays (ED₅₀ values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine- and apomorphine-induced stereotypy, indicative of D₂-dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting cardiorespiratory side effects.     

Farm Work is Dangerous for Teens: Agricultural Hazards and Injuries Among North Carolina Teens

Children who work in agriculture suffer more than 23,000 injuries and 300 fatalities on American farms every year. Using survey data collected from a random sample of working teens (ages 14 to 17) in North Carolina, the authors analyze the farm-based hazard exposure and injury experiences of teens who work on farms. The group of farmworking teens (N = 141) is 72 percent male, has a mean age of 16.6 years, and is, on average, in the 10th grade. The data show that teens working on farms in North Carolina are exposed to significant safety hazards throughout their farmworking careers. A majority of the respondents in this group of farmworkers reported exposure to tractors, large animals, all-terrain vehicles, farm trucks, and rotary mowers, and more than one-third reported exposure to pesticides and tobacco harvesters. Common reported injuries include insect stings, cuts, burns, and falls. The researchers find that gender, age, and farmwork experiences are related to variations in types of hazards to which teens are exposed and in the types of injuries they suffer. These variables also are related to the overall complexity of the teens' farmwork experiences and the burden of injury endured by teens.     

The impact of technology and improved perioperative management upon survival from carcinoma of the pancreas

A community hospital experience of 238 instances of carcinoma of the pancreas during a 23 year period has been reviewed to see if there has been any change in survival, hospital stay, morbidity and operative strategy during the two decades included in this study as a result of improved diagnostic modalities and perioperative management. The results of this review indicate an increasing incidence of carcinoma of the pancreas in the second half of the study but also document a large number of patients whose diagnosis has been unsuspected until autopsy. The mortality for palliative bypass procedures dropped significantly in the second half of the study and provided a mean survival time of 7.6 months for this group of patients, approximately twice that of patients explored without palliation. Resectional procedures showed a very significant drop in mortality rate in the second half of the study and were used more extensively. Mean survival time of patients undergoing resectional procedures was 18.3 months with two prolonged survivors out of 22 patients. Significant operative morbidity remains a major problem and the chief cause of protracted postoperative stay and did not diminish in the second half of this study. Complications were primarily technical in nature. With this in mind, consideration should be given to concentrating the experience in pancreatic resectional operations in the hands of a limited number of surgeons within any given community.     

Intermittent obstruction of a Bjork-Shiley mitral valve prosthesis--an unusual diagnosis aided by Doppler ultrasound

Obstruction of a Bjork-Shiley mitral valve prosthesis occurred in a 41 year old woman due to pannus tissue growing over the valve and impairing disc opening. The unusual intermittent nature of the obstruction was clearly demonstrated by Doppler ultrasound. The pannus was excised and the valve prosthesis replaced successfully with a Carpentier-Edwards xenograft.     

Adjuvante und additive Therapie beim Pankreaskarzinom

Recent advances have been made in the treatment of pancreas cancer. Specialized pancreas centres have reported an increasing rate of resections with reduced postoperative mortality. On account of the highly aggressive nature of pancreas cancer, there is a great challenge in identifying effective therapy concepts for advanced stages of the cancer as well as for the development of resection-associated measures. As large-scale, randomised, controlled studies are lacking, the additive therapy concepts after resection do not have a sufficiently scientific basis. The ESPAC-1 study, which included 600 patients, surpassed all previous studies on adjuvant therapy for pancreas cancer. This study has shown,for example, that the most promising adjuvant chemotherapy with 5-fluorouracil and folic acid leads to an equal if not better result than the multimodal regimen. This regimen can be superseded with the use of Gemcitabine, which will be evaluated in the ESPAC-3 study that includes 990 patients from various European countries including Germany, as well as from Canada and Australia. Participation in the large, phase-3 study therefore plays a key role in the continued development of the management of pancreas cancer.     

The role of intestinal flora on the interactions between nonparenchymal cells and hepatocytes in coculture

Kupffer cells are exposed directly to a number of factors in the portal circulation that can modify or regulate their responses to septic stimuli. The gut represents a potential source of a number of these factors including endotoxin, lymphokines, and prostaglandins. We examined Kupffer cells from germfree rats and germfree rats exposed to endotoxin or bacteria via their GI tracts to determine the importance of the intestinal flora in maintaining or modulating Kupffer cell responses. Kupffer cells from germfree animals were reduced in numbers and failed to respond to LPS in Kupffer cell: hepatocyte coculture. When germfree rats were exposed to bacterial endotoxin or bacteria via the gastrointestinal tract their Kupffer cells increased in numbers to normal and the cells responded to LPS in culture. Intestinal overgrowth with Escherichia coli for 2 days activated the Kupffer cells and significantly increased Kupffer cell sensitivity to LPS. These data suggest that the environment of the gastrointestinal tract is important for normal Kupffer cell responses and that intestinal bacterial overgrowth can modify Kupffer cell responses to septic stimuli.