Search

Total parenteral nutrition (TPN) provides all nutrition intravenously. Although TPN therapy has grown enormously, it causes significant complications, including gut and hepatic dysfunction. Current models use animal tethering which is unlike ambulatory human TPN delivery and is cost prohibitive. We hypothesize that using ultramobile infusion pumps, TPN can be delivered cost-effectively, resulting in classical gut and hepatic injury, and we thus aim to establish a new model system. Neonatal pigs (n=8) were implanted with jugular vein and duodenal catheters. Animals were fitted in dual-pocket jackets. An ultramobile ambulatory pump was placed in one pocket and connected to the jugular vein or duodenal catheter. Isocaloric TPN or swine formula was placed in the other pocket. Rigorous Wifi-based video and scheduled monitoring was performed. After 14days, the animals were euthanized. The mean (±SD) daily weight gain (in grams) for enteral-fed control (EN) vs TPN animals was 102.4±10.8 and 91.03±12.1 respectively (P

Parenteral nutrition (PN) is a lifesaving therapy but is associated with gut atrophy and cholestasis. While bile acids (BAs) can modulate intestinal growth via gut receptors, the gut microbiome likely influences gut proliferation and inflammation. BAs also regulate the bile salt export pump (BSEP) involved in cholestasis. We hypothesized that the BA receptor agonist oleanolic acid (OA) regulates gut TGR5 receptor and modulates gut microbiota to prevent PN-associated injury.Neonatal piglets were randomized to approximately 2 weeks of isocaloric enteral nutrition (EN), PN, or PN + enteral OA. Serum alanine aminotransferase, bilirubin, BAs, hepatic BSEP, gut TGR5, gut, liver morphology, and fecal microbiome utilizing 16S rRNA sequencing were evaluated. Kruskal-Wallis test, pairwise Mann-Whitney U test, and multilevel logistic regression analysis were performed.PN support resulted in gut atrophy substantially prevented by OA. The median (interquartile range) for villous/crypt ratio was as follows: EN, 3.37 (2.82-3.80); PN, 1.73 (1.54-2.27); and OA, 2.89 (2.17-3.34; P = .006). Pairwise comparisons yielded P = .002 (EN vs PN), P = .180 (EN vs OA), P = .026 (PN vs OA). OA upregulated TGR5 and BSEP without significant improvement in serum bilirubin ( P = .095). A decreased microbial diversity and shift toward proinflammatory phylum Bacteroidetes were seen with PN, which was prevented by OA.OA prevented PN-associated gut mucosal injury, Bacterioides expansion, and the decreased microbial diversity noted with PN. This study demonstrates a novel relationship among PN-associated gut dysfunction, BA treatment, and gut microbial changes.

OBJECTIVES To analyze results of intensity-modulated radiotherapy after cryotherapy ablation for adenocarcinoma of the prostate. METHODS Patients were either treated adjuvantly after targeted cryotherapy or treated for salvage after local failure of standard whole-prostate cryotherapy. Patients were treated with intensity-modulated radiotherapy to a minimum dose of 73 Gy (mean dose, >75Gy). Prostate-specific antigen (PSA) failure was defined according to the Radiation Therapy Oncology Group-American Society for Therapeutic Radiology and Oncology 2006 consensus definition. Late gastrointestinal and genitourinary toxicity were graded according to the Radiation Therapy Oncology Group late toxicity scale and the Late Effects of Normal Tissue-Subjective, Objective, Management, and Analytic scale. RESULTS A total of 16 patients were treated from 1997 to 2007. Three patients were treated adjuvantly, and 13 patients were treated for local failure. The mean pre-cryotherapy PSA value was 8.7 ng/mL. The mean PSA value before irradiation was 6.0 ng/mL. Most patients were intermediate to high risk (8 intermediate risk, 7 high risk). Median follow-up was 33 months. No grade 3 or greater toxicity was seen. Biochemical (PSA) control was achieved in 12 of the 16 patients at last follow-up. CONCLUSIONS Full-dose intensity-modulated radiotherapy after cryotherapy is well tolerated, without excess late morbidity. This study supports the use of radiation for cryotherapy failure salvage. Furthermore, the combination of cryotherapy and irradiation may be considered in a phase II trial.

Objectives/Hypothesis: Absorbable hemostatic agents are used routinely following sinus surgery. Recent studies suggest that current biomaterials, such as FloSeal Matrix Hemostatic Sealant (Fusion Medical Technologies, Mountain View, CA) may interfere with mucosal regeneration. This study was designed to evaluate the effects of Microporous Polysaccharide Hemospheres (MPH, Medafor, Inc., Minneapolis, MN), a novel rapidly-absorbing hemostatic powder, on healing and intact sinus mucosa. Study Design: Prospective, controlled study using the rabbit model. Methods: Both maxillary sinuses of 14 New Zealand white rabbits were surgically opened. The mucosa of 10 rabbits were stripped bilaterally, and the left sinus of each was then treated with either MPH or FloSeal. The mucosa of four additional rabbits were incised but otherwise remained undisturbed. Again, the left sinus of each of the four additional rabbits was treated with either MPH or FloSeal. The right sinus served as an untreated control (stripped or intact) in both arms of the study. Animals were recovered and euthanized 2 weeks later. Specimens were examined by a blinded pathologist using light microscopy. Results: Untreated regenerated mucosa showed expected areas of sparse cilia, mild serous gland reduction, and fibrosis. MPH-treated sinuses showed no significant changes compared to respective controls, and no MPH substance was identified. In contrast, regenerating mucosa treated with FloSeal showed extensive loss of cilia, inflammation, and fibrosis. Residual FloSeal particles were present within the sinus cavity and grossly incorporated within healing mucosa. Unexpectedly, intact mucosa exposed to FloSeal showed similar findings. Conclusions: Absorbable hemostatic materials have starkly different effects on mucosal healing. Unlike other agents, MPH is rapidly cleared and has no negative effects on healing or intact sinus mucosa.

Surgical manipulation of the sensory and motor nerves of the rat tongue is often employed in studies evaluating the oral cavity functions of mastication and deglutition. A noninvasive, atraumatic approach that will then facilitate sufficient manipulation of these structures is required. In this study, we detail an approach that consistently allows identification of the hypoglossal (motor) and lingual (sensory) nerves of the rat. Six Wistar rats (250-500 g) were anesthetized and dissected either as fresh tissue (N = 3) or following transcardial perfusion with 4% paraformaldehyde (N = 3). Both fixed and non-fixed specimens of the rat head and neck were incised in the right submandibular region. The first animal in each group was used to gain a basic understanding of the regional muscular anatomy with reference to the hypoglossal and lingual nerves. Subsequent animals were used for the development of an efficient and minimally invasive approach to these nerves. The resultant approach begins as an incision through skin and platysma, followed by medial reflection of the digastric muscle. This allows visualization of the hypoglossal nerve in the region of the bifurcation of the common trunk into medial and lateral subdivisions. Next, the lingual nerve dissection is approached by reflection rostrally of the transversus mandibularis muscle and a caudal reflection of the mylohyoid muscle. This dissection reveals the geniohyoid muscle which when separated bluntly using forceps, exposes the lingual nerve. The anatomical approach described and illustrated herein will aid investigators in consistent identification of these two nerves as fundamental methods of their projects.

Nutrition support with parenteral nutrition (PN) is associated with gut atrophy. Prior studies have shown improvement with enteral chenodeoxycholic acid, a dual agonist for the farnesoid X receptor (FXR) and bile acid receptor TGR5. We hypothesized that gut growth is induced by TGR5 activation, and gut atrophy during PN administration could be prevented with the TGR5-specific agonist oleanolic acid (OA).Neonatal pigs were implanted with duodenal and jugular vein catheters. Animals were provided equi-nutritious PN or enteral swine milk. A PN subgroup received enteral OA at 50 mg/kg/d.PN caused marked gut atrophy compared with enterally fed (EN) control animals. OA treatment led to preservation of gut mass demonstrated grossly and histologically. The mean ± SD gut weight as a percentage of body weight was 4.30 ± 0.26 for EN, 1.92 ± 0.06 for PN (P.05, EN vs PN), and 3.39 ± 0.79 for PN+OA (P.05, PN+OA vs PN). Mean ± SD gut density (g/cm) was 0.31 ± 0.03 for EN, 0.18 ± 0.03 for PN (P.05 EN vs PN), and 0.27 ± 0.01 for PN+OA (P.05 PN+OA vs PN). Histologically, a markedly decreased villous to crypt ratio was noted with PN, and OA significantly prevented this decrease. The mean ± SD v/c ratio was 3.51 ± 0.59 for EN, 1.69 ± 0.10 for PN (P.05, EN vs PN), and 2.90 ± 0.23 for PN+OA (P.05, PN+OA vs PN). Gut TGR5 messenger RNA expression was significantly elevated with OA treatment compared with both PN and EN.The bile acid-activated G protein-coupled receptor TGR5 agonist OA prevented gut atrophy associated with PN.

RET fused gene (RFG)/ELE1alpha/androgen receptor-associated protein 70(ARA70) was first found to be involved in the activation of the RET proto-oncogene in thyroid neoplasm and has recently been shown to be a ligand-dependent transcriptional coregulator for androgen receptor (AR). The functionality of RFG/ELE1alpha/ARA70 remains controversial, and little is known about factors regulating its expression in the prostate. Of significant interest is whether this molecule is involved in prostate carcinogenesis. Using reverse transcriptase-polymerase chain reaction semiquantitation, we compared RFG/ELE1alpha/ARA70 mRNA levels in four prostate cancer cell lines (LNCaP, TSU-Pr1, DU-145, and PC-3) with those found in primary cultures of normal prostatic epithelial cells (PrECs). In addition, we examined the effects of androgen and antiandrogen, estrogen and antiestrogen, and a demethylating agent on RFG/ELE1alpha/ARA70 mRNA expression levels in AR- and AR+ PC-3 cells. Reduced levels of RFG/ELE1alpha/ARA70 message were observed in all four prostate cancer cell lines when compared with normal PrECs in primary cultures. RFG/ELE1alpha/ARA70 mRNA levels in PC-3 cells, which express both estrogen receptor subtypes, were upregulated by 17beta-estradiol and inhibited by the antiestrogen ICI-182780. In PC-3(AR+) cells, which were genetically engineered to express AR, exposure to androgen upregulated RFG/ELE1alpha/ARA70 mRNA expression, whereas treatment with 4-hydroxyflutamide lowered expression of this transcript. Furthermore, treatment of DU-145 cells, which did not express RFG/ELE1alpha/ARA70 transcripts, with a demethylating agent reactivated transcription of this gene. Polymerase chain reaction analyses of monochromosomal human-rodent hybrid panels localized a putative RFG/ELE1alpha/ARA70 isoform on human chromosome 5q31.1-31.2. In summary, we identified sex hormones and DNA hypermethylation as regulators of RFG/ELE1alpha/ARA70 expression in prostate cancer cells. In addition, we found reduced levels of RFG/ELE1alpha/ARA70 expression in prostate cancer cell lines when compared with expression levels in normal PrECs in culture. These findings suggest that RFG/ELE1alpha/ARA70 may be involved prostate carcinogenesis and that it may serve as a key mediator of estrogen-androgen synergism.

Potential reasons for discordance between the Gleason score in biopsies and surgical specimens are: 1) pathological interpretation bias, and 2) sampling effects. The importance of sampling effects in grading errors was examined in a series where the number of biopsy cores obtained was high. Biopsies were obtained using a technique whereby 18 directed cores were systematically obtained and mapped out within the gland. Gleason scores from biopsies and matched prostatectomy specimens were compared among 28 consecutive patients with localized prostate cancer. A pooled database from 10 series (n = 2,687) served as a baseline for comparison in the accuracy of Gleason score grading. With the present biopsy technique, an exact Gleason score match was achieved in 57% of cases, compared with the pooled database (PD) mean of 42% (P = 0.055), and was within 1 point in 93% of cases compared with 78% (PD) (P = 0.029). Upgrading of biopsies was seen in 35% of cases, compared with 43% (PD) (P = 0.19). With respect to Gleason score 7, an exact match was present in 78% of cases, compared with 63% (PD) (P = 0.17), and upgrading was 0%, compared with 20% (PD) (P = 0.07). The data suggest a significant reduction in grade errors by minimizing sampling effects, one that it is of the same order of magnitude as the reduction achieved from consensus pathologic evaluation. In our study, seven patients (25%) would have had their cancers missed altogether with sextant biopsies. Sampling effects may contribute significantly to grading errors in prostate needle biopsies, although a larger study is needed to confirm this. A methodology which adopts a higher number of cores combined with a consensus pathologic evaluation could potentially reduce grading errors substantially. The optimal number of cores remains to be determined in a larger study. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 326–330 (2000). © 2000 Wiley-Liss, Inc.

Purpose: Several reports have documented that the MB isoenzyme of creatine kinase is present in prostatic tissue. However, since it has been shown that lower urinary tract manipulations, including transurethral prostatectomy, do not significantly increase serum creatine kinase isoenzyme MB levels, such elevations, which are found in patients after prostatic surgery, are believed to be specific for myocardial infarction. We examined whether cryosurgical ablation of the prostate altered serum creatine kinase or isoenzyme MB levels.Materials and Methods: In 81 consecutive patients undergoing routine cryosurgical ablation of the prostate serum levels of creatine kinase and creatine kinase isoenzyme MB were measured from peripheral blood specimens drawn preoperatively, in the recovery room and at 8 and 24 hours postoperatively. Postoperative electrocardiograms were compared to the preoperative study.Results: In 72 of 81 patients (89%) significant elevations in creatine kinase and creatine kinase isoenz...

Objectives. To determine if transrectal ultrasound-guided (TRUS) prostate biopsy causes dissemination of prostate cells into the circulation as assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) targeted against prostate-specific antigen (PSA) mRNA. Methods. RT-PCR PSA analysis was performed before and after prostatic invasive manipulations in 50 men. The cases consisted of 47 patients with TRUS and 3 with transurethral resection of the prostate (TURP). Peripheral venous blood (8 mL) was drawn before and within 60 minutes after the procedure. Total RNA was extracted from fractionated blood, and RNA/cDNA quality was assured and normalized with beta-actin RT-PCR analysis. The PSA primers hybridize exons 3 and 5, yielding a 254-basepair PCR product. The assay detects one LNCaP cell in a background of 100 million lymphoid cells and a single copy of PSA cDNA on an ethidium bromide gel. Results. Among the 47 TRUS cases, 43 specimens were evaluable. Forty-two cases were negative before biopsy; among these patients, 4 cases (9.5%) converted to a positive RT-PCR PSA result. Both benign and malignant TRUS biopsies were capable of producing a positive RT-PCR PSA signal implicating iatrogenic dissemination of cells. All three TURP cases converted from a negative to a highly intense positive signal. Conclusions. We conclude that a positive RT-PCR PSA signal may result from release of prostate cells into the peripheral circulation after a TRUS biopsy and TURP. TURP causes greater dissemination than TRUS. Based on these preliminary data, we recommend that future molecular staging studies should be based on blood specimens drawn before performance of TRUS biopsy. This may be an important mechanism of prostate cancer dissemination meriting further investigations.

A case of collecting-duct carcinoma associated with abnormal urine cytology is described. The finding of an abnormal cytologic examination, yet not typical of transitional-cell carcinoma (TCC), suggests that a close relationship between the cytology and histology of this uncommon malignancy may be demonstrated.

The von Hippel-Lindau syndrome is the most well known cause of familial renal cancer. Because affected individuals with renal lesions can have complex, multisystem manifestations of von Hippel-Lindau disease, our renal management strategy has included parenchymal sparing surgery whenever possible. From May 1988 to January 1993,20 patients with hereditary renal cell carcinoma (19 with von Hippel-Lindau disease and 1 with hereditary papillary renal cancer) underwent renal exploration with the intent of performing parenchymal sparing surgery. A total of 7 nephrectomies and 27 parenchymal sparing procedures was performed. Additional procedures performed included 2 bilateral adrenalectomies for pheochromocytomas, 1 resection of a renal vein thrombus and 1 resection of a pancreatic islet cell tumor. Renal atrophy occurred in 3 of 27 kidneys (11%) treated by parenchymal sparing surgery. In 8 kidneys of 7 patients new solid lesions developed and in 14 kidneys of 12 patients no new solid lesions developed during a mean followup of 26 months (range 6 to 60 months). The use of parenchymal sparing surgery in patients with familial forms of kidney cancer is based on a desire to maintain renal function as long as possible while reducing the risk of metastases. The potential advantages and disadvantages of more ablative surgical treatment requiring subsequent dialysis or transplantation in patients with existing or potential central nervous system, eye, pancreas and/or adrenal tumors must be weighed against the possibility of renal cancer metastases or recurrence when deciding on the use of parenchymal sparing surgery. von Hippel-Lindau disease is an autosomal dominant hereditary disorder characterized by hemangioblastomas of the central nervous system, retinal angiomas, pheochromocytomas, epididymal cystadenomas, pancreatic cysts and tumors, and renal cysts and carcinomas.’.2 The von Hippel-Lindau gene has recently been identified on chromosome and is associated with the formation of clear cell renal carcinoma~.~,~ Before the widespread use of noninvasive imaging 23 to 45% of patients with von Hippel-Lindau disease were reported to have renal cell carcinoma and about a third died of metastatic renal cell carcinoma.1.2*6.7 Because von HippelLindau disease is genetic in origin, multiple, bilateral cysts and tumors can develop in young patients and patients are at risk of new tumors developing throughout life?ss*9 Treatment strategies for renal tumors in patients with von Hippel-Lindau disease have included bilateral nephrectomy with subsequent dialysis andor transplantation or renal sparing operation^.'^-'^ Removal of both kidneys, while eliminating the risk of metastatic renal cell carcinoma, impacts greatly on quality of life, especially since many patients are already afflicted with other manifestations of von HippelLindau disease. We have chosen a parenchymal sparing surgical approach in select patients with von Hippel-Lindau disease and renal tumors in an attempt to control local tumor growth, prevent metastases and maintain a higher quality of life than is possible for those undergoing renal transplantation or dialysis.

CK-1649C is a new quaternary ammonium class III antiarrhythmic agent undergoing clinical trials. The side effect profile of a class III antiarrhythmic agent is generally unknown. This study compared CK-1649C with quinidine and lidocaine (class I), acecainide (class I/III), and clofilium (class III), in several models of smooth muscle, platelet, skeletal muscle, and central and peripheral nervous system function, to evaluate the potential side effects of this new drug. CK-1649C was devoid of neuropharmacologic activity in the mouse and rat. CK.-1649C did not promote gastrointestinal hypermotility in the mouse fed a charcoal meal and was also inactive in the rat carrageenan-induced paw edema test. Ten to 30 times the antiarrhythmic dose of concentration of CK-1649C was devoid of activity on transmural nerve stimulation and did not exhibit α1-muscarinic, nicotinic, or β-adrenoceptor blocking activity in canine vascular and guinea pig nonvascular smooth muscle. CK-1649C was devoid of effects on human platelets, nonvascular smooth muscle of guinea pig vas deferens and uteri, and rabbit bronchi, responses of the anesthetized dog to intravenous acetylcholine (ACh), isoproterenol, and nicotine; cervical sympathetic transmission to the nictitating membrane of dog; and free water clearance in water-loaded dogs. CK-1649C (30mg/kg, i.v.) was devoid of all but transient inhibitory activity against vagal nerve stimulation in the dog. CK-1649C should not have significant hemodynamic, neural, or smooth muscle side effects at proposed therapeutic doses of 1–3 mg/kg in man.

Sematilide is a new, non-quaternary class III antiarrhythmic agent currently undergoing clinical trials. We showed that a quaternary ammonium class III antiarrhythmic agent exhibits few extracardiac effects (Greenberg et al., Drug Dev. Res. 25.107–123, 1992). However, the extracardiac effects of a non-quaternary, pure class III antiarrhythmic agent are unknown. Sematilide, a pure class III antiarrhythmic agent, is effective in a canine model of arrhythmia at 0.3–1.0 mg/kg, intravenously (i.v.). We compared the nervous system and extracardiac effects of sematilide to acecainide (a class I/III) and several class I antiarrhythmic agents to evaluate the potential side effects of this new drug. Sematilide was devoid of neuropharmacologic activity in the mouse and rat, devoid of gastrointestinal activity in the mouse fed a charcoal meal, and without effect in the rat carrageenan-induced paw edema test. Ten to 30 times the average antiarrhythmic dose or plasma levels of sematilide were devoid of α1, muscarinic, nicotinic, and β-adrenoceptor blocking activities in a variety of preparations. Moreover, sematilide was devoid of depressant activity on (1) cholinergic, nicotinic, and sympathetic neurotransmission; (2) vascular and non-vascular smooth muscle reactivity and contractility; (3) aggregation of human platelets; (4) responses of the anesthetized dog to i.v. acetylcholine, isoproterenol, and nicotine; and (5) displacement of quinuclidinyl benzilate (QNB) binding to dog atrial membranes. Sematilide (10–30 mg/kg, i.v.) inhibited vagal nerve stimulation in the dog and slightly enhanced free water clearance in water-loaded dogs. The data show that effective antiarrhythmic doses and concentrations of sematilide are devoid of significant, injurious neural, hemodynamic, or smooth muscle side effects. © 1992 Wiley-Liss, Inc.

The studies show that unilateral microinjection of nitroglycerin (NTG) into nucleus tractus solitarii (NTS) produce dose-dependent decreases in mean arterial pressure (MAP) and heart rate, but injection of sodium nitroprusside (SNP) into the area induced slight effects. Hypotensive responses to NTG injected into the NTS showed that the compound was 20 times more potent than after i.v. administration. Responses to NTG injected into the NTS were abolished in an additive fashion by either rauwolscine, an alpha 2-adrenoceptor antagonist, or guanethidine which inhibits release of norepinephrine (NE). Injection of prazosin, an alpha 1-adrenoceptor antagonist, into the NTS reduced the hypotensive responses of NTG, but did not alter the bradycardia induced by the drug. Tachycardic responses following i.v. administration of either NTG or SNP were attenuated by bilateral injection of rauwolscine into the NTS, whereas only hypotensive responses to i.v. NTG were reduced by the pretreatment. NTG produced a dose-dependent increase in concentrations of 3,4-dihydroxyphenylalanine in media bathing medulla-pons, which were quantified using high-performance liquid chromatography with electrochemical detection. NE and 3,4-dihydroxyphenylglycol concentrations in media of incubated medulla-pons slices were simultaneously increased following higher concentrations of NTG. The results suggest that NTG in the NTS induces hypotensive and bradycardiac responses, and an increase in turnover of NE may stimulate alpha 2-adrenoceptors and be responsible for the effects of the drug. The NTS may contribute a component of action to the cardiovascular effects of intravenous NTG. The cardiovascular responses of intravenous SNP appear to involve peripheral action.

Nitroglycerin produced concentration-dependent increases in outflow of norepinephrine (NE) in perfused guinea-pig hearts. These effects of nitroglycerin were inhibited by guanethidine, but were not blocked by desmethylimipraminc or rauwolscine. Nitroglycerin-induced increases in NE outflow correlated with its positive chronotropic responses. Higher concentrations of nitroglycerin also increased outflow of 3,4-dihydroxyphenylglycol (DOPEG) which were inhibited by desmethylimipramine. Nitroglycerin-induced maximal outflow of NE occurred during the first 2 min, but maximal outflow of DOPEG was 2–4 min. In addition, the 3,4-dihydroxyphenylalanine formation in atrial and striatal slices were enhanced by nitroglycerin in the presence of m-hydroxybenzylhydrazine dihydrochloride (an inhibitor of aromatic L-amino acid decarboxylase). The results suggest that nitroglycerin increases release of NE which correlates with cardiac stimulation by the drug. The drug also stimulates tyrosine hydroxylase activity resulting in increased synthesis of NE.

Background: Total parenteral nutrition (TPN) is a life-saving therapy in critically ill patients. Unfortunately, it is associated with significant morbidity and mortality, including gut atrophy and Parenteral Nutrition Associated Liver Disease. A lack of enteral feeding during TPN, disrupts key signaling molecules and the enterohepatic circulation, which appears to be a major contributor to disease pathology. Our group previously demonstrated thatenterally administeredbile acid,oleanolic acid (OA)significantly improved gut density andmorphology. OAis a ligand for the G-protein coupled receptor TGR-5. TGR-5 is known to induce transcription of glucagon-like peptide (GLP)-1 and GLP-2. While GLP-1 regulates hepatic steatosis and inflammation, GLP2 is involved in gut growth and motility.Hypothesis: We hypothesize that TPN infusion disrupts the TGR5-GLP axis and exogenous GLP-1, GLP-2 infusion will ameliorate TPN induced injury. Methods: Seven to ten day old piglets were implanted with jugular venous (JVC) and duodenal catheters (DC). Animals were randomized to receive Enteral Feeding (EN) or TPN. The TPN group was subdivided into TPN plus GLP-1 and GLP-2 (n=3). Milk was delivered via the DC and TPN was infused via the JVC. GLP-1 and GLP-2 were dosed at3 mcg/kg/day and 30 mcg/kg/day respectively. Results: Mean daily weight gain (grams) for control Enteral Fed (EN) vs TPN animals and standard deviation (±SD) was 102.4±10.8, 91.03±12.1 respectively, p>0.05. Marked gut atrophy was noted with TPN.Mean gut density as measured in grams/cm of gut tissue and standard deviation (±SD) in EN vs TPN was 0.35±0.03, 0.185±0.05, p

G A A b st ra ct s previously have described the presence of cytokines in saliva which also are present in blood and esophageal tissue and have been suggested as playing a fundamental role in the pathogenesis of EoE. However, the usefulness of these salivary cytokines in discriminating between patients with/without EoE and their potential correlation with esophageal eosinophilia have not been examined. Methods In this cross−sectional study, we collected saliva using oral swabs (OS; Salimetrics Oral Swab®, Salimetrics LLC, PA) at the time of upper gastrointestinal endoscopy in sixteen children being evaluated for gastroesophageal and/or dyspeptic symptoms. Children with oral lesions, neurodevelopmental disorders, inflammatory bowel disease, or celiac disease were excluded. Six children were diagnosed with EoE and ten children had no evidence of EoE and were considered Controls (Table). Esophageal histology was compared between groups. Salivary cytokines: IL−4, IL−5, and IL−13 were measured on a high sensitivity human multiplex platform, and eotaxin 3 (Eo3) and thymic stromal lymphopoietin (TSLP) by sandwich ELISA technique. Differences between groups were evaluated using the Wilcoxon rank sum test. Spearman's correlation was performed to examine potential associations between salivary cytokines and esophageal eosinophils per high powered field (eos/hpf). Results See Table. Age and sex were comparable between groups. Median salivary IL−5 and IL−4 concentrations were significantly greater in patients with EoE than in Controls. In contrast, there were no differences between groups in median IL−13, Eo3, or TSLP concentrations although values were numerically higher in patients with EoE. Salivary IL−4 and IL−5 were positively correlated with eos/hpf in the distal esophagus (Spearman's ρ=0.53; P=0.03 and ρ=0.56; P=0.02, respectively). In contrast, IL−13, Eo3, and TSLP did not correlate with histologic findings. Conclusions Our preliminary data suggest that salivary cytokines, specifically IL−4 and IL−5 have the potential to distinguish children with vs without EoE. Salivary concentrations of these cytokines appear to reflect esophageal eosinophilic infiltration in EoE. Confirmation of our findings in a larger sample with additional types of disease controls may simplify management and reduce the cost of caring for children with EoE. Table: Summary of results

Objectives. To define the potential role of cryosurgical ablation of the prostate (CSAP) as a treatment option for patients with localized prostate carcinoma (PCA), we performed a retrospective outcomes analysis of a large database of patients undergoing CSAP constructed from five institutions and compared this with matching outcomes from contemporary reports of patient outcomes after radiotherapy. Methods. A total of 975 patients who underwent CSAP as primary therapy from January 1993 to January 1998 with sufficient outcomes data available were identified. Patients were stratified into three groups on the basis of their clinical features. Biochemical-free survival (BFS), post-CSAP biopsy results, and post-CSAP morbidities were calculated and recorded. Results. The median follow-up for all patients was 24 months. The percentages of patients in the low, medium, and high-risk groups were 25%, 34%, and 41%, respectively. For prostate-specific antigen thresholds of less than 0.5 and less than 1.0 ng/mL, the 5-year actuarial BFS ranged from 36% to 61% and 45% to 76%, respectively, depending on the risk category. Overall, the positive biopsy rate was 18%. Morbidities included impotence in 93%, incontinence in 7.5%, rectourethral fistula in 0.5%, and transurethral resection of the prostate in 13% of patients (10% approved warming catheters versus 40% nonapproved). Conclusions. For each risk group, the 5-year BFS and positive biopsy rate after CSAP was comparable to matching outcomes reported after radiotherapy. Morbidities also seemed comparable, with impotence rates higher and rectal injury rates lower after CSAP than after radiotherapy. These data indicate that CSAP can be performed with low morbidity and can produce cancer-related results comparable to those reported for patients undergoing radiotherapy.

In vitro experiments using isolated atria with and without superfusion can be used to quantify the dopamine-2 (DA-2) receptor stimulating activity of compounds. This receptor mechanism decreases the amount of norepinephrine released from sympathetic nerve terminals by neuronal impulses. DA-2 receptor agonists (stimulants) are very active and induce several physiological changes, such as bradycardia, hypotension, lower intraocular pressure, etc. In this unit, tissue preparation and dopamine receptor assays are described for isolated cat atria with field stimulation or with superfusion, and isolated guinea pig atria with field stimulation.

Several reports have documented that renal cryoablation when used either via open or laparoscopic surgical techniques can be well tolerated in animal models. We sought to examine the feasibility of performing renal cryoablation percutaneously, under ultrasound guidance, in a porcine model. A total of 13 juvenile swine was treated. In each animal the lower pole of the left kidney was used as the target. Each animal had serum drawn for Hct, Wbc, CK, BUN, creatinine, and myoglobin pre- and postcryoablation and again at the time of sacrifice. Animals were sacrificed at 0–42 days postoperatively, and the treated renal units were harvested and submitted for histologic examination. The procedures were divided into three groups based on the extent of the freeze time. Group 1 (n= 4) was treated for 3–4 min, single freeze; Group 2 (n= 3), 6–7 min, single freeze; and Group 3 (n= 6), a double freeze-thaw cycle, each for 10 min. None of the animals in this experiment died or experienced significant clinical deteriorations at any time post-treatment. No significant differences in any of the measured serum markers were noted between pre- and post-treatment values. For animals in Groups 1 and 2 discrete cryolesions were created with sharp 1-mm borders and no perirenal reaction/damage to surrounding structures. For animals in Group 3 large areas of renal infarction/cryolesions were produced, with significant perirenal reaction in 5/6 animals and gross hydronephrosis/total renal loss in 2/6. Percutaneous renal cryoablation appears to be well tolerated in the porcine model which we used. Associated morbidity appears to be related to the extent of freezing, with a safety tolerance in the present study limited to target areas of approximately 3–5 cm3. These findings suggest that a pilot study of percutaneous renal cryoablation for patients with 3–4-cm exophytic lesions may be warranted.

A series of congeners of hemicholinium-3, in which the 1,4-oxazinium rings of hemicholinium are replaced by pyrrolidine, piperidine, 1,3-dioxane, or 1,4-oxazine rings, is described. Several of the target compounds produced blockade of neuromuscular transmission in the rabbit, and three heterocyclic derivatives, 10, 11, and 13, significantly antagonized paraoxon-induced lethality in mice. 1,3-Dioxane derivative 11 was an extremely potent antagonist of paraoxon-induced toxicity in mice, compared with prototypical protective agents physostigmine and pyridostigmine. Compound 11 exhibited a much more favorable therapeutic ratio than the reference drugs. The mechanism of action of 11 has not been elucidated, although it is concluded that it differs from that of hemicholinium-3 (inhibition of high-affinity, sodium-dependent uptake of choline into nerve terminals).

Cryosurgical ablation of the prostate is a novel therapeutic modality that induces cell lysis in the prostate by direct application of low temperatures. We have been conducting an ongoing prospective pilot study of the use of cryosurgical prostate ablation in treating patients with nonmetastatic prostate adenocarcinoma since January 1993. Results in 145 consecutive patients with mean 36 months and minimum 12 months of followup are presented.Accrual was open to patients with clinical stages T1a to T3c prostate adenocarcinoma. Pelvic lymph node dissections were recommended but not required for patients with prostate specific antigen (PSA) greater than 15 ng./ml. before study entry. PSA changes, random prostate biopsy findings and morbidities after cryosurgical prostate ablation were recorded for each patient.Overall actuarial rates at 42 months for maintaining PSA less than 0.3 and less than 1.0 were 59% and 66%, respectively. The overall actuarial progression-free rate at 60 months was 56%. Among 160 biopsies performed 16% showed some evidence of residual carcinoma. Overall crude rates of maintaining either a negative biopsy or PSA less than 0.3 at 6 and 24 months after cryosurgical prostate ablation were 87% and 73%, respectively. Significantly higher morbidities were seen in previously radiated patients undergoing cryosurgical prostate ablation compared to those with no prior radiation. Among nonradiated patients 85% experienced no significant morbidity after cryosurgical prostate ablation.Although preliminary, short-term outcomes after cryosurgical prostate ablation appear to be comparable to identical outcomes reported for external beam radiotherapy. Based on these results cryosurgical prostate ablation appears to be an effective therapeutic alternative for treating patients with localized prostate adenocarcinoma.

The management of metastatic renal cell carcinoma remains challenging and controversial. There is some evidence of improved response to interleukin-2 (IL-2) based immunotherapy in patients who undergo nephrectomy before systemic treatment. However, recent reports have suggested that surgery prior to immunotherapy may not be an efficient strategy, since many patients will not be able to receive systemic treatment after nephrectomy. We describe our criteria for determining which patients are candidates for nephrectomy before immunotherapy and present our series of patients treated with this approach.Based on our initial experience with IL-2 based immunotherapy we developed certain inclusion criteria for treatment with initial nephrectomy followed by systemic immunotherapy, including greater than 75% debulking of tumor burden possible, no central nervous system, bone or liver metastases, adequate pulmonary and cardiac function, and Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, patients in whom biopsies show other than predominantly clear cell type histology are excluded. From 1991 through 1996, 28 patients met these criteria and were treated with this approach. Patients were followed to determine the number receiving immunotherapy as well as overall response and survival rates.Radical nephrectomy was performed in all patients. One patient died of respiratory failure from disease progression 1 month after nephrectomy. Another patient had poor pulmonary function and, therefore, was treated with an alternative cytokine therapy. The remaining 26 patients (93%) received at least 1 course of IL-2. Median interval between nephrectomy and initiation of immunotherapy was 1.5 months (range 1 to 3). Overall response rate was 39% with 5 complete (18%) and 6 partial (21%) responses. Actuarial median survival of the entire group was 20.5 months (range 1 to 66) from the initiation of treatment. Currently 13 patients are alive, including 8 who are disease and/or progression-free.Using these strict criteria nephrectomy can be effectively performed before immunotherapy without compromising the likelihood that patients will receive systemic treatment. The activity of IL-2 in patients treated with this approach is encouraging and justifies its consideration in properly selected patients.

The successful excision of genitourinary malignancies extending to the inferior vena cava relies heavily on accurate preoperative imaging. For the majority of these patients magnetic resonance imaging, inferior venacavography, abdominal ultrasound or abdominal computerized tomography will reliably predict the extent of inferior vena caval involvement by tumor. However, occasionally the results of these studies will conflict or be called into question intraoperatively. We report on 8 patients considered to be at risk for inferior vena caval involvement by tumor and for whom intraoperative ultrasound was obtained to clarify the presence or extent of thrombus. Five patients had renal cell carcinoma and 3 had adrenal carcinoma. In all patients concern as to the extent or presence of tumor was based on either inconclusive preoperative studies or unexpected intraoperative findings. In each case intraoperative ultrasound clearly visualized the inferior vena cava and established the presence or extent of tumor invasion. In 4 patients venacavotomy was avoided as a consequence of these findings. Intraoperative ultrasound is a useful tool that can accurately assess the inferior vena cava for possible tumor invasion, especially when the presence or extent of tumor involvement is not definitively established preoperatively.

The role of interleukin-2 based immunotherapy in advanced renal cell carcinoma is gradually expanding. Among patients who achieve significant responses to these regimens the subsequent development of isolated recurrences raises difficult management questions. We report 2 unusual cases of isolated recurrence in the remaining kidney following a sustained, complete response to interleukin-2 based adoptive immunotherapy. Both patients were treated with interleukin-2 based therapy following surgical resection of the primary renal tumor. The disease course of each patient is described and the literature is reviewed. Both patients were free of disease after relatively short-term followup. Surgery for patients with limited recurrence of renal cell carcinoma following an objective response to immunotherapy may, in select cases, be a reasonable treatment alternative.

The usefulness of serum acid phosphatase (SAP) in monitoring patients with advanced prostate carcinoma has been questioned. We reviewed a series of 59 patients with stage D2 prostate carcinoma. All patients had extended follow-up through at least one clinical relapse, or death. Responses to a variety of therapies were characterized as absent, subjective, or objective. All patients with an elevated pre-treatment SAP that fell to normal following therapy had prolonged survivals and improved prognoses. Conversely, all patients with an elevated SAP which did not normalize following therapy had poorer survivals. Among 36 objective responses to therapy, the SAP was elevated prior to or simultaneous with disease progression in 33 (93% sensitivity). In each ease where the pretreatment SAP normalized following therapy, any subsequent elevation in SAP above normal was always associated with clinical evidence of disease progression (100% specificity). Changes in SAP following therapy correlate well with both disease regression and disease progression in patients with advanced prostatic carcinoma.

The neuroblastoma-glioma hybrid cell (NG108-15) has a sodium-dependent, high-affinity choline transport system with a Km of 16.0 ± 3.4 μM and Vmax of 214.5 ± 27.7 pmol/min/mg protein. A-4, A-5 and HC-3 produce dose-dependent inhibition of high-affinity choline transport in NG108-15 cells. Following 24 h exposure to approximately the EC50 of each inhibitor, no significant decrease was found in total choline accumulation or in choline incorporation into phosphatidylcholine. However, when additional inhibitor was added during the 24 h incubation, significant decreases in choline accumulation were produced by A-4 and A-5. Following 24 h exposure to each compound, only A-4 was able to significantly affect free choline content. In contrast, each inhibitor was able to significantly decrease acetylcholine content following 24 h exposure. Possible reasons for consistent decreases in acetylcholine versus minimal changes in choline metabolism will be discussed.

Metastasis of renal cell carcinoma (RCC) to the penis or spermatic cord is rare. We present an unusual case of initial metastasis to the cord with delayed involvement of the penis. This is the first report of metachronous involvement of the genitalia from RCC metastases.

The authors describe what appears to be the first case of transperitoneal marsupialization of a lymphocele following laparoscopic pelvic lymph node dissection. The 9.7 x 5.6 x 6-cm collection was opened, its edges were cauterized, and the internal membranes were resected with an operative time of 90 minutes and a blood loss of less than 30 mL. A multicenter trial may be useful to determine whether excision of a portion of the peritoneum or an inverted-V rather than a linear incision would decrease the incidence of lymphoceles after laparoscopic pelvic lymphadenectomy.

RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane) is a novel dopamine (DA) receptor agonist with potent central actions. RDS-127, apomorphine (APO), and bromocriptine (BRM) were compared for their ability to inhibit locomotor activity in rats following oral administration. APO, BRM, and RDS-127 produced time- and dose-dependent decreases in locomotor activity. While APO and BRM were equipotent in inhibiting locomotor activity, RDS-127 was 13.5 times more potent than either APO or BRM. A single oral dose of 32.0 μmol/kg of RDS-127 decreased locomotor activity greater than 50% for a period of 2 hr. The inhibitory effects of RDS-127 on locomotor activity were blocked by prior administration of sulpiride, suggesting the effects are mediated by DA receptors. While oral administration of APO or RDS-127 generally decreased locomotor activity, similar doses given subcutaneously increased locomotor activity. These data suggest that the route of administration can profoundly affect the biological actions of DA receptor agonists and the accompanying conclusions concerning the selectivity with which they interact with different receptor subtypes. The therapeutic application and design of orally effective DA autoreceptor agonists are discussed.

Various synthetic dopamine (DA) analogues have been shown to produce glucose intolerance and inhibit the compensatory increase in serum insulin during an oral glucose tolerance test (OGTT). To investigate the possibility that there is a direct action of dopamine analogues to inhibit glucose-stimulated insulin release from the endocrine pancreas, the following compounds were compared with the effects of epinephrine (EPI) on isolated rat pancreatic islets: apomorphine (APO), pergolide, lergotrile, TL-99 (2-dimethylamino-6,7-dihydroxytetralin), and RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane). EPI, TL-99, and pergolide inhibited insulin release in a concentration-dependent fashion (10 −7–10−5 M), whereas lergotrile inhibited at K)10−5 M but not at 10−6 M. RDS-127 and APO were ineffective at 10 −5 M, but produced a greater than 50% inhibition at 2 × 10−4;M. The potencies of the DA analogues fell into two groups: compounds that are approximately as active as EPI (e.g., TL-99 and pergolide) or compounds that are relatively inactive (e.g., APO, lergotrile, and RDS-127). The inhibitory actions of EPI, TL-99, and pergolide were blocked by the α2-adrenergic receptor antagonist yohimbine, whereas the DA receptor antagonist, sulpiride, had no effect, suggesting an action initiated at α2-adrenergic receptors. Drugs from both groups produced marked glucose intolerance and inhibited the compensatory increase in insulin during an OGTT. Adrenodemedullation blocked the glucose intolerance and inhibition of insulin release caused by RDS-127, whereas these effects of TL-99 were not attenuated. These data, obtained in vitro and in vivo, show that selective dopamine agonists, such as RDS-127, reduce glucose-stimulated insulin release indirectly through adrenal medullary secretions, whereas the effect of less selective agonists, such as TL-99, directly inhibit the release of insulin from the endocrine pancreas.

Modification of food intake and motor activity was investigated following administration of amphetamine (AMP), apomorphine (APO) and three novel 2-aminoindanes (2-AI): 2-di-n-propylaminoindane (JPC-60-36), 2-di-n-propylamino-5,6-dimethoxyindane (JPC-211) and 2-di-n-propylamine-4,7-dimethoxyindane (RDS-127). These compounds demonstrated dose- and time-related inhibition of food intake in male rats which were habituated to eating 4 hr each day. The ranked potencies were as follows: RDS-127 greater than AMP = APO greater than JPC-60-36 and JPC-211 was inactive. 2-di-n-Propylamine-4,7-dimethoxyindane (RDS-127) did not increase motor activity in a dose range that Significantly inhibited food intake (66% of control intake with 0.08 mumol/kg). Food intake inhibition was blocked by pimozide, but not by propranolol or phentolamine. The anorectic-like actions of RDS-127 were long-lasting (greater than 4 hr) and RDS-127 was approximately 3-fold more potent than amphetamine or apomorphine in producing increased locomotor activity; the other 2-aminoindanes were less potent in producing hyperactivity. Hyperactivity responses were blocked by pimozide, but not by alpha-methyl-p-tyrosine. These results suggest that 2-aminoindanes may modify motor behaviors, at least in part, via direct stimulation of dopamine receptors. The structure-activity relationships of 2-aminoindanes on locomotor activity and inhibition of food intake are discussed.

Summary Previous reports suggest that analogs of dopamine (DA) can produce hyperglycemia in rats by interacting with DA receptors. Experiments reported here indicate the site of action and describe the metabolic sequalae associated with the hyperglycemic effect of apomorphine (APO), produced in conscious unrestrained rats. Apomorphine was more potent when administered by intracerebroventricular (i.c.v.) injection than when given subcutaneously (s.c.). Very small doses of the DA receptor antagonist pimozide, given intraventricularly, blocked the hyperglycemic effect of apomorphine administered subcutaneously. Sectioning of the spinal cord at thoracic vertebra T1-2, or sectioning the greater splanchnic nerve blocked apomorphine-mduced hyperglycemia; whereas section of the superior colliculus or section at T5-6 had no effect. A dose of apomorphine or epinephrine (EPI) producing a similar degree of hyperglycemia elevated the concentration of EPI in serum to a similar degree, and the increase in EPI in serum preceded the increase in glucose in serum. Fasting animals for 2 or 18 hr had no significant effect on EPI- or apomorphine-induced hyperglycemia despite a reduction (91-93%) of the glycogen content of liver and skeletal muscle during the 18 hr fast. 5-Methoxyindole-2-carboxylic acid (MICA), an inhibitor of gluconeogenesis, blocked EPI- and apomorphine-induced hyperglycemia in rats fasted for 18 hr. However, 5-methoxyindole-2-carboxylic acid was ineffective in blocking hyperglycemia in animals fasted for 2 hr. Changes in insulin or glucagon in serum alone cannot account for the hyperglycemic action of apomorphine. These data demonstrate that apomorphine interacts with central DA receptors located in the hindbrain to activate sympathetic neuronal activity to the adrenal gland which subsequently releases epinephrine to alter homeostasis of glucose. Epinephrine may then, depending on the nutritional status, facilitate glycogenolytic or gluconeogenic processes to produce hyperglycemia.

Superfused helical strips of canine anterior mesenteric arteries and veins and canine dorsal metatarsal veins contract in response to prostaglandin B 2 (PGB 2 ). Reserpine pretreatment and phentolamine reduce the constrictor response to PGB 2 . PGB 2 enhances the contractile responses of these preparations to potassium, barium and norepinephrine. PGB 2 also produced a shift to the left in the duration of the barium response curve. The data presented demonstrate that PGB 2 is not an inactive metabolite of PGA 2 metabolism but possesses potent constrictor activity probably dependent on release of norepinephrine from adrenergic nerves. Furthermore, PGB 2 enhances the responses of vascular smooth muscle to vasoactive stimuli.

Three 5,8-dimethoxylated derivatives of 2-aminotetralin (2-AT) were compared with clonidine, methoxamine and phenylephrine in tests for sedation (inhibition of exploratory activity) and analgesia. In both tests the 2-AT derivatives were less potent than clonidine, but more potent than methoxamine or phenylephrine. Antagonism of the 2-AT derivative, DR-31, and clonidine by yohimbine in both tests argues for the involvement of α 2 -adrenoreceptors in the mediation of these behavioral effects. α 1 -Adrenoreceptors also mediate an inhibition of exploratory activity since the inhibition induced by methoxamine was antagonized by phenoxybenzamine (POB) but not by yohimbine. The methoxylated 2-AT derivatives, which have previously been shown to exert potent peripheral α 1 -agonism are now demonstrated to have sedative and anlgesic effectscharacteristic of central α 2 -adrenergic stimulation.

Phentolamine, which is considered a specific alpha-adrenoceptor antagonist, was tested for antagonist properties at presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors present on sympathetic nerve terminals in isolated right cat atria. Field stimulation induced a transient tachycardia which was inhibited by stimulation of presynaptic dopamine receptors using apomorphine or by stimulation of presynaptic alpha 2-adrenoceptors using clonidine. The presynaptic inhibitory effects of apomorphine were competitively antagonized by sulpiride, which is considered a specific dopamine receptor antagonist, and by phentolamine and yohimbine which are considered alpha-adrenoceptor antagonists. The presynaptic inhibitory effects of clonidine were competitively antagonized by phentolamine and yohimbine but not by sulpiride. pA2 values for phentolamine against apomorphine and phentolamine against clonidine suggest that phentolamine may be an antagonist at both presynaptic dopamine receptors and presynaptic alpha 2-adrenoceptors.

The cardiovascular effects of RDS−127 [2−di-n-propylamino−4,7−dimethoxyindane] were examined in normotensive, anaesthetized rats. RDS−127 given i.v. (12·5–125 μ kg−1) produced dose-dependent bradycardia. The bradycardic effect was 20·5 times more potent when the drug was administered intracerebroventricularly (i.c.v.) than when given i.v. RDS−127 produced a slight, but significant hypotension. Haloperidol given i.c.v. or i.v. reversed these bradycardic and hypotensive actions, whereas phentolamine was ineffective. Methylatropine partially reduced the bradycardic effect. These results suggest that RDS−127 activates central DA receptors to produce hypotension and bradycardia in rats.

d-Amphetamine was found to induce a pecking response in pigeons. The pecking response induced by d-amphetamine was antagonized by chlorpromazine, haloperidol or bulbocapnine indicating that this pecking response was caused by dopaminergic receptor stimulation. Pretreatment of pigeons with alpha-methyltyrosine (alpha-MT) reduced d-amphetamine-induced pecking, while the combined treatment of pigeons with alpha-MT and L-dihydroxyphenylalanine (L-DOPA, 100 mg/kg) partially restored the pecking response. d-Amphetamine-induced pecking was not reduced by a dopamine-beta-hydroxylase inhibitor, 1-phenyl-3-(2-thiazolyl)-2-thiourea (U-14,624). Alpha-MT reduced brain dopamine but not norepinephrine level, whereas U-14,624 decreased brain norepinephrine but not dopamine. Thus there is a correlation between brain dopamine level and d-amphetamine-induced pecking response. It is concluded that d-amphetamine-induced pecking is mediated indirectly by the release of dopamine.

A series of rigid analogs of apomorphine lacking aromatic hydroxyl substituents were evaluated for dopaminergic properties. Three compounds, N-methyl-N-propyl-2-aminotetralin (Me-Pr-2-AT), N, N-dipropyl-2-aminotetralin (Di-Pr-2-AT) and N, N-dipropyl-2-aminoindane (Di-Pr-2-AI) induced emesis in dogs, contralateral circling in unilaterally lesioned rats, and inhibited prolactin secretion. The induced circling responses, however, were attenuated by prior treatment with α-methyl-p-tyrosine methyl ester (AMPTME) and the compounds were weak inhibitors of 3H-dopamine binding in calf caudate homogenates. The posssiblity that these agents may be metabolically activated in vivo is discussed.

The cardiovascular effects of two N-di-alkyl substituted analogs of dopamine and dopamine were tested in the dog. Intravenous administration of N, N-diethyldopamine (DEDA) decreased mean arterial pressure, heart rate, and mildly depressed cardiac output. Intravenously administered N, N-dipropyldopamine (DPDA) decreased mean arterial pressure, heart rate, and total peripheral vascular resistance. Both compounds inhibited reflex sympathetic responses produced by a bilateral common carotid occlusion. Femoral artery injections of DEDA or DPDA produced biphasic responses. A transient increase in femoral bed vascular resistance was followed by a decrease in femoral bed vascular resistance sensitive to alpha adrenoceptor antagonism. In contrast to DEDA and DPDA, intravenously administered dopamine increased cardiac output and heart rate while reducing arterial pressure and total peripheral vascular resistance. Femoral artery injections of dopamine resulted in a dose-dependent constrictor response which was antagonized by alpha receptor blockade. These data demonstrate that DEDA and DPDA induce different cardiovascular responses from dopamine.

Aminotetralin derivatives M-8 and JOD-176, were studied in relation to isoproterenol for beta-adrenergic activity. M-8 and JOD-176 were found to be very weak in activating cardiac beta-receptors. These compounds were also found to be considerably more active in uterine and bronchial smooth muscle. Because these compounds were also shown to be very inactive in vascular smooth muscle, the possibility that beta-receptors in different smooth muscle types may also differ was suggested.

Low doses of 5,6-dihydroxy-2-dimethylaminotetralin (M-7) produced inhibition of the linguomandibular reflex in the cat. This inhibition was similar to that produced by apomorphine and was blocked by haloperidol, bulbocapnine or chlorpromazine. M-7 also had a brief but marked hypertensive effect. Gradual bradycardia also developed. These results indicate that M-7 inhibits the linguomandibular reflex by interaction at dopamine receptors, or ‘apomorphine’ receptors.

The effect of droperidol on miniature endplate potential (mepp) frequency and amplitude, acetylcholine sensitivity, action potential generation, twitch tension, input resistance and alteration of acetylcholine release were studied in frog muscle. Interaction with d-tubocurarine was studied in the cat sciatic gastrocnemius preparation. Between 10 −11 and 10 −7 g/l droperidol did not change mepp frequency or amplitude. Between 7.5 × 10 −6 and 2.5 × 10 −5 g/l mepp amplitude, endplate sensitivity to acetylcholine and twitch tension were depressed. At 5 × 10 −5 g/l the threshold for action potential generation increased while amplitude and rate of rise decreased. Input resistance was unaltered. With indirect interrupted tetanic stimulation of the muscle for 30 min droperidol 10 −6 to 10 −4 g/l reduced the contraction height while acetylcholine release was concomitantly depressed. Droperidol 10 mg/kg in cats did not block muscle contraction, but combination with d-tubocurarine prolonged recovery time.

The contractile responses of the acutely denervated (g.f.n.m.) and decentralized (d.n.m.) nictitatingmembrane of the cat to angiotensin (0.2 – 0.4 μg/kg), tyramine (50 – 100 μg/kg) and norepinephrine (1 – 2 μg/kg) were measured before and after the administration of cumulative doses of DMAE (0.8 – 3.2 mg/kg, i.v.). The contractile responses of the g.f.n.m. and d.n.m. to each of the agonists did not differ. Twenty minutes after the administration of DMAE the contractile responses of both nictitating membranes to angiotensin, tyramine and norepinephrine were enhanced to the same extent. Nerve terminal blockade by bretylium and reserpine-induced catecholamine depletion antagonized the responses to angiotensin and tyramine and blocked DMAE-induced potentiation of the contractile responses to these agonists. Atropine reduced significantly the contractile responses of the g.f.n.m. and d.n.m. to angiotensin but did not affect either the response of the membrane to tyramine or DMAE-induced potentiation of the responses to angiotensin. These results suggest that DMAE acts to enhance, as well as cause, release of catecholamines from the adrenergic nerve terminal. The results also suggest that a portion of the contractile response of the d.n.m. and g.f.n.m. to angiotensin is mediated by stimulation of neuronal cholinergic muscarinic receptors which result in release of norepinephrine.

Superfused helical strips of canine anterior mesenteric arteries relaxed in approximately 12% of the preparations when challenged with vasoconstrictor agents such as serotonin, norepinephrine, barium chloride and KCl. The muscle fibers in most of these preparations were longitudinally oriented.

Superfusion of an isolated segment of guinea pig ileum with BTM effectively blocks the contractions induced by histamine, potassium chloride, acetylcholine, and BTM itself for a period of 60–90 min. Spontaneous contractions are also eliminated during this period. Incorporation of atropine in the superfusate removes the blocking activity of BTM, while hexamethonium has no effect on BTM blockade under similar experimental conditions. Perfusion of isolated gut loops of dogs by BTM causes blockade of contractions induced by histamine and acetylcholine. Epinephrine responses were unaffected. However, BTM caused a reduction in the perfusion pressure response to acetylcholine and histamine while the epinephrine response was increased. The pressor response of epinephrine and the depressor response of acetylcholine were significantly reduced in both the systemic and perfused limb blood pressures of the dog following i.m. administration of 1 mg./kg. of BTM.