The Intriguing Effects of Substituents in the -Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments.

(-)--Phenethyl analogs of optically pure -norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). "Body" and "tail" interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address" can be considered the "body" of the hydromorphone molecule and the "message" delivered by the substituent (tail) on the aromatic ring of the -phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, ), was found to have nanomolar binding affinity at MOR and DOR.

How 4 Companies Became One: Co-development Under an Outsourced Model With Focus on Phase 3 Analysis and Reporting Deliverables.

With the growth in co-development deals between pharmaceutical companies and the increased use of contract research organizations (CROs) in drug development, more and more employees are encountering projects that require working across different companies. Navigating the mix of corporate cultures as well as variations in standards and procedures can lead to unanticipated challenges and delays. The development of ertugliflozin, a recently approved medicine for type 2 diabetes mellitus, involved both co-development and CRO engagement across 4 companies.

A pilot study on delirium in the intensive care unit: a creative inquiry project with undergraduate nursing students.

Introduction: Delirium continues to be a major issue in intensive care units (ICUs). Sedation and lack of rapid eye movement (REM) sleep could be important factors in the development of delirium. Improper sedation may interfere with a patient's sleep pattern, specifically time spent in REM sleep, and could be a contributor to the development of delirium.

Pylephlebitis due to perforated diverticulitis.

Pylephlebitis or septic thrombophlebitis of the portal vein is an uncommon and frequently fatal complication of diverticulitis. We describe a case report of a patient with pylephlebitis due to a perforation of the sigmoid. The patient was successfully treated with broad spectrum antibiotics and a Hartmann procedure.

GIST (gastro-intestinal stromal tumour) of the gallbladder: a case report.

The authors report a case of a gastrointestinal stromal tumour (GIST) of the gallbladder. GISTs are rare mesenchymal tumours of the gastrointestinal tract, mesentery and omentum. GISTs are characterized by the expression of the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor.

Malingered neurocognitive dysfunction in neurotoxic exposure: an application of the Slick criteria.

Toxic torts are increasing across the country and often the results of the neuropsychological evaluation are crucial for defining damages. Therefore, the accurate differentiation of those damaged by toxic exposure from those exaggerating or fabricating deficits is important. However, there is little research on malingering in this context.

Legal, ethical and clinical implications of prescribing involuntary, life-threatening treatment: the case of the Sunshine Kid.

Involuntary treatment is a concept often familiar to psychiatrists. In clinical practice, it usually involves the hospitalization and pharmacological management of patients with severe mental disorders. However, the scope of involuntary treatment is not limited to the management of mental illness alone.

The biomimetic [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+ )decreases plasma insulin, cholesterol, and triglycerides in healthy and type II diabetic rats but not type I diabetic rats.

The in vivo effects of administration of the synthetic, functional biomimetic cation [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+) to healthy and type I and type II diabetic model rats are described. In contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, the trinuclear cation has been shown in in vitro assays to interact with the insulin receptor, activating its kinase activity, presumably by trapping the receptor in its active conformation. Thus, treatment of rats with the trinuclear cation would be expected to result in changes in lipid and carbohydrate metabolism related to insulin action.

Evaluation of suspected stress fractures.

Stress fractures can occur if normal bone is exposed to repeated abnormal stress (fatigue fractures) or if normal stress is placed on bones with compromised elastic resistance (insufficiency fractures). This article describes two patients without a history of excessive stressful activity or apparent metabolic bone disease who developed bilateral distal tibial stress fractures. Different etiologies, clinical presentation, differential diagnosis, and diagnostic imaging modalities of stress fractures are discussed.

Patient satisfaction and symptom relief after anal dilatation.

Anal dilatation is used as a simple method of treatment and has been used for both anal fissure and haemorrhoids. This study examined longer-term results among a cohort of 162 patients, 132 of whom responded to a detailed questionnaire, an 82% response (66 patients were male; age range 17-75 years, median 42 years). Follow-up ranged from 16 months to 36 months (median 27 months) after anal dilatation (68 patients for fissure, 32 for haemorrhoids, and 32 for both).

Five-year audit of the acute complications of diverticular disease.

Background: The objective of this study was to audit the presentation and outcome for patients admitted with an acute complication of diverticular disease.

Methods: This study was a retrospective review of 418 admissions with an acute complication of diverticular disease over a 5-year interval.

Results: Of the 418 admissions, 15 patients were eventually found to have an alternative diagnosis.

The acute surgical admission: is mortality predictable in the elderly?

Most scoring systems used to predict mortality are complex. A simple preoperative assessment, the Sickness Assessment (SA), was evaluated as a predictor of mortality in elderly patients admitted as surgical emergencies. The three parameters comprising the SA are: hypotension on admission, the presence of severe chronic disease, whether the patient was independent and self-caring.

Developmental effects of petroleum creosote on mice following oral exposure.

Petroleum creosote, dissolved in dimethyl sulfoxide, was administered by gavage to pregnant ICR mice on days 5-9 of gestation at a single dose (400 mg/kg body weight per day). Animals were euthanized on day 17 of gestation, and live fetuses were weighed and examined for skeletal and visceral malformations. Maternal body weights were significantly lowered in both the group administered creosote and the group administered the solvent alone.

Delay in the diagnosis and prognosis of carcinoma of the right colon.

Of 152 consecutive patients with carcinoma of the right colon, 61 (40 per cent) suffered delays in treatment of more than 12 weeks from the onset of symptoms, with a mean delay of 48 weeks. The most common error was failure to initiate or complete the investigation of iron-deficiency anaemia (33 patients). False-negative barium enema investigations occurred in 16 cases.

In vitro embryotoxicity of petroleum creosote monitored via mouse preimplantation embryo culture.

A mouse preimplantation embryo culture system was utilized to characterize the in vitro embryotoxicity of petroleum creosote (PC), a complex mixture of aliphatic and polycyclic aromatic hydrocarbons. ICR mouse embryos, collected on d 3.5 of gestation (blastocyst stage), were exposed for 1 h to varying concentrations of petroleum creosote in serum-supplemented culture medium.

Role of biotransformation in the in vitro preimplantation embryotoxicity of naphthalene.

The in vitro developmental toxicity of the bicyclic aromatic hydrocarbon naphthalene was characterized with a preimplantation mouse embryo culture system. Day 3 ICR mouse blastocysts were co-cultured with naphthalene for 1 h either alone or in media supplemented with an Aroclor-induced rat S-9 preparation and cofactors. Toxin-treated blastocysts were subsequently cultured in NCTC 109 media with 10% fetal bovine serum for 72 h to observe the developmental effects of exposure.

Abdominal pain: a surgical audit of 1190 emergency admissions.

In an audit of 1190 emergency admissions with abdominal pain (1166 patients) in a general surgical unit, the diagnosis was non-specific abdominal pain (NSAP) in 415 (35 per cent), acute appendicitis in 200 (17 per cent) and intestinal obstruction in 176 (15 per cent). The largest number of admissions occurred in the age groups 10-29 years (31 per cent) and 60-79 years (29 per cent). Surgical operations were performed in 551 patients (47 per cent) and there was a 16 per cent incidence of unnecessary appendicectomy (22 per cent in the age group 20-29 years).

Mortality and perforated peptic ulcer: a case for risk stratification in elderly patients.

In a consecutive series of 284 patients with a perforated peptic ulcer (229 pyloroduodenal, 55 gastric) there was a 26 per cent hospital mortality rate, and patients aged greater than or equal to 70 years (n = 176) had a significantly higher mortality rate (34 per cent) than patients aged less than 70 years (14 per cent, P less than 0.001). Multiple clinical variables were significantly more common in the elderly group of patients (65 per cent), in those having non-steroidal anti-inflammatory drugs or steroid therapy (56 per cent), in patients where there is an absence of a previous dyspeptic history (69 per cent), and when risk factors such as delayed presentation (33 per cent) and the presence of shock on admission to hospital (27 per cent) are present.

Management of symptomatic gallstones in the elderly.

In a study of 544 patients with symptomatic gallstones 158 subjects were aged greater than 70 years. Elderly patients had a significantly higher incidence of emergency presentation, jaundice, cholangitis, ductal stones, biliary drainage procedures, and acute complications requiring urgent or emergency surgery (P less than 0.001); they had more than twice the incidence of postoperative complications in comparison with patients aged less than 70 years.

Prognosis of colorectal cancer in the elderly.

The prognosis of colorectal cancer in the elderly was examined in a study of 306 consecutive patients. The patients were divided into two groups: Group 1 included 171 patients of average age 77 years (range 70-97); Group 2 comprised 135 patients of average age 59 years (range 22-69). There was no significant difference between the two groups with regard to the mode of presentation, the location and Duke's classification of the tumours, the incidence of palliative operations, and the perioperative mortality.

Gastric cancer: an audit of 122 consecutive cases and the results of R1 gastrectomy.

In a consecutive series of 122 patients with gastric carcinoma, 9 per cent had no operation, 27 per cent had incurable disease at laparotomy, and 64 per cent underwent gastric resection. R1 gastrectomy was performed in 73 of the 78 resections. The operative mortality after gastric resection was 4 per cent, but there were no deaths after potentially curative resections.