Pharmacokinetics and acute toleration of the beta-carboline derivative abecarnil in man

Plasma levels of the beta-carboline, abecarnil (isopropyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido [3,4-b]indole-3- carboxylate, ZK112119) which is presently under development as an anxiolytic, were measured by HPLC with fluorescence detection in six healthy male volunteers given 30 micrograms/kg i.v. and 5 and 10 mg p.o. Following i.v. injection, plasma levels declined biphasically with half-lives of 6 min and 3.4 h. The total clearance was 13 ml/min/kg. After oral administration, maximum concentrations were reached after 2 h. The bioavailability was approximately 60%. The terminal half-life after p.o. administration was 7 h. No clinically relevant changes in ECG, vital signs or standard laboratory measurements occurred. Eight different adverse reactions were noted by the subjects. The most frequently reported side-effects were tiredness, dizziness, unsteady gait and lack of concentration.     

Effects of Lovastatin Alone or Combined with Irradiation on Tumor Cells in Vitro and in Vivo

PURPOSE: To evaluate the effect of lovastatin alone or combined with radiation on U87MG and FaDu cells in vitro and U87MG tumors in vivo. MATERIAL AND METHODS: Cell number, p21(WAF1) expression, apoptosis, reproductive cell death, and cell-cycle distribution were investigated after incubation of U87MG and FaDu cells in vitro. The effect of lovastatin (50 mg/kg/day) on tumor growth and on tumor growth delay after single-dose irradiation with 20 Gy was investigated using U87MG tumors in nude mice. RESULTS: Lovastatin dose dependently decreased cell number and proliferation of U87MG and FaDu cells. The proportion of cells in G0/G1 phase, apoptosis and p21 protein expression increased after lovastatin alone or combined with 4-Gy irradiation in both cell lines. Effects of lovastatin on cell cycle and cell number were more pronounced in U87MG compared to FaDu. No radiosensitization of clonogenic cells by lovastatin could be demonstrated in both cells lines, but the colony-forming ability after lovastatin alone was decreased in FaDu cells. In vivo, lovastatin decreased tumor volume over time but did not increase growth delay after irradiation of U87MG tumors with 20 Gy. CONCLUSION: The data support effects of lovastatin on proliferation, apoptosis and colony-forming ability in vitro and tumor volume in vivo. At the drug concentration achievable, lovastatin did not improve the effects of radiation on U87MG tumors in vivo.     

National survey of ethical issues presented to drug information centers

Whether and how drug information centers respond to calls from the public that involve ethical issues was studied. A survey describing six ethical dilemmas typical of those presented by calls from the public was mailed to pharmacists in 154 drug information centers to see how the questions would be handled. Centers that had written policies governing responses to questions with ethical implications were asked to submit those policies. One hundred twenty-six centers (82%) responded to the survey; of these, 81 (64.3%) answered questions from the public. There were no significant differences in characteristics between centers that did and did not respond to public calls. The case analyses, completed only by pharmacists in centers that responded to public calls, covered such issues as invasion of privacy, social responsibility, personal liability, and interference with the patient-physician relationship. Respondents exercised a wide degree of discretion in determining if they would answer a question; for example, while only 4% would not answer a question concerning the efficacy of a weight-loss diet patch, 77% reported they would not respond to a caller asking for information on drugs that could interfere with the results of a polygraph test. Although respondents often cited institutional policy as the reason for failing to respond to a question, none submitted a copy of such a policy. The pharmacists' responses indicated a high degree of moral and social sensitivity; nonetheless, written policies should be developed to assist drug information center staff members in handling questions that have ethical implications.     

Iris fluorescein angiography and fluorescein gonioscopic photography after implantation of Choyce Mk IX anterior chamber lenses

Patients underwent intracapsular cataract extraction and implantation of a Choyce Mk IX anterior chamber intraocular lens. At fluorescein angiography (FAG) at a mean of 8 months post-operatively, 9 showed leaking from the iridal vessels, and 3 were normal: Three cases were excluded because of factors affecting the iris FAG. At a mean of 37 months 5 still had a slight degree of leakage. No primarily negative iris FAG changed to positive later. Fluorescein gonioscopic photography (FGP) revealed leakage in 29.5% of the tips of the foot plates at a mean of 37 months. No correlation was observable between FGP and gonioscopy. The pupillary deformation quotient DQ (greatest: smallest pupillary diameter) was significantly greater at a mean of 8 months in the eyes with leakage in iris FAG than in eyes without leakage (P = 0.0145). Individually a change both in direction against normalisation and in elongation was recorded during the observation time.     

A new technique for reconstruction of the common bile duct after severe injury by laparoscopic cholecystectomy

Zusammenfassung Schwere Gallengangsverletzungen sind nach laparoskopischen häufiger als nach konventionellen Cholezystektomien zu beklagen. Sie resultieren meist aus technischen Problemen oder unzureichender Identifikation der entsprechenden Strukturen. Das sofortige Erkennen der Gallengangsverletzung ist fur eine entsprechende Therapie ebenso wichtig wie die ädequate chirurgische Technik, die angewendet wird. Hier wird eine neue Methode der Gallenwegrekonstruktion unter Verwendung eines Jejunalkonduits vorgestellt. Das Verfahren wurde bislang bei 5 Patienten mit schweren Gallengangsverletzungen (Typ 3 and 4 nach Bismuth) [2] nach laparoskopischer Cholezystektomie erfolgreich angewendet. Der Verlauf nach nunmehr 9 Monaten bis zu mehr als 2 Jahren war ohne Probleme and vielversprechend. Die Methode der Anwendung des Jejunalkonduits erscheint uns zur Rekonstruktion bei schweren Gallengangverletzungen sehr empfehlenswert.

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A new technique for reconstruction of the common bile duct after severe injury by laparoscopic cholecystectomy

Laparoscopic cholecystectomy involves a higher incidence of severe common bile duct injury than did open cholecystectomy. The severe injuries most often result from technical problems and inadequate exposure. Reconstruction of the bile duct is then possible provided that an immediate diagnosis is made and an appropriate surgical technique is applied. The report focuses on a new method of reconstruction of the common bile duct by interposition of a small jejunal conduit. The procedure was performed in five patients with severe bile duct injury (Bismuth class 3–4) that occurred during laparoscopic cholecystectomy. The outcome after follow-up periods of 9 months to more than 2 years is promising. This method of reconstruction is therefore recommended for severe forms of bile duct injury.

     

Making a home in the community for the academic medical center.

Academic medical centers (AMCs) have traditionally provided primary care for low-income and other underserved populations. However, they have had difficulty developing lasting partnerships with other organizations serving the same populations. This article describes an exception to the rule, in which an academic division was created at Duke University Medical Center to develop effective collaborations with health care and social service providers in Durham, North Carolina, including both public agencies and private organizations. Together, the division and its partners have created and operate programs that improve health outcomes and access to care for those at risk. These programs share a number of characteristics: they are designed to meet the needs of the patient, not the provider; they are based in the community, not in the AMC; they bring services to people's homes, schools, and neighborhoods; they are multidisciplinary, combining health, social, and even mental health services; and, once established, they are revenue-generating and can be made self-supporting when grant funding ends. These programs are also innovative. They are designed to model and test new ways of organizing and delivering care. Preliminary indications suggest that they also strengthen the AMC's relationships with the surrounding community.     

Mycotic Aneurysm of the Thoracic Aorta Caused by Clostridium septicum

We describe a case of a 78-year-old man who presented with a mycotic aneurysm of the thoracic aorta caused by Clostridium septicum and underwent successful resection. There are only 3 cases of mycotic aneurysms caused by Clostridium septicum reported in the literature. Clostridium septicum infections have been shown to have a high association with gastrointestinal and hematologic malignancies. All patients with Clostridium septicum infections, therefore, require a search for gastrointestinal lesions, as they may represent a source of persistent bacteremia. This patient had no malignant lesions but did have multiple benign sigmoid polyps.     

Reoperative coronary surgery. Comparative analysis of 6591 patients undergoing primary bypass and 508 patients undergoing reoperative coronary artery bypass

During an 18-year period a consecutive series of 6591 patients underwent primary coronary bypass grafting and 508 patients underwent reoperative bypass. The mean patient age for the reoperative group was identical to that of the primary group, 59.8 years, but the mean age at initial operation for the reoperative group was 55.2 years. Mammary grafts were done at initial operation in 59% of patients who have had one operation versus only 46% of patients who subsequently required reoperation (p less than 0.001). The overall operative mortality rate was 2.0% (134/6591) for primary coronary bypass versus 6.9% (35/508) for reoperations (p less than 0.001). Patients with a reoperative interval of 1 to 10 years had a 6.0% (18/312) mortality rate, compared with 17.6% (13/74) for those in whom the interval between operations was greater than 10 years (p less than 0.01). Ventricular arrhythmias, excessive bleeding, prolonged ventilatory support, intraaortic balloon pump insertion (all p less than 0.05), and perioperative myocardial infarction (p less than 0.001) were all more prevalent after reoperations. Including perioperative mortality, the actuarial survival rate at 5 years was 80% for reoperations versus 90% for primary operations. The corresponding figures at 10 years were 65% and 75%. The probability of undergoing reoperation within 5 and 10 years was 0.034 +/- 0.003 and 0.055 +/- 0.005, respectively. Ten years postoperatively, 36% of patients having the initial operation had recurrent angina whereas 58% of the reoperative group had significant recurrent angina. Ten years after reoperation, 30% of operative survivors were free of heart-related morbidity and mortality compared with 50% of patients having a primary operation. Univariate analysis of factors increasing the probability of reoperation include the absence of a mammary graft and younger age at operation. Patients undergoing a second bypass operation represent a substantially higher risk subgroup than patients undergoing initial operation in terms of perioperative morbidity, mortality, decreased long-term survival, and decreased relief of recurrent cardiac morbidity.     

New Potent Azomethine Prodrugs of the Histamine H3-Receptor Agonist (R)-α-Methylhistamine Containing a Heteroarylphenyl Partial Structure

The therapeutic value of histamine H₃-receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H₃-receptor agonist (R)-α-methyl-histamine ( 1 ) a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vitro activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1 , and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino](1H-pyrrol-2-yl)methyl]phenol ( 8c ), the 2-furanyl analogue 8d , and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a ‘retard’ prodrug. Assuming that a therapeutic indication of histamine H₃-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.