Retrometabolic approaches for drug design and targeting

Retrometabolic drug design approaches incorporate targeting and metabolic considerations into the drug design process and represent a novel, systematic methodology for the design of safe, localized compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Brain-targeted delivery of different agents like estradiol or AZT was successfully achieved, and recent progresses include delivery of peptides using a complex strategy designated as molecular packaging. Sequential site- and stereospecific enzymatic activation of oxime/alkoxime precursors of beta-adrenergic antagonists allows their eye targeted delivery. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Many examples are available to illustrate soft drug design, e.g., soft anticholinergics, soft b-blockers, soft antiinflammatory steroids. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on molecular size/shape, electronic properties, predicted solubility/partition properties, and atomic charge distributions. Recent developments in the field are presented in a supplement to this issue.     

Renal drug targeting using a vector "alkylglycoside"

Cirrhosis and portal hypertension may be associated with pulmonary hypertension and pulmonary dysfunction. However, morphological pulmonary vascular lesions in patients with cirrhosis have not been well characterized morphometrically. We morphometrically evaluated pulmonary vessels in liver transplant recipients with pretransplantation cirrhosis and correlated our findings with pretransplantation cardiopulmonary function, postoperative course, and postmortem cardiopulmonary findings. Autopsy lung slides from 23 transplant recipients with pretransplantation cirrhosis were examined. External vessel diameter, intimal thickness, and arterial medial thickness were measured with a micrometer after pentachrome staining. The percent of total diameter comprised by intima or media was calculated for each vessel. Medical records were reviewed for smoking history, pretransplantation cardiopulmonary function testing, and postoperative course. Autopsy cases without liver or significant cardiopulmonary diseases, matched for age, sex, and smoking history, served as controls. Transplant recipients had significantly more pulmonary venous intimal thickening than matched controls (P <.0001). Sixty-five percent (15 of 23) of these patients had some degree of pretransplantation pulmonary dysfunction, defined by abnormalities in pulmonary function tests, oxygen saturation, and/or increased pulmonary artery pressures. However, the severity of venous intimal thickening did not correlate with the severity of pretransplantation pulmonary dysfunction. Arterial intimal and medial thickness were not statistically significantly different from controls. Pulmonary venous intimal thickening and resultant luminal impingement are morphological findings not previously described in this population. The arterial lesion, when present, is similar to that seen in pulmonary hypertension from other causes. These pulmonary vascular lesions may be implicated in pulmonary dysfunction in patients with cirrhosis and may be associated with increased posttransplantation cardiopulmonary morbidity and mortality.     

Colonic anastomoses. Methods compared

The authors used Bar-Valtrac for 18 months to perform colic anastomoses. To weigh up the effectiveness of this method they compare manual, Stapler and Bar-Valtrac anastomoses performed in this period. They examined 169 anastomoses in the same number of patients being careful of complications, post-operative canalizing, periods in hospital. It is clear that Bar-Valtrac is a good alternative to the stapler and to manual anastomoses because it is done in a way that doesn't determine anastomotic foreign body reactions and consequently reduces stenotic complications. The limit of this method is the great difficulty in performing low and very low colo-rectal anastomoses. Actually, to perform low and very low anastomoses, the authors prefer to use the Stapler that offers higher probabilities of recovery without complications and higher speed of carrying out.     

Colonic involvement in ileal Crohn's disease

OBJECTIVES: To determine the risk and predictive factors for colonic extension in patients with ileal Crohn's disease. METHODS: One hundred and fifty patients with ileal Crohn's disease and no specific colonic lesions on initial colonoscopy were studied retrospectively (median follow-up: 51 months). RESULTS: Twelve patients (8%) developed colonic lesions. Ten-year cumulated risks (95% confidence interval) for colonic extension were 17.2% (range: 5.8-28.6) in the whole group, and 22.4% (range: 8.7-36.1) in the group of 86 patients with repeated colonoscopy. Young age at diagnosis was the only factor predicting colonic extension. Seven patients with colonic extension required immunosuppressive therapy but none underwent surgery. CONCLUSION: Ileal Crohn's disease has a low tendency for colonic extension. Colonic extension has no major prognostic implications.     

Colonic ischemic necrosis following therapeutic embolization

Transcatheter embolization of the middle colic artery for diverticular bleeding was followed by ischemic necrosis in the transverse colon at the site of previous anastomosis and stricture formation. This is a potential complication of intra-arterial embolization for colonic bleeding.     

Colonic ganglioneuroma presenting as filiform polyposis

Hypereosinophilia is a rare manifestation of cancer. We reported four cases of tumor-associated hypereosinophilia. These cases presented with peripheral hypereosinophilia and disseminated metastatic malignancies. All cases were male, including two cases with cancer of unknown primary site, one with hepatocellular carcinoma, and one with a liver tumor. The age ranged from 27 to 55 years. They all had liver involvement. Two cases had bone marrow metastases. The leukocyte counts ranged from 78,600/microliters to 190,000/microliters. The percentage of eosinophils ranged from 20% to 77%. The eosinophil counts ranged from 15,720 to 126,350/microliters with a mean of 74,700/microliters. The first three cases died within 8 days after the malignancies were pathologically confirmed. We suggest that peripheral hypereosinophilia is a poor prognostic sign which is frequently associated with disseminated cancer.     

Colonic motor activity in women during sleep

Regulators of G-protein signalling (RGS) are recently identified proteins that shorten the lifetime of the activated G protein. We now show that rat cardiac myocytes express mRNA for at least 10 RGS. The mRNA for RGS-r is barely detectable in rat ventricles, but increases more than 20-fold during the 60- to 90-min process of isolating ventricular myocytes, and after 90 min of culture of atrial pieces in medium with Ca2+. Both in myocytes and in atria, the rise in RGS-r is transient. The mRNA for cardiac RGS5, but not RGS-r, is developmentally regulated. These studies suggest that rapid regulation of RGS levels may be a new mechanism that governs how signals are transmitted across the cardiac cell membrane.     

Colonic anastomosis-a new approach: preliminary report

A case of fetal death from abruptio placentae is reported in which the placenta was the seat of multiple chorangiomata. This association is believed not to have been fortuitous and a possible mechanism is suggested by which chorangioma may contribute to the pathogenesis of placental abruption. The incidence, morphological variation and clinical manifestations of placental chorangiomata are briefly discussed.     

Drug targeting using low density lipoprotein (LDL): physicochemical factors affecting drug loading into LDL particles

Low density lipoprotein (LDL) has been found suitable as a targeting carrier for cytotoxic drugs. However, higher drug loading into LDL particles without disrupting their native integrity remains a major obstacle. The purpose of this study is to investigate the different physicochemical factors that may affect drug loading and to characterize LDL-drug conjugates. Doxorubicin (Dox) and 3', 5'-O-dipalmitoyl-5-iodo-2'-deoxyuridine (dpIUdR) were used as reference cytotoxic drugs. Drugs were loaded into LDL particles using the dry film method with or without surfactants, liposomal and the direct addition method. The effects of incubation temperature, time and stoichiometry of LDL-drug conjugates on drug loading were investigated. The LDL-drug conjugates were evaluated for their stability and characterized by differential scanning calorimetry (DSC), denatured gel (SDS-PAGE), and electron microscopy (EM). We have suitably incorporated 45+/-10 Dox and 150+/-25 dpIUdR molecules/LDL particle. A seven-fold increase in Dox incorporation was achieved with the liposomal preparation compared to the dry film method. A 4- to 6-h incubation at 37 degreesC was suitable to restore the native structure of LDL particles. No apo B fragmentation of LDL particles was noted on denatured gel. DSC studies showed no change in the Tm of the LDL and the LDL-drug conjugates. An increase in particle size of LDL-dpIUdR, not LDL-Dox was observed in EM compared to the native LDL which may be related to higher incorporation of dpIUdR. The results indicate that physicochemical factors significantly affect drug loading efficiency and may need to be considered to optimize drug incorporation into LDL particles.     

Colonic strictures in children with cystic fibrosis

PURPOSE: To determine the radiographic, clinical, surgical, and histologic findings in children with cystic fibrosis who develop strictures of the colon. MATERIALS AND METHODS: Ten children (five boys, five girls; age range, 2.5-9.0 years; mean age, 5.5 years), who were treated at the practices of the authors, were retrospectively identified and their medical records reviewed. RESULTS: Radiographic manifestations of the colonic disease included mucosal irregularity and spiculation with nodular thickening of the colonic wall and loss of normal colonic haustration. Luminal narrowing involved long segments of the colon. Longitudinal shortening of the colon was also a prominent feature. The decrease in caliber of the bowel ranged from mild narrowing to complete occlusion of the lumen. Histologic examination revealed severe submucosal fibrosis and fatty infiltration with transmural extension of the fibrosis to involve the serosa in some cases. Unlike in Crohn disease, however, acute inflammatory changes were minimal or absent. CONCLUSION: Colonic stricture in children with cystic fibrosis is due to irreversible and frequently progressive narrowing of the colonic lumen.     

Colonic atresia secondary to a choledochal cyst

Colonic atresia and choledochal cyst are both uncommon congenital abnormalities. We report a case in which the two conditions coexisted and propose an aetiological link.