Coronary artery vasospasm causing acute myocardial infarction in a heart transplant recipient.

The etiology of cardiac allograft vasculopathy is not known, but may be preceded by both endothelial cell and smooth muscle dysfunction of the epicardial coronary arteries. We here report a case of acute, reversible coronary artery vasospasm which caused a myocardial infarction in a cardiac transplant recipient. The patient had a complex post-transplant course, including an episode of severe vascular rejection several months before this presentation. Interestingly, the event was captured in its early stages because the patient presented with chest pain: a rare event because of the denervation of the transplanted heart. Our ability to document the etiology of this patient's myocardial infarction supports the concept that cardiac allograft vasculopathy is a progressive disease that, in its early stages, may include a reversible component of abnormal vasoreactivity.     

Different impacts of intestinal lymphatic transport on the oral bioavailability of structurally similar synthetic lipophilic cannabinoids: Dexanabinol and PRS-211,220

The aim of this article was to investigate the role of intestinal lymphatic transport in the oral bioavailability of two structurally similar synthetic lipophilic cannabinoids: dexanabinol and PRS-211,220. For this purpose, the long chain triglyceride (LCT) solubility and affinity to chylomicrons ex vivo of both cannabinoids were evaluated. Their oral bioavailability was assessed in rats following administration in a lipid-free and a LCT-based formulation. The intestinal lymphatic transport of these two molecules was also directly measured in a freely moving rat model. LCT solubility of dexanabinol and PRS-211,220 was 7.9 ± 0.2 and 95.8 ± 5.3 mg/g, respectively. The uptake by chylomicrons was moderate (31.6 ± 5.2%) and high (66.1 ± 2.4%), respectively. The bioavailability of dexanabinol (37%) was not affected by LCT solution, whereas administration of PRS-211,220 in LCT improved the absolute oral bioavailability three-fold (from 13 to 35%) in comparison to the lipid-free formulation. The intestinal lymphatic transport of dexanabinol and PRS-211,220 was 7.5 ± 0.8 and 60.7 ± 6.8% of the absorbed dose, respectively. In conclusion, despite structural similarity and similar lipophilicity, dexanabinol and PRS-211,220 exhibited a very diverse pattern of oral absorption, and the lymphatic system played quite a different role in the oral bioavailability of these molecules. The low lymphatic transport of dexanabinol is likely driven by relatively lower affinity to chylomicrons and lower LCT solubility.     

Conversion of Ouabain-Induced Ventricular Tachycardia in Dogs with Epicardial Lidocaine: Pharmacodynamics and Functional Effects

Epicardial antiarrhythmic drug administration was studied as a therapeutic approach for experimental ventricular tachycardia (VT) in an open-chest dog model. Lidocaine-polyurethane matrices (28%, w/w) were formulated as a model system. Matrices were placed on the left ventricular epicardium in each of 23 anesthetized open-chest dogs with ouabain-induced VT, to evaluate effectiveness in restoring sinus rhythm. Conversion occurred in all animals treated with matrices containing 300 mg or more of lidocaine after 1.5 to 7.0 min. The matrix lidocaine content correlated linearly with the time required for conversion to sinus rhythm (r = 0.75, P = 0.0002); irrespective of matrix size the myocardial/plasma lidocaine ratio was 20.1 ± 4.2 (mean ± SD) at the time of conversion. In a separate series of five dogs without ventricular tachycardia, systolic wall thickening measured with sonomicrometers after 5 min of controlled-release lidocaine administration (500- to 1000-mg matrix lidocaine content, 7.48 ± 3.49-mg/kg dose) was only minimally diminished (–14.1%) and this effect was observed only at the site of matrix placement on the anterior-apical epicardium. In contrast, intracoronary injection of 0.3 or 1.0 mg/kg of lidocaine-HCl resulted in complete elimination of wall thickening or replacement by systolic thinning. Thus epicardial administration of lidocaine from polyurethane matrices was an effective means of treating ouabain-induced ventricular tachycardia. Regional myocardial function in the vicinity of the matrices was modified to a very limited degree, supporting the view that the matrices can be used safely, without serious risk to ventricular contractile performance.     

Iatrogenic diaphragmatic hernia due to laparoscopic gastric banding

A patient developed a huge diaphragmatic hernia following laparoscopic gastric banding. Almost the entire stomach was incarcerated within the left chest. Segmental necrosis of the greater curvature of the stomach necessitated partial gastrectomy. The postoperative course was uneventful. The etiology, diagnosis and treatment of this previously undescribed complication of laparoscopic gastric banding are addressed in relation to the present case.     

The relationship between receptor-effector unit heterogeneity and the shape of the concentration-effect profile: Pharmacodynamic implications

The apparent concentration-effect relationship is the ensemble of many effector units (such as individual cells or channels) that do not always exhibit a uniform stimulus-effect relationship. This concept is substantiated by many observations of heterogeneity in receptor-effector populations including hormone secreting cells, response to hormonal stimuli, activity pattern of second messengers, stimulus-evoked synaptic currents, and single ion channels. The relationship between drug concentration and magnitude of pharmacologic response is commonly described by the sigmoidalE _max model which was derived from the Hill equation. The sigmoidicity factor (N) in this model is assumed to be a pure mathematical parameter without physiological connotations. This work demonstrates that the numerical value ofN (measured empirically) is the product of two factors: (i) the degree of heterogeneity of the effector subunits, i.e., the elemental component that upon drug stimulus contributes its pharmacological effect independently and does not interact with other subunits (it could range from a single receptor up to a whole tissue), and (ii) value ofN ^*—the shape factor of the subunits' concentration-effect relationship. A special case of this approach occurs whenN ^*>5, which is an on-off case. HereN is determined by the distribution (density equation) of the subunit values. In case of heterogeneity of the microparameters of the effector subunits the apparentN will always have a lower value thanN ^*. According to this theory it can be concluded that without knowledge of the distribution of the microparameters no mechanistic interpretation can be deduced from the apparentN value. If in the futureN ^* can be determined by theoretical or experimental methods, the distribution function relatingN ^* toN can be calculated. The relevance of this theory is increased in view of the progress being made in advanced research techniques which may enable us to determine the concentration-effect relationship at the level of the individual effector unit.     

Colonic Drug Delivery: Enhanced Release of Indomethacin from Cross-Linked Chondroitin Matrix in Rat Cecal Content

Pharmaceutical Research -     

A phage display system for detection of T cell receptor-antigen interactions

The process of T cell recognition involves a complex set of interactions between the various components of the TCR/MHC/peptide trimolecular complex. We have developed a system for exploring the specific binding interactions contributed by the constituent subunits of TCR complexes for components of their ligands. We utilized an M13 phage display system, designed for multivalent receptor display, to explore specific binding interactions between various TCRα chains and specific antigen in the absence of MHC. The multivalent TCR-phage display system was sensitive enough to reveal some TCRα chains capable of binding directly to antigen with the same fine specificity shown by the MHC-restricted T cells from which the α chains were derived. Cross-specificity analysis using two antigen-binding TCRα chains derived from T cells with different polypeptide antigen specificities confirmed the fidelity of this binding. In mixtures of antigen-binding and non-binding TCRα-displaying phage, specific selection was achieved at a starting frequency of 1/1000, suggesting that this system can be employed for selection and analysis of TCR-displaying phage libraries. While the binding specificities exhibited by these TCRs are unusual, they provide a novel perspective from which to study the specific binding interactions that constitute TCR antigen binding.     

Increased CD8+ T Cell Apoptosis in Scleroderma Is Associated with Low Levels of NF-κB

Our objectives were (1) to compare lymphocyte subpopulation apoptosis rates in SSc patients versus healthy controls and (2) to compare Bcl-2 and NF-kappa B expression in cultured CD8 lymphocytes of SSc patients versus controls. Peripheral blood samples were obtained from 27 SSc patients meeting the American College of Rheumatology criteria for SSc and 28 healthy individuals. Mononuclear cells were isolated by Ficoll-Hypaque density gradient separation and cultured for 48 hr. For determination of apoptosis within specific cell populations, samples were labeled with PE-conjugated monoclonal antibody to CD8, CD4, and a FITC-conjugated monoclonal antibody to Annexin V. Flow cytometry was carried out with a FACS operating with Cellquest software. CD8+ lymphocytes were positively selected with magnetic microbeads conjugated to antihuman CD8. CD8 T cells were separated, then incubated with activation for 48 hr, and NF-kappa B and Bcl-2 analysis was carried out using Western immunoblotting. The CD4:CD8 ratio was increased in SSc compared to controls (2.6 +/- 1.13 vs.1.87 +/- 0.76; P = 0.018). The spontaneous apoptosis rate of SSc CD8 lymphocytes was increased compared to that of controls of (21.9 +/- 13.7 vs. 13.3 +/- 9.9; P = 0.019). No difference was found in the rate of CD4 apoptosis of SSc patients versus controls (9.8 +/- 5.2 vs. 7.18 +/- 4.89%; P = ns). The expression of NF-kappa B in SSc CD8 lymphocytes was decreased compared with that of CD8 lymphocytes from healthy controls (144 +/- 13 vs. 188 +/- 11; P = 0.018). Whereas expression of Bcl-2 was similar in activated CD8+ T cells of SSc patients and healthy controls, CD8+ T cell apoptosis rate was found to be in reverse correlation with expression of NF-kappa B in these cells ( r = - 0.53, P = 0.029). The increased CD4:CD8 ratio in SSC may result from increased CD8+ T cell apoptosis. Increased SSc CD8 T cell apoptosis is associated with low levels of NF-kappa B.     

ω-123I-Hexadecanoic acid metabolic probe of cardiomypathy

The utility of -¹²³I-hexadecanoic acid myocardial scintigraphy as a metabolic probe of cardiomyopathies was investigated. Sixteen patients with a variety of cardiomyopathies and myopathies that involve cardiac muscle and ten volunteers were imaged in the postabsorptive state in a 40° LAO projection after a standard dose of -¹²³I-hexadecanoic acid. An elimination T_1/2 was calculated from the left ventricular myocardial time-activity curve. An uptake index, corrected for chest wall attenuation, was also computed in 7 of 10 volunteers and 8 of 16 patients.Of the 16 patients, only 2 had distinctly abnormal -¹²³I-hexadecanoic acid myocardial tracer kinetics. The first patient had a metabolic disorder of which cartine deficiency was one component. The second patient had endocardial fibroelastosis, a process which has been linked to disorders which deprive the myocardium of oxygen and energy. Therefore, the cardiomyopathy may have been caused by some abnormality of cardiac metabolism other than carnitine deficiency. Although of limited utility in the overall cardiomyopathic population, -¹²³I-hexadecanoic acid myocardial scintigraphy should be further investigated as a screening test for carnitine deficiency and related metabolic abnormalities in patients at risk.Supported by a Canadian Heart Foundation Research FellowshipSupported by an Australian Heart Foundation Travel Grant