Disposition of Tablet and Capsule Formulations of Digoxin in the Elderly

Study Objective . To compare digoxin tablets and liquid-filled capsules with respect to excretion of the drug and its metabolites in urine and feces at steady state. Design . A randomized, crossover trial, each period lasting 3 weeks, with no washout period. Setting . A university hospital. Patients . Six patients, five of whom were elderly, with histories of gastrointestinal disorders, such as hypochlorhydria, intestinal bacterial overgrowth, and inflammatory bowel disease. Interventions . The patients received digoxin once/day in either tablet or capsule form for 3 weeks, and then were switched to the other formulation. Total urinary and fecal excretion from the last 3 days of each regimen were analyzed for the drug and metabolites. Measurements and Main Results . No statistically significant differences were found between tablets and capsules in recovery of digoxin or its metabolites in urine or feces (p=0.05). One subject had a 4-fold increase in urinary drug excretion and 50% decrease in fecal excretion after taking the capsules compared with tablets. Intersubject variability in extent and type of metabolite excretion was greater than intrasubject variability. Conclusions . Fecal analyses may be an accurate way to classify patients as formers of digoxin reduction products.     

The rhomboid flap for pilonidal disease

Introduction There have been many surgical techniques described for the treatment of pilonidal sinuses. Recurrent disease causes significant morbidity particularly with time from work. Aim To assess the rhomboid flap's role in promoting one‐stage primary healing in pilonidal disease and to evaluate the morbidity and recurrence. Methods Fifty‐three patients were prospectively recruited of which 27 had previous multiple abscess formation requiring surgical drainage from their pilonidal disease, although none had acute disease at the time of surgery. By using the transposition flap, we were able to obliterate the natal cleft and therefore the rolling action of the buttocks between the cleft in these patients and thereby remove one of the factors involved in pilonidal disease. Hospital stay, healing time, wound infection, wound breakdown and recurrence were noted. Results There were 47 males and 6 females with a median age of 28 years (range 16–64 years). Median follow‐up was 24 months (range 3–36 months). Post‐operative morbidity involved superficial wound infection in 7 (13%) which settled with out‐patient dressings. There were four recurrences (7%), two occurred between the flap and the anal canal, and the other two in the flap margin needing intervention. All the patients healed their wounds and the median healing time was 14 days. Conclusion As this condition affects a predominantly young population causing significant time off from work, we feel that the Rhomboid Flap is useful for difficult cases in that it allows early return to full activity and does not necessitate prolonged postoperative care.     

The transformation-related protein p53 is not bound to the SV40 T antigen in BALB 3T12 cells expressing T antigen

In most murine cells transformed by the SV40 virus, virtually all of the cellular phosphoprotein p53 is in a complex with the SV40 T antigen. Here, we report that, in SV40-infected T-antigen-positive Balb 3T12 mouse cells, most (approximately 80%) of the p53 is not in complex. Complex formation was determined by measuring the amounts of [35S]methionine-labeled p53 which coprecipitated with T antigen when using monoclonal antibody to T antigen. The amount of complex formation was expressed as a percentage of total p53 present, measured by the amount of p53 precipitated with the monoclonal antibody to the p53. The values were confirmed by Western blotting procedure, in which the steady-state levels of the proteins were measured. In these measurements after complete precipitation with antibody to T antigen, the residual p53 in the supernatant was precipitated by antibody to p53, and this amount was denoted as free p53. There was no significant difference seen between the [35S]methionine-labeled tryptic peptides of complexed and the free p53 (or between complexed and free T antigens) as determined by two-dimensional gel electrophoresis and chromatography. Virus rescue experiments and retransformation by the rescued virus showed that there was no mutation in the SV40 DNA coding for the T antigen which could account for the lack of complex formation. Both p53 and T antigen were underphosphorylated in cells which exhibited reduced complex formation. Tumorigenicity in syngeneic mice and anchorage-independent cell growth in culture of various cloned mouse cells with or without T antigen expression was compared. The changes in the biologic properties were explainable solely on the basis of known or expected effects of expression of the T antigen and were independent of complex formation or of absence of complex formation between p53 and T antigen.     

Characterization of the murine H2–M3wt-restricted CD8 response against a hydrophobic, protease-resistant, phospholipid-associated antigen from Listeria monocytogenes

Summary: Mice infected with Listeria monocytogenes (LM) generate protective CD8 cells of varying specificity. One subset, unlike conventional LM-immune CDS cells, can respond to antigen-presenting cells (APC) treated with heat-killed LM (HKLM), These cells proved to have surprisingly uniform specificity, recognizing a product we designated HKLM-associated antigen (HAA) presented by the non-classical dass Ib product H2–M3'. HAA proved to be extremely hydrophobic and the bioactive portion of the molecule was highly protease-resistant, leading us initially to speculate that it might be a non-peptide. Recent studies, however, identify HAA as a complex containing lemA, a listerial protein bearing the immunogenic amino terminal peptide sequence fMIGWII, tightly associated with bacterial cardiolipin. A variety of cell types can process and present exogenous HAA/lemA. and the phospholipid component appears essential for this processing. Endosomal acidification and proteolysis are required for processing, but the site where antigen binds to H2–M3^wt within APC remains uncertain. HAA/lemA-immune effectors are unusually cross-reactive. We could readily detect H2–M3^wt-restricted responses to APC incubated with unrelated N -formylated peptides, and bacteria, HAA-like products represent an intriguing new set of bacterial antigens recognizable by immune CD8 cells.     

Biochemical mechanisms for the scheduled synergism of (αS, 5S)-2 amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid and 5-fluorouracil in P388 leukemia

Summary A study was made of the in vivo effects of equitoxic doses of AT-125 and 5-FU combination, being administered either simultaneously (% ILS 152) or with a 6-h pretreatment with AT-125 (% ILS 184). To examine the biochemical basis for the scheduled synergism, measurements were made of the concentration of PRPP, the specific activities of CPS II, cytidine, thymidine, uridine, deoxyuridine kinases, and fluorinated nucleotide formation in P388 tumors and the small intestine. Two hours after in vivo simultaneous treatment of mice bearing tumors the concentration of PRPP increased 9- and 6-fold above baseline in the tumor and the small intestine, respectively. In the AT-125 pretreatment arm the concentration of PRPP increased 18- and 7-fold above baseline in the tumor and the small intestine, respectively. CPS II activity was reduced to 28%–18% of control in the tumors in the simultaneous and pretreatment groups, respectively, whereas it remained unchanged in the small intestine. Specific activities of cytidine kinase (5.5±1), thymidine kinase (4.0±1.6), uridine kinase (35.6±6.5), and deoxyuridine kinase (2.4±1.1) nmol/mg protein/h remained unchanged with treatment. In concert with the increased intratumor concentration of PRPP, fluorinated nucleotide formation was proportionally increased in the treatment arms. These results indicate the importance of drug scheduling of the above two agents in treating P388 leukemia.Abbreviation AT 125 - S,5S -amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid - 5-FU 5-fluorouracil - 5-FdUMP 5-fluorodeoxyuridine monophosphate - PRPP phosphoribosyl pyrophosphate - 5-FUMP 5-fluorouridine monophosphate - 5-FUDP 5-fluorouridine diphosphate - 5-FUTP 5-fluorouridine triphosphate - UMP uridine monophosphate - UDP uridine diphosphate - UTP uridine triphosphate - ATP adenosine triphosphate - CPS II carbamylphosphate synthetase II - PCA perchloric acid Presented in part at the Seventy-fourth Annual Meeting of the American Association for Cancer Research, San Diego, California, May 1983     

A comparative study of portal vein embolization versus radiation lobectomy with Yttrium-90 micropheres in preparation for liver resection for initially unresectable hepatocellular carcinoma

BackgroundPortal vein embolization before liver resection is considered the therapy of choice for patients with inadequate future liver remnants. The concept of radioembolization with Yttrium-90 to achieve the same goal has limited data.MethodsWe retrospectively compared patients who underwent portal vein embolization and Yttrium-90 lobectomy before resection of hepatocellular carcinoma in patients with chronic liver disease.ResultsSeventy-three patients underwent portal vein embolization and 22 patients underwent Yttrium-90. Forty-seven percent of patients before portal vein embolization required additional procedures for tumor control, and 27% of patients after Yttrium-90 required additional procedure to mainly induce further hypertrophy. Both therapies achieved the goal of future liver remnants >40%, but the degree of hypertrophy was significantly higher in Yttrium-90 patients (63% for Yttrium-90, 36% for portal vein embolization, P < .01). Tumor response was significantly better with Yttrium-90, achieving complete response in 50% of patients. Resectability rate was higher after portal vein embolization (85% for portal vein embolization, 64% for Yttrium-90, P = .03). Tumor progression was the most common reason precluding surgery. Complete tumor control was the reason not to pursue surgery in 18% of patients after Yttrium-90.ConclusionBoth preoperative portal vein embolization and Yttrium-90, increases liver resectability rates by inducing hypertrophy of future liver remnants in patients with hepatocellular carcinoma and chronic liver disease. Yttrium-90 lobectomy achieved better tumor control and provided more time to assess therapy response, optimizing the indication for surgery.     

Anticarcinogenic effect of bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione a curcumin analog on DMH-induced colon cancer model.

1,2-Dimethylhydrazine (DMH) is a toxic environmental pollutant which was reported also to be a colon-specific carcinogen. This study was performed to study the effect of bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione, a bisdemethoxycurcumin analog (BDMC-A) on DMH-induced colon carcinogenesis in male Wistar rats and effects were compared with that of the reference drug, curcumin. Rats were given a weekly subcutaneous injection of DMH (20mg/kg body weight) in the groin, for 15 weeks. After a total experimental period of 32 weeks (including 2 weeks of acclimatization) tumor incidence was 100% in DMH-treated rats. Tumor was identified histologically as adenocarcinoma. Dysplasia, papillary pattern, cellular pleomorphism and carcinomatous glands were also noticed in DMH-treated rats. However, there was no colonic tumor in DMH+BDMC-A- and DMH+curcumin-treated rats but, lymphocyte infiltrations were observed. The levels of total bile acids and cholesterol in 24h fecal samples were significantly lower in DMH administered rats when compared to control rats, while, the excretion of bile acids and cholesterol were significantly increased and was near normal levels in DMH+BDMC-A- and DMH+curcumin-treated rats. In DMH-induced tumor bearing rats the levels of colonic and intestinal cholesterol was significantly increased whereas, the levels of phospholipid was decreased with a concomitant increase in the activities of phospholipase A (PLA) and phospholipase C (PLC), compared to untreated control rats. Intragastric administration of BDMC-A and curcumin to DMH administered rats significantly lowered the cholesterol content and raised the phospholipid content and lowered the activities of PLA and PLC towards near normal values. Our study shows that the protective effect of BDMC-A during DMH-induced colon carcinogenesis may be due to its modulatory effects on (i). histological changes, (ii). bile acids, (iii). cholesterol, and (iv). phospholipid metabolism in the target organ. Absence of histological changes in the colon of rats treated with BDMC-A, shows that long term administration of BDMC-A is nontoxic to experimental animals. Our study suggest that BDMC-A may emerge as a potent anticarcinogenic agent against colon cancer. As both BDMC-A and curcumin are equipotent in inhibiting the DMH-induced colon tumor incidence and normalizing histological changes, it could be concluded that the terminal phenolic group and the conjugated double bonds in the central seven carbon change may be responsible for the beneficial effects.     

An Integrative Model of Subcortical Auditory Plasticity

In direct conflict with the concept of auditory brainstem nuclei as passive relay stations for behaviorally-relevant signals, recent studies have demonstrated plasticity of the auditory signal in the brainstem. In this paper we provide an overview of the forms of plasticity evidenced in subcortical auditory regions. We posit an integrative model of auditory plasticity, which argues for a continuous, online modulation of bottom-up signals via corticofugal pathways, based on an algorithm that anticipates and updates incoming stimulus regularities. We discuss the negative implications of plasticity in clinical dysfunction and propose novel methods of eliciting brainstem responses that could specify the biological nature of auditory processing deficits.     

Enhancing the Reliability in the Noninvasive Measurement of the His Bundle Magnetic Field Using a Novel Signal Averaging Methodology

Background: Extraction of the weak electrical activity of the “His Bundle” (HB) by noninvasive methods has not been very successful in the past. The study reassesses the use of signal averaged magnetocardiography (SAMCG), overcoming some of the limitations in earlier studies including in the signal averaging methodology. Methods: SAMCG on healthy subjects (14 male and 1 female) were performed using R‐peak as the fiducial point in all cases and also using QRS‐onset as the fiducial point in select cases. Results: A conspicuous feature (H) with a magnitude up to 200 femto Tesla (fT) attributed to the HB activity was observed in the PR segment at several spatial positions on the thorax, with onset at 35–50 ms before the QRS‐onset (V) in 15 out of 18 trials constituting 83% of cases studied. The QRS‐onset as the fiducial point resolved the feature better compared to the conventionally used R‐peak, especially in trials exhibiting spread in heart rate (HR). This is attributed to the fluctuations in Q_onRD (the time interval between QRS‐onset and R‐peak) compared to the temporal stability of the H‐V duration. Conclusions: SAMCG reveals a well‐resolved H feature. The double hump morphology of the feature extended at least up to a frequency of 150 Hz. The importance of the choice of QRS‐onset as the fiducial point is unequivocally demonstrated, illustrated by measurements on subjects exhibiting considerable heart rate variability. The latter has a general validity and should be applicable to SAECG as well.     

Exosomes expressing the self‐antigens myosin and vimentin play an important role in syngeneic cardiac transplant rejection induced by antibodies to cardiac myosin

Long‐term success of heart transplantation is hindered by humoral and cell‐mediated immune responses. We studied preexisting antibodies to cardiac self‐antigens, myosin and vimentin, and exosomes induced by antibodies to self‐antigens in eliciting immune responses to cardiac grafts. After syngeneic heterotopic murine heart transplantation, rabbit anti‐myosin or normal rabbit immunoglobulin was administered at day 0 or 7. Sera were collected after heartbeat cessation, cellular infiltration was analyzed, and exosomes were isolated from sera. Histopathologic examination of the controls' transplanted hearts demonstrated normal architecture, and their sera demonstrated neither antibodies to self‐antigens nor exosomes expressing self‐antigens. Administration of antibodies to cardiac myosin immediately posttransplantation (day 0) but not on day 7 triggered graft failure on day 7, and histopathologic examination revealed marked cellular infiltration with neutrophils and lymphocytes. Histopathologic examination of rejected hearts also demonstrated myocyte damage as sera had increased antibodies to myosin and vimentin and development of exosomes expressing self‐antigens. Administration of exosomes isolated from failed grafts containing self‐antigens induced graft dysfunction; exosomes isolated from stable mice did not induce graft failure. Antibodies to self‐antigens can induce exosomes containing self‐antigens, initiating an immune response and causing graft failure after cardiac transplantation.