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Background: Medication adverse events are important and common yet are often not identified by clinicians. We evaluated an automated telephone surveillance system coupled with transfer to a live pharmacist to screen potentially drug-related symptoms after newly starting medications for four common primary care conditions: hypertension, diabetes, depression, and insomnia., Methods: Cluster randomized trial with automated calls to eligible patients at 1 and 4 months after starting target drugs from intervention primary care clinics compared to propensity-matched patients from control clinics. Primary and secondary outcomes were physician documentation of any adverse effects associated with newly prescribed target medication, and whether the medication was discontinued and, if yes, whether the reason for stopping was an adverse effect., Results: Of 4876 eligible intervention clinic patients who were contacted using automated calls, 776 (15.1%) responded and participated in the automated call. Based on positive symptom responses or request to speak to a pharmacist, 320 patients were transferred to the pharmacist and discussed 1021 potentially drug-related symptoms. Of these, 188 (18.5%) were assessed as probably and 479 (47.1%) as possibly related to the medication. Compared to a propensity-matched cohort of control clinic patients, intervention patients were significantly more likely to have adverse effects documented in the medical record by a physician (277 vs. 164 adverse effects, p < 0.0001, and 177 vs. 122 patients discontinued with documented adverse effects, p < 0.0001)., Discussion: Systematic automated telephone outreach monitoring coupled with real-time phone referral to a pharmacist identified a substantial number of previously unidentified potentially drug-related symptoms, many of which were validated as probably or possibly related to the drug by the pharmacist or their physicians. Multiple challenges were encountered using the interactive voice response (IVR) automated calling system, suggesting that other approaches may need to be considered and evaluated., Trial Registration: ClinicalTrials.gov : NCT02087293.

Background: The bowel purgative Visicol contains microcrystalline cellulose (MCC) residue, which may impair full visibility during a colonoscopy. An MCC residue-free sodium phosphate (RF-NaP; OsmoPrep) tablet was developed., Objective: To investigate appropriate RF-NaP dosing., Design: Phase 2, randomized, investigator-blinded study., Setting: Six research centers in the United States., Patients and Interventions: Patients undergoing a colonoscopy received Visicol (n = 34) or 1 of 6 RF-NaP regimens administered as either split (S) dosing (the evening before and the day of colonoscopy) or evening-only (E) dosing. Dosing regimens for RF-NaP were 40 tablets S, 3 every 15 minutes (n = 33); 40 tablets S, 4 every 15 minutes (n = 34); 32 tablets E, 4 every 15 minutes (n = 34); 32 tablets S, 4 every 15 minutes (n = 36); 28 tablets E, 4 every 15 minutes (n = 34); 28 tablets S, 4 every 15 minutes (n = 34). Visicol was administered as 40 tablets S, 3 every 15 minutes., Main Outcome Measure: Overall colon cleansing (OCC) was assessed by a physician questionnaire (4-point scale, based on colonic contents). An OCC rating of "excellent" or "good" was considered a response. Safety measures were also monitored., Results: Split dosing with RF-NaP was associated with high OCC and achieved response rates of 90%, 97%, and 100% for 28, 32, and 40 tablets, respectively, compared with 86% for Visicol. In addition, RF-NaP evening-only regimen response rates were 90% (32 tablets) and 72% (28 tablets). Transient shifts in electrolyte levels were reduced, and GI adverse events were less common with lower RF-NaP dose regimens., Conclusions: Administration of RF-NaP retains the benefits of a tablet purgative but eliminates MCC issues. Split dosing and 32-tablet evening-only dosing of RF-NaP tablets were efficacious and well tolerated, and split dosing of RF-NaP tablets is recommended.

Background: The tablet formulation of sodium phosphate (NaP) is a prescription osmotic purgative that has been marketed since 2001. The use of NaP tablets in patients with constipation has not been studied previously., Objective: This study assessed the tolerability and efficacy of 28 days of therapy with NaP tablets (1.5 g NaP/tablet) in patients with chronic constipation., Methods: Adults with functional constipation or constipation-predominant irritable bowel syndrome and Z-3 spontaneous bowel movements (BMs) during the 7-day screening/baseline period were eligible for this open-label, dose-ranging study. Patients were randomized to receive starting doses of 4 NaP tablets (group A) or 8 NaP tablets (group B) each morning for 28 days. After a minimum of 48 hours, the NaP dose could be titrated upward (in the case of no BM or no relief of symptoms) or downward (in the case of a predefined excess laxative response) by 2 tablets/d to a minimum of 2 tablets/d or a maximum of 12 tablets/d. Patients kept a diary of their BMs and gastrointestinal symptoms. A serum chemistry panel was obtained weekly. The primary end points were the constipation response (based on the change from baseline in weekly number of BMs) and the global sense response (based on daily scores for the patient's overall sense of change in their bowel problems)., Results: At randomization, there were 18 patients in group A and 25 in group B. Of these, 40 patients (16 group A, 24 group B) had > or 7 days of diary information while taking study treatment and were evaluable for efficacy. The constipation response rate was 100% in group A and 95.8% in group B, and the respective global sense response rates were 68.8% and 79.2%. Four patients in group B withdrew due to adverse events, none of which were serious. Five patients had occasional hypokalemia that required no treatment. Changes from baseline in serum concentrations of calcium, inorganic phosphorus, and potassium were not clinically significant and did not require treatment., Conclusions: In this small study, NaP tablets taken daily were generally well tolerated (particularly in the low-dose group) and produced prompt relief of constipation--generally within the first week of treatment--that was sustained over the 28-day treatment period. A reasonable starting dose appears to be 2 to 4 tablets (3-6 g NaP) daily.

Although it is generally accepted that tumor-bearing patients may be immunosuppressed, the mechanism for this effect is unclear. Therefore, we tested the hypothesis that a tumor-associated macromolecule, carcinoembryonic antigen (CEA), could itself suppress lymphocyte function, as quantitated by uptake of [3H]thymidine by lymphocytes stimulated with the plant lectin, phytohemagglutinin. Normal human peripheral blood mononuclear cells, after exposure to CEA for 48 hr, subsequently released a factor in vitro which markedly inhibited phytohemagglutinin-stimulated lymphocytes. In further experiments, this factor release was confirmed to be initiated by CEA and not by a contaminant, and to be induced over a broad range of CEA concentrations (0.2 to 100 ng/ml). Suppression could not be accounted for by factor-associated cytotoxicity toward indicator cells, nor was it secondary to a mixed-lymphocyte reaction, nor could CEA alone (without factor) modulate proliferation. In studies to characterize the factor, its molecular weight was greater than 10,000, its activity was partially denatured by heat and proteases, and the isoelectric point was 3.4. Polyacrylamide gel electrophoresis of an "active" fraction revealed protein bands with molecular weights of 52,000, 77,000, and 171,000. Knowledge of immunomodulatory molecules present in cancer patients may suggest new modalities for therapy.

While reported cases of sulfonamide-induced pancreatitis meet many criteria for an allergic drug reaction, antibody or lymphocyte recognition of the offending drug or its metabolite has yet to be demonstrated. A patient with sulfonamide-induced pancreatitis is reported in whom lymphocytes were stimulated in vitro by sulfamethoxazole, sulfapyridine, and sulfasalazine. Lymphocytes from a normal volunteer were not stimulated. This in vitro lymphocyte recognition of sulfonamides provides further evidence that sulfonamide-induced pancreatitis is an allergic drug reaction.

Evidence from our laboratory indicates that microtubules are involved in the differentiation of the dimorphic, pathogenic fungus Histoplasma capsulatum; therefore, we cloned the tubulin genes from a virulent strain of the organism. We report that the H. capsulatum genome contains a single alpha (TUB1) and a single beta (TUB2) tubulin gene rather than the more typical multigene family which is common in even the simplest eukaryotes. Sequence data from these genes reveal a high degree of nucleotide and protein sequence conservation relative to tubulins from other species. The coding regions of TUB1 and TUB2 contain five and eight intervening sequences, respectively. Field inversion gel electrophoresis of H. capsulatum chromosome-sized DNA fragments indicates that the TUB1 and TUB2 genes are unlinked. Potential regulatory elements common to both genes have been identified in the 5' promoter regions. These elements may direct the coordinate expression of TUB1 and TUB2 during differentiation. The cloning and characterization of alpha and beta tubulin genes from H. capsulatum provides the first description of gene structure in this widely distributed pathogenic fungus. Isolation of the tubulin genes will facilitate future studies of tubulin gene expression during the dimorphic phase transitions and clarify the role of microtubules in the differentiation process.

HeLa cells, which were selected for resistance to actinomycin D on the basis of decreaded penetration of the antibiotic into the cells, were treated with nontoxic concentrations of the polyene antibiotic amphotericin B. In the presence of amphotericin B, the cells became sensitive to the effects of actinomycin D, as demonstrated by loss of cell viability, typical morphological changes, and effects on the pattern of RNA synthesis. Furthermore, we were able to demonstrate that amphotericin B increased the amount of (3H)actinomycin D incorporated into HeLa cells as determined by both radioactive counts and radioautography. Amphotericin B might be useful in overcoming the resistance is based on decreased entry of the agents into cells.

The possible role of nerve on growth of embryonic parenchymal organs such as kidney was explored by measuring macromolecular synthesis (DNA, RNA, and protein and three enzymes) in aggregates of mixed suspensions of cells from dissociated chick embryo kidney and nerve tissue. One and one-half to threefold increments in net synthesis of the three different types of macromolecules were observed in the mixed aggregates of kidney and nerve cells as compared with those of single organs or mixtures of kidney with nonneural cells. The addition of nerve-growth factor (NGF) did not significantly affect the results. Increased incorporation of label was paralleled by increases in chemically measured DNA and protein, suggesting an increase in growth in the mixed kidney-nerve aggregates compared with those of single tissues. Measurements of survival rate did not indicate increased cell stability in the mixed aggregates. The activities of three enzymes, acid phosphatase, alkaline phosphatase, and lactic dehydrogenase, were also enhanced two to four times in cultures of kidney plus nerve cells. Morphologic studies indicated a high degree of reorganization of tubular structures within the reaggregates of kidney cells alone or in those mixed with nerve. In addition, radioautographs of thymidine-(3)H-labeled cells in the aggregates showed a high level of DNA synthesis in the reformed tubular cells. Electron micrographs revealed the presence of large numbers of nerve fibers containing microtubules in the mixed cell aggregates. The data suggest a significant role for nerve in the growth processes of embryonic parenchymal organs.