Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.     

Efficacy of bicozamycin in preventing traveler's diarrhea

Bicozamycin was compared with a placebo in a prospective, randomized, double-blind study of the prevention of acute diarrhea among 30 American travelers newly arrived in Guadalajara, Mexico. None of the 11 subjects given bicozamycin orally for 3 wk at a dosage of 500 mg four times a day developed diarrhea as compared with an incidence of 53% diarrhea (10 of 19 subjects) in the placebo group (p = 0.003). Bicozamycin was well tolerated. Studies of changes in predominant aerobic fecal flora among the 11 subjects treated with bicozamycin showed the appearance of only one highly resistant Citrobacter freundii at the end of 1 wk of therapy and only a total of six resistant isolates at the end of 3 wk. All resistant isolates failed to transfer this resistance to a recipient Escherichia coli. Bicozamycin seems to be well suited and safe as a prophylactic agent against traveler's diarrhea.     

Patient perspectives on de‐simplifying their single‐tablet co‐formulated antiretroviral therapy for societal cost savings

Objectives

The incremental costs of expanding antiretroviral (ARV) drug treatment to all HIV‐infected patients are substantial, so cost‐saving initiatives are important. Our objectives were to determine the acceptability and financial impact of de‐simplifying (i.e. switching) more expensive single‐tablet formulations (STFs) to less expensive generic‐based multi‐tablet components. We determined physician and patient perceptions and acceptance of STF de‐simplification within the context of a publicly funded ARV budget.

Methods

Programme costs were calculated for patients on ARVs followed at the Southern Alberta Clinic, Canada during 2016 (Cdn$). We focused on patients receiving Triumeq® and determined the savings if patients de‐simplified to eligible generic co‐formulations. We surveyed all prescribing physicians and a convenience sample of patients taking Triumeq® to see if, for budgetary purposes, they felt that de‐simplification would be acceptable.

Results

Of 1780 patients receiving ARVs, 62% (n = 1038) were on STF; 58% (n = 607) of patients on STF were on Triumeq®. The total annual cost of ARVs was $26 222 760. The cost for Triumeq® was $8 292 600. If every patient on Triumeq® switched to generic abacavir/lamivudine and Tivicay® (dolutegravir), total costs would decrease by $4 325 040. All physicians (n = 13) felt that de‐simplifying could be safely achieved. Forty‐eight per cent of 221 patients surveyed were agreeable to de‐simplifying for altruistic reasons, 27% said no, and 25% said maybe.

Conclusions

De‐simplifying Triumeq® generates large cost savings. Additional savings could be achieved by de‐simplifying other STFs. Both physicians and patients agreed that selective de‐simplification was acceptable; however, it may not be acceptable to every patient. Monitoring the medical and cost impacts of de‐simplification strategies seems warranted.

     

Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation

We describe our 9-year experience with lectin-treated T-cell-depleted haplocompatible parental bone marrow transplantation (BMT) for 24 patients with severe combined immunodeficiency disease (SCID). Nineteen of 21 evaluable patients had T-cell engraftment; 2 of 11 patients tested had B-cell and monocyte engraftment. Fourteen of 24 (58%) patients are alive 7 months to 9.8 years post-BMT. Seventeen of 24 patients received pretransplant conditioning with chemotherapy and/or total body irradiation, and 8 of 24 received more than one transplant. Patients who received conditioning had a survival rate of 61% versus 57% for those who received no conditioning. None received graft-versus- host disease (GVHD) prophylaxis and no patient had acute or chronic GVHD greater than grade I. Kinetics and follow-up of immune recovery were analyzed in 14 patients who are greater than 1 year from transplant. Half of the patients showed evidence of T-cell function by 3 months and normal T-cell function by 4 to 7 months post-BMT. On average, T-cell numbers and subsets became normal 10 to 12 months posttransplant. Recovery of B-cell function was more delayed, although in most patients B-cell numbers and IgM levels were normal by 12 months post-BMT. B-cell function, as determined by isohemagglutinin titers or specific antibodies to pneumococcal polysaccharide, keyhole limpet hemocyanin, or tetanus toxoid, became normal in 10 of 14 patients 2 to 8 years post-BMT. Seven of the 14 are off gammaglobulin therapy. Production of isohemagglutinins tended to predict recovery of antibody response to pneumococcal polysaccharide (P < .064). Based on these results, we believe that haplocompatible BMT is an effective, curative treatment for patients with SCID who lack an HLA-matched related donor.     

Characterization of primitive subpopulations of normal and leukemic cells present in the blood of patients with newly diagnosed as well as established chronic myeloid leukemia

Elevated numbers of primitive Philadelphia chromosome-positive (Ph+) progenitors, including long-term culture-initiating cells (LTC-IC) as well as colony-forming cells (CFC), have been previously described in the blood of patients with chronic myeloid leukemia (CML) in chronic phase with high white blood cell counts. In the present study, which focused primarily on an analysis of circulating progenitors present in such patients at diagnosis, we discovered the frequent and occasionally exclusive presence of circulating normal (Ph-) LTC-IC, often at levels above those seen for LTC-IC in the blood of normal individuals. The presence of detectable numbers of circulating Ph- LTC-IC was independent of the fact that the same peripheral blood samples also contained elevated numbers of predominantly or exclusively Ph+ CFC. Interestingly, both the Ph+ and Ph- LTC-IC in these samples were CD34+CD71- and variably CD38- and Thy-1+, as previously documented for LTC-IC in normal marrow. Thus, neither CD38 nor Thy-1 expression was useful for discriminating between Ph+ and Ph- LTC-IC in mixed populations. Nevertheless, an association of these phenotypes with LTC- IC function did allow highly enriched (> 5% pure) suspensions of either Ph+ or Ph- LTC-IC to be obtained from selected samples of CML blood in which the initial LTC-IC population was either predominantly Ph+ or Ph- , respectively. These findings suggest that the mechanisms causing mobilization of leukemic stem cells in untreated CML patients may affect their normal counterparts. They also indicate a possible new source of autologous cells for the support of intensive therapy of CML patients. Finally, they provide a method for obtaining the most highly purified populations of Ph+ LTC-IC described to date. This method should be useful for further analyses of the molecular activities of these very primitive neoplastic cells.     

Recommendations from GESIDA/SEFH/PNS to improve adherence to antiviral treatment (2004)

Since the early days of antiretroviral therapy, adherence has emerged as the milestone of success; in fact, it is the most potent predictor of effectiveness. The main factors related to adherence include the complexity of the therapeutic regimen, adverse effects, psychological problems, alcoholism and active addiction to drugs, lack of social and family support and the patient's beliefs and attitudes about the treatment. Adherence monitoring should be part of the HIV patient's regular care, and should be done with feasible, easily applied methods adapted to the different clinical settings. The minimally acceptable measures should include use of a validated questionnaire, together with data from the Pharmacy Department's drug dispensation registry. All patients that begin HAART or undergo a change of treatment should participate in a treatment education program imparted by health professionals with knowledge and experience in the management of patients with HIV infection. The health team (doctors, pharmacists and nursing professionals) should offer maximum availability to solve the doubts and problems that may occur during treatment. When sub-optimal adherence is detected, intervention strategies based on psychological therapy, educational efforts and personal advice should be attempted, in order to adapt the treatment scheme to the patient's habits and provide solutions to the problem of non-compliance. In certain situations, co-morbid conditions will also require attention. Treatment adherence, being a multidimensional problem, needs a multidisciplinary team approach. The choice of therapy, only one aspect of the multidimensional problem of adherence, must be a careful and individualized decision; however, simpler regimens with regard to the number of pills and daily dose are desirable.     

Down-regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas-mediated apoptosis

OBJECTIVE: Hyperplasia of fibroblast-like synoviocytes (FLS) contributes to chronic inflammation and joint destruction in rheumatoid arthritis (RA). FLICE-inhibitory protein (FLIP) is an antiapoptotic protein that might prevent apoptotic elimination of FLS in response to death ligands such as tumor necrosis factor alpha (TNFalpha) or Fas ligand, which are present in RA synovium. Previous studies on FLIP expression by osteoarthritis (OA) and RA FLS have shown variable results, and the specific role of FLIP as an apoptosis inhibitor in these cells remains unclear. We undertook this study to investigate the expression and antiapoptotic function of FLIP in FLS. METHODS: We studied the expression of FLIP by immunohistochemistry and immunoblotting in synovial tissues or cultured FLS from RA and OA patients. FLS apoptosis was induced by an agonistic anti-Fas monoclonal antibody and FLS were then quantified. We studied the effects of cycloheximide (CHX), TNFalpha, and FLIP antisense oligonucleotide on FLIP expression and FLS apoptotic susceptibility. RESULTS: FLIP(L) was the isoform mainly expressed in lining synoviocytes and cultured FLS. Synovial tissues and cultured FLS from OA and RA tissues displayed similar patterns and levels of expression of FLIP. Fas-induced apoptosis was variable in different FLS lines, but differences between OA and RA groups were not detected. TNFalpha induced increases in FLIP(L) and FLIP(S) expression and protected RA FLS from apoptosis, while CHX induced the opposite effects. Down-regulation of FLIP by antisense oligonucleotide strongly sensitized RA FLS to Fas-mediated apoptosis. CONCLUSION: Apoptosis susceptibility and FLIP expression are similar in OA and RA FLS. Down-regulation of FLIP sensitizes RA FLS to Fas-mediated apoptosis and may be a valuable tool for targeting RA FLS hyperplasia.     

Platelet glycoproteins IIb and IIIa as a calcium channel in liposomes

Human platelet membrane glycoproteins IIb and IIIa (GPIIb and IIIa) were incorporated into phospholipid vesicles by the reverse-phase technique to assess the ability of GPIIb and IIIa to function as a Ca2+ channel. Movement of Ca2+ across the lipid bilayer was quantitated by injection of proteoliposomes with encapsulated Fura-2 into Ca2+ buffers and measurement of Fura-2 fluorescence as an indicator of Ca2+ influx. Reciprocally, to assess the function of proteins in an inside-out orientation, Ca2+-loaded vesicles were injected into Ca2+-free buffer and Ca2+ efflux monitored by a calcium electrode. Incorporation of the IIb-IIIa complex produced significant facilitation of Ca2+ movement across the lipid bilayer. No net transmembrane Ca2+ movement was seen with dissociated IIb and IIIa. Movement of Ca2+ was proportional to the transmembrane Ca2+ gradient. Ca2+ movement into the vesicles was inversely proportional to extravesicular NaCl from 25 to 150 mmol/L, analogous to several studies in the intact platelet. Adenosine triphosphate had no effect on Ca2+ movement into or out of the vesicles. Specific inhibition of a Ca2+ shift into the vesicles was seen with M148, a monoclonal antibody to IIb/IIIa, while no inhibition was observed with a panel of other anti-IIb/IIIa monoclonal antibodies. This suggests that a specific site on the complex or orientation of the complex is essential for calcium channel function. These data demonstrate that the GPIIb/IIIa complex can serve as a passive Ca2+ channel across a phospholipid bilayer and has the potential to play a role in Ca2+ flux across the platelet plasma membrane.