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S MacKinnon

Publications and source records attributed to S MacKinnon.

13 recordsLinked to original sources
PubMed2003

Traditionally-used antimalarials from the Meliaceae.

A quantitative ethnobotanical approach to antimalarial drug discovery led to the identification of Lansium domesticum Corr. Ser. (Meliaceae) as an important antimalarial used by Kenyah Dyak healers in Indonesian Borneo. Triterpenoid lansiolides with antimalarial activity were isolated from the bark and shown to have activity in both in vitro bioassays with Plasmodium falciparum, and in mice infected with P. berghei. A survey of African and tropical American Meliaceae led to further development of the limonoid gedunin from the traditionally used medicinal plants, tropical cedar, Cedrela odorata L., and neem, Azadirachta indica A. Juss. Gedunin has significant in vitro activity but initially showed poor in vivo activity. In vivo activity was improved by (1) incorporation into an easy to absorb suspension, (2) preparation of a more stable compound, 7-methoxygedunin; and (3) synergism with dillapiol, a cytochrome P450 3A4 inhibitor. The results show the potential for both antimalarial drug and phytomedicine development from traditionally used plants.

Antimalarials↗
PubMed2001

Regulation of apoptosis during neuronal differentiation by ceramide and b-series complex gangliosides.

Lipid analysis of gestational day E14.5 mouse brain revealed elevation of ceramide to a tissue concentration that induced apoptosis when added to the medium of neuroprogenitor cells grown in cell culture. Elevation of ceramide was coincident with the first appearance of b-series complex gangliosides (BCGs). Expression of BCGs by stable transfection of murine neuroblastoma (F-11) cells with sialyltransferase-II (ST2) resulted in a 70% reduction of ceramide-induced apoptosis. This was most likely due to an 80% reduced expression of prostate apoptosis response-4 (PAR-4). PAR-4 expression and apoptosis were restored by preincubation of ST2-transfected cells with N-butyl deoxinojirimycin (NB-DNJ) or PD98059, two inhibitors of ganglioside biosynthesis or p42/44 mitogen-activated protein (MAPK) kinase, respectively. In sections of day E14.5 mouse brain, the intermediate zone showed intensive staining for complex gangliosides, but only low staining for apoptosis (TUNEL) and PAR-4. Apoptosis and PAR-4 expression, however, were elevated in the ventricular zone which only weakly stained for complex gangliosides. Whole cell patch clamping revealed a 2-fold increased calcium influx in ST2-transfected cells, the blocking of which with nifedipine restored apoptosis to the level of untransfected cells. In serum-free culture, supplementation of the medium with IGF-1 was required to maintain MAPK phosphorylation and the anti-apoptotic effect of BCG expression. BCG-enhanced calcium influx and the presence of insulin-like growth factor-1 may thus activate a cell survival mechanism that selectively protects developing neurons against ceramide-induced apoptosis by up-regulation of MAPK and reduction of PAR-4 expression.

1-Deoxynojirimycin↗
PubMed2001

CAMPATH-1 antibodies in stem-cell transplantation.

BACKGROUND: CAMPATH-1 (CD52) Abs have been used in stem-cell transplants for the prevention of GvHD and graft rejection. These complications can effectively be prevented by depletion of T lymphocytes from both donor and recipient. However, donor lymphocytes might contribute an anti-leukemia effect and lymphocyte depletion may exacerbate problems with immune reconstitution. There is a fine balance between the risks of GvHD and host-versus-graft reactions, relapse and infection. METHODS: Clinical outcomes for 4264 patients were reported to a central registry and analyzed by univariate and multivariate methods to determine the superior protocols. Various protocols of lymphocyte depletion were tested, using either CAMPATH-1M (IgM) plus complement or CAMPATH-1G (IgG2b) to treat the donor BM ex vivo and CAMPATH-1G in vivo to treat the recipient. The humanized antibody CAMPATH-1H has recently replaced CAMPATH-1G. A meeting of the clinical collaborators was convened to discuss the results and to review the experiences of individual centers. RESULTS: Interest focused on the use of mobilized PBSC for transplantation and on the use of reduced-intensity conditioning regimens ('mini' or 'non-Correspondence myeloablative' transplants). These approaches are likely to become increasingly important in the future and will allow transplant procedures to be used for relatively older patients. The use of CAMPATH-1G or CAMPATH-1H was associated with a low incidence of GvHD or rejection, though there were some differences that might be related to the longer half-life of the humanized antibody. An unexpected and apparently paradoxical effect of post-transplant CYA was observed - it appeared to reduce the risk of dying from infection after 6 months. Although part of the benefit could be explained by a reduction in GvHD, the effect was still evident when patients with GvHD or graft rejection were excluded from analysis. DISCUSSION: CAMPATH-1H appears to have a useful role in the prevention of graft rejection and GvHD, particularly in patients who are at high risk of these complications. It can equally well be used by admixture with the infused stem cells, or by administration to the patient prior to the transplant. Future studies will seek to understand the mechanism of the CYA effect and to improve the quality of immune reconstitution.

Alemtuzumab↗
PubMed2001

In vivo CAMPATH-1H prevents GvHD following nonmyeloablative stem-cell transplantation.

BACKGROUND: We have investigated a novel nonmyeloablative conditioning regimen in 44 patients with hematological malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. METHODS: Recipient conditioning consisted of CAMPATH-1H 20 mg/day on Days -8 to -4, fludarabine 30 mg/m(2) on Days -7 to -3 and melphalan 140 mg/m(2) on Day -2. Thirty-six recipients received unmanipulated G-CSF mobilized PBSC from HLA identical siblings and eight received unmanipulated BM from MUD. GvHD prophylaxis was with CYA alone for 38 patients and CYA plus MTX for six sibling recipients. RESULTS: Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite PCR indicate that 18 of 31 patients studied were full donor chimeras, while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range, 3-29 months) 33 patients remain alive in CR, or with no evidence of disease progression. Seven patients relapsed or progressed post-transplant and four of them subsequently died. Four patients died from regimen-related complications. There were no cases of Grades III-IV acute GvHD. Only two patients developed Grade II acute GvHD and only one had chronic GvHD. The estimated probability of non-relapse mortality at 1 year was 11%.Results: Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity and low incidence of GvHD.

Adolescent↗
PubMed2001

Monitoring end-tidal carbon dioxide during weaning from cardiopulmonary bypass in patients without significant lung disease.

End-tidal carbon dioxide tension (PETCO(2)) changes with fluctuations in cardiac output (CO). We compared PETCO(2) to pulmonary artery blood flow (PAQt) during weaning from cardiopulmonary bypass (CPB) in normothermic patients without significant pulmonary disease. Fifteen consecutive adult cardiac surgical patients were prospectively studied during and shortly after weaning from CPB. Before separation from CPB, PETCO(2) and PAQt were measured, the latter by transesophageal Doppler echocardiography. At the time of measurements patients were normothermic, and ventilated at 6 breaths/min with tidal volumes of 10 mL/kg. After separation from CPB, thermodilution cardiac output (TDCO) was measured in addition to PAQt and PETCO(2). Regression and bias analyses were used to compare PETCO(2), PAQt, and TDCO. Seventy measurements were recorded; 31 before separation from CPB and 39 after separation from CPB. A good correlation was seen between PAQt and PETCO(2) (r = 0.88) and between TDCO and PAQt (r = 0.93; mean bias 0.03 L/min; SD 0.52 L/min). The regression analysis of PAQt on PETCO(2) showed greater variability at PETCO(2) levels > 34 mm Hg (n = 22; r = 0.14). Increases in PETCO(2) plateaued at this level, although PAQt continued to increase. When PETCO(2) was more than 30 mm Hg, all PAQt and TDCO values were >4.0 L/min (>2.0 L/min/m(2)). When PETCO(2) exceeded 34 mm Hg, all values of PAQt, and 28/29 values of TDCO were more than 5 L/min (>2.5 L/min/m(2)). One patient had TDCO of 4.69 L/min (2.39 L/min/m(2)). In normothermic patients without significant pulmonary disease, PETCO(2) is a useful index of PAQt during separation from CPB. Under the clinical settings in this study, a PETCO(2) greater than 30 mm Hg was invariably associated with a CO more than 4.0 L/min or a cardiac index >2.0 L/min/m(2).

Aged↗
PubMed2000

Polyphenolics enhance red blood cell resistance to oxidative stress: in vitro and in vivo.

In this study we investigated the potential antioxidant properties of blueberry polyphenolics in vitro and vivo, using red blood cell (RBC) resistance to reactive oxygen species (ROS) as the model. In vitro incubation with anthocyanins or hydroxycinnamic acids (HCA) (0.5 and 0.05 mg/ml) was found to enhance significantly RBC resistance to H2O2 (100 microM) induced ROS production. This protection was also observed in vivo following oral supplementation to rats at 100 mg/ml. However, only anthocyanins were found to afford protection at a significant level, this at 6 and 24 h post supplementation. This protection was not consistent with the measured plasma levels of anthocyanins. Indeed, plasma polyphenolic concentrations were highest after 1 h, declining considerably after 6 h and not detected after 24 h. The difference in absorption between anthocyanins and HCA is likely to have contributed to the observed difference in their abilities to afford protection to RBC. This protection represents a positive role following dietary consumption of polyphenolics from blueberries, against ROS formation within RBC in vivo.

Animals↗
PubMed1999

Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions.

Unrelated bone marrow transplantation (BMT) is often complicated by fatal opportunistic infections. To evaluate features unique to immune reconstitution after unrelated BMT, the lymphoid phenotype, in vitro function, and life-threatening opportunistic infections after unrelated and related T-cell-depleted (TCD) BMT were analyzed longitudinally and compared. The effects of posttransplant donor leukocyte infusions to treat or prevent cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infections on immune reconstitution were also analyzed. This study demonstrates that adult recipients of TCD unrelated BMTs experience prolonged and profound deficiencies of CD3(+), CD4(+), and CD8(+) T-cell populations when compared with pediatric recipients of unrelated BMT and adults after related BMT (P <.01), that these adults have a significantly increased risk of life-threatening opportunistic infections, and that the rate of recovery of CD4 T cells correlates with the risk of developing these infections. Recovery of normal numbers of CD3(+), CD8(+), and CD4(+) T-cell populations is similar in children after related or unrelated BMT. This study also demonstrates that adoptive immunotherapy with small numbers of unirradiated donor leukocytes can be associated with rapid restoration of CD3(+), CD4(+), and CD8(+) T-cell numbers, antigen-specific T-cell responses, and resolution of CMV- and EBV-associated disease after unrelated TCD BMT.

Adolescent↗
PubMed1997

Antimalarial activity of tropical Meliaceae extracts and gedunin derivatives.

Extracts of 22 species of Meliaceae were examined for antimalarial activity using in vitro tests with two clones of Plasmodium falciparum, one sensitive to chloroquine (W2) and one chloroquine-resistant (D6). Twelve extracts were found to have activity, including extracts of Cedrela odorata wood and Azadirachta indica leaves, which contained the limonoid gedunin. These extracts were more effective against the W2 clone than the D6 clone, suggesting there is no cross-resistance to chloroquine. Gedunin was extracted in quantity, and nine derivatives prepared for a structure-activity study, which revealed essential functionalities for activity. The study also included four other limonoids derived from related Meliaceae. Only gedunin had better activity than chloroquine against the W2 clone. This active principle could be used to standardize a popular crude drug based on traditional use of A. indica in West Africa.

Animals↗
PubMed1989

Total lymphoid irradiation preceding bone marrow transplantation for chronic myeloid leukaemia.

Between August 1985 and October 1987 we treated 35 patients with chronic myeloid leukaemia (CML) by high dose chemotherapy, total body irradiation (TBI) (1000 or 1200 cGy, n = 31) and total lymphoid irradiation (TLI) (800 or 600 cGy, n = 35) preceding allogeneic bone marrow transplantation (BMT). Both TBI and TLI were given at 200 cGy/fraction. Twenty-three patients had HLA-identical sibling donors, nine patients had HLA-matched but unrelated donors, and three partially HLA-mismatched donors. Twenty-two patients received T-cell depleted marrow. The addition of TLI to the standard protocol did not add greatly to the toxicity. Four patients had recurrent leukaemia before engraftment was evaluable. The other 31 patients engrafted and no graft failed. Twenty-two patients survive at a median time from transplant of 305 days (range 81-586 days). Fourteen have no evidence of disease; eight have or had only cytogenetic evidence of leukaemia. We conclude that the addition of TLI to pretransplant immunosuppression increases the probability of reliable engraftment in patients receiving T-cell depleted marrow. This benefit is not associated with significantly increased toxicity.

Adolescent↗
PubMed1979

Treatment of localized pulmonary phycomycosis.

A patient cured of localized pulmonary phycomycosis occurring at the site of a previous lung abscess is described and the other survivors of this unusual entity are discussed. Whole-lung computerized tomographic (CT) scanning was useful in confirming the presence of a single localized lesion and led to the choice of surgical excision. A diagnostic and therapeutic approach including whole-lung CT scanning and preoperative and postoperative systemic amphotericin B therapy is suggested pending pathologic review of the tissues for possible fungal invasion beyond the resected area. The value of surgical excision when the disease appears localized is emphasized.

Amphotericin B↗
PubMed1978

False-positive cryptococcal antigen test and cervical prevertebral abscess.

A false-positive latex agglutination test for cryptococcal antigen occurred in a patient with a cervical prevertebral abscess and vertebral osteomyelitis caused by Klebsiella pneumoniae. Using a commercial latex agglutination test kit, a cryptococcal antigen titer of 1:32 was found in the CSF, but no cryptococcal antigen was found when the CSF was retested at a reference laboratory. The false-positive test resulted in unnecessary therapy with amphotericin B and delay in appropriate diagnostic studies and therapy.

Abscess↗