Pharmacist-led biometric screenings: A retrospective chart review in a community pharmacy.

BACKGROUND: Biometric screenings have gained popularity in employer-based wellness programs and are increasingly offered at community pharmacies. OBJECTIVE: This study aimed to analyze biometric screening data collected at a community pharmacy in North Alabama to examine the prevalence of risk factors and the role of pharmacist-led screenings in identifying at-risk individuals and facilitating referrals to primary care providers. METHODS: A retrospective chart review was conducted using biometric screening data collected between 2020 and 2021. Descriptive statistics were calculated to analyze the data. RESULTS: A total of 801 patients were included in the analysis. The mean age was 45.4 years, and 56.2 % were female. The mean systolic blood pressure was 132 mmHg, and the mean diastolic blood pressure was 84 mmHg. Mean total cholesterol was 174 mg/dL, and the mean blood glucose was 109 mg/dL. Mean BMI was 35.1 kg/m2. Among the screened patients, 22.5 % were referred to a primary care provider due to an elevated level of at least one of the measured variables, with BMI being the most common reason for referral. CONCLUSION: This study provides valuable insights into the prevalence of risk factors in a population undergoing pharmacist-led biometric screenings in a community pharmacy. The findings emphasize the important role of pharmacists in identifying at-risk individuals and facilitating appropriate referrals to primary care. Further research is needed to evaluate the long-term impact of these referrals and explore the feasibility of similar programs in diverse healthcare settings.

Geriatric Pharmacotherapy Case Series: Potential Drug Interactions With Antiplatelet Medications and Cannabidiol-A Focus on P2Y12 Inhibitors.

Background A 76-year-old man was admitted to a local rehabilitation inpatient facility following an acute myocardial infarction. Patient history included hypertension and previous stroke. The patient was being treated with clopidogrel and aspirin for secondary stroke prevention along with other medications to treat hypertension. The patient admitted to using cannabidiol (CBD) oil up to three times a day for knee pain prior to acute myocardial infarction and requested to continue its use in the facility. Assessment Prior to this hospital stay, the patient was able to continue activities of daily living with knee pain that was controlled by CBD oil used three times daily. The option to continue CBD oil would create a possible drug interaction with current cardiovascular medications leading to increased cardiovascular or bleeding risks. Outcome The patient was advised against the use of CBD products because of potential interaction with clopidogrel and was prescribed acetaminophen for osteoarthritis (knee pain). The patient continued to improve and was discharged to his home after two weeks of rehabilitation. Conclusion Based on limited pharmacodynamic and pharmacokinetic studies in older people, patients should avoid using cannabidiol and products containing its derivatives with P2Y12 inhibitors. A potential interaction between cannabidiol and its derivatives with P2Y12 inhibitors may increase a patient's cardiovascular or bleeding risks. Patients and health care providers must be adequately informed about potential risks associated with cannabidiol products and oral antiplatelets to prevent negative outcomes.

Three Generations of FLNA-Associated Periventricular Nodular Heterotopia.

We present a family with 3 generations of FLNA gene-associated periventricular nodular heterotopia (PVNH), with a unique presentation in a fetus with multiple neurologic malformations. Neurologic abnormalities were noted on routine fetal imaging for a 33-year-old G1P0 woman; absence of the corpus callosum and PVNH was confirmed on follow-up MRI. This prompted genetic evaluation, revealing a nonsense mutation in the FLNA gene. Familial genetic analysis and neuroimaging revealed the same variant and MRI evidence of PVNH in the fetus's asymptomatic mother, and maternal grandmother, who had a long history of seizure disorder. Such phenotypic variability within a single family demonstrates the spectrum of PVNH and the importance of genetic counseling for patients with PVNH. This case also adds to existing literature on the rare but not unique presentation of FLNA-associated fetal malformations.

Evaluation of Vitamin B12 Monitoring in Patients on Concomitant Metformin and Proton Pump Inhibitors.

BACKGROUND: Type 2 diabetes mellitus and gastroesophageal reflux disease are highly prevalent in the United States. First-line therapies for these disease states include metformin and proton pump inhibitors, respectively. Both of these medications have been associated with a decreased absorption of vitamin B12. OBJECTIVE: The objective of this study was to assess the prevalence of B12 monitoring and supplementation in patients receiving concomitant metformin and PPI therapy. METHODS: A retrospective data analysis was performed at a single federally qualified health center. Patients receiving concomitant metformin and PPI therapy (specifically omeprazole and pantoprazole) over the past year were included. Data collected included demographics, dosing, therapy duration, and vitamin B12 level. Data were analyzed using descriptive statistics. RESULTS: A total of 104 patients met the inclusion criteria for this study. Metformin 1000 mg immediate release tablets was the most common dose and formulation prescribed. Omeprazole and pantoprazole were the most commonly prescribed PPIs. The most frequent duration of therapy was 1 to 4 years. Fourteen patients had a documented B12 level and no patients were categorized as deficient. Seven patients were prescribed a B12 supplement during the study period. CONCLUSION: In this single center, retrospective chart review of patients receiving concomitant metformin and PPI therapy, the average duration of therapy for both agents was 1-4 years. Only 13.5% of patients had a documented B12 level. Of those patients, none were categorized as deficient. Though routine monitoring of B12 levels may be important for patients on long-term therapy with both agents or who present with symptoms of B12 deficiency, this study does not support routine monitoring of B12 levels for patients with duration of therapy of 4 years or less.

The Inflammatory Cytokine IL-21 is Expressed by Splenic Neutrophils in Response to Transplantation of Allogeneic Cells.

We have previously reported that GR-1 neutrophil/monocytes rose dramatically in the spleen, peaked by day 7 and declined through day 14. This period corresponded to the peak of acute Graft-Versus-Host Disease (aGVHD) in BALB/c mice transplanted with allogeneic donor cells. We now asked: what cytokines did these splenic neutrophil/monocytes express on day 7 and 14 post transplant? BALB/c mice were transplanted with allogeneic B6 or syngeneic BALB/c donor cells. Long term survival was recorded through day 31. Other groups were sacrificed on days 3, 5, 7, 14, 21 and 31 days post transplant to record the total number of cells in the spleens and their phenotypes. Neutrophils were isolated from the spleens of mice transplanted with B6 and BALB/c cells on days 7 and 14. Daily body weight demonstrated a transient drop in the syngeneic transplants on day 2 but a much greater drop with its nadir at day 7 and never fully recovering through 31 days. CD8/CD4 T lymphocytes peaked in the spleen on day 5 and were followed on day 7 by GR-I cells in all of the allogeneic transplants. In syngeneic transplants this early rise in lymphocytes did not occur and GR-1 cells peaked on day 14. Highly purified neutrophils were isolated in two separate experiments from the spleens on days 7 and 14 post transplant. In both experiments day 7 allogeneic neutrophils expressed significantly elevated levels of Interleukin-21 (IL-21) mRNA whereas the day 7 and 14 syngeneic cells expressed lower but significant levels of TNFα. Intracellular IL-21 was demonstrated in the allogeneic neutrophils on day 7 before and after in vitro stimulation. In conclusion Purified neutrophils isolated from the spleen on day 7, the early peak of allogeneic transplantation a GVHD, express high levels of IL-21 message and intracellular IL-21.

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists.

It has now been demonstrated that the µ, δ1 , δ2 , and κ1 opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct-reducing effect with prophylactic administration and prevent reperfusion-induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia-induced arrhythmias.

Activation of peripheral delta opioid receptors increases cardiac tolerance to arrhythmogenic effect of ischemia/reperfusion.

OBJECTIVES: The objective of this study was to investigate the role of peripheral µ, δ1, δ2, and nociceptin opioid receptors agonists in the regulation of cardiac tolerance to the arrhythmogenic effect of ischemia/reperfusion in rats. METHODS: Anesthetized open-chest male Wistar rats were subjected to either 45 minutes of left coronary artery occlusion (phase 1a 10 minutes and phase 2b 35 minutes) and 2 hours of reperfusion in Experiment 1 or 10 minutes of ischemia and 10 minutes of reperfusion in Experiment 2. In Experiment 1, saline or vehicle controls and the mu-specific opioids dermorphin-H (Derm-H) and ([d-Ala2, N-Me-Phe4, Gly-ol5] enkephalin (DAMAGO); the delta-1-specific opioid d-Pen2,5enkephalin (DPDPE); nociceptin; and the delta-2-specific opioids deltorphin-II (Delt-II), Delt-Dvariant (Delt-Dvar), and deltorphin-E (Delt-E) were infused 15 minutes prior to ischemia. In Experiment 2, DPDPE, Delt-D, Delt-Dvar, and Delt-E were infused at 15 minutes prior to ischemia. The universal opioid receptor antagonist naltrexone, the peripherally acting antagonist naloxone methiodide, the selective δ1 antagonist 7-benzylidene naltrexone maleate, and the specific δ2 antagonist naltriben mesylate were infused 25 minutes prior to ischemia. RESULTS: In Experiment 1, pretreatment with the µ opioids Derm-H and DAMGO, DPDPE, and nociceptin at all doses tested did not reduce the incidence of ischemia-induced arrhythmias compared to controls during 45 minutes of ischemia. The δ2 opioids Delt-II (0.12 mg/kg), Delt-Dvar (0.3 mg/kg), and Delt-E (0.18 mg/kg) all demonstrated significant antiarrhythmic effects at the 150 nmol/kg dose compared to saline or vehicle controls. Nine of 19 animals treated with Delt-II were tolerant without ventricular arrhythmias to the arrhythmogenic effect of ischemia during the first 10 minutes of ischemia (phase 1a) and 11 of 19 were without ventricular arrhythmias during the following 35 minutes of ischemia (phase 1b). Delt-II also decreased the incidence of premature ventricular contractions and ventricular tachycardia by almost half during phase 1a. Delt-II did not affect the incidence of ventricular fibrillation (VF). Pretreatment with Delt-Dvar and Delt-E completely blocked the incidence of VF in phase 1b. Delt-E also decreased premature ventricular contractions by 50%, and the incidence of ventricular tachycardia decreased over twofold in phase 1b of ischemia. There was no enhanced tolerance by any of the delta-2 opioids to the arrhythmogenic effect of reperfusion after long-term ischemia. In Experiment 2, after 10 minutes of ischemia and 10 minutes of reperfusion, Delt-II (0.12 mg/kg) reduced the incidence of premature ventricular contractions and ventricular tachycardia compared to controls, and completely blocked the incidence of VF following 10 minutes of reperfusion. Delt-Dvar and Delt-E were without effect, as was DPDPE following 10 minutes of reperfusion. The antiarrhythmic effect of Delt-II during 10 minutes of ischemia and 10 minutes of reperfusion was completely blocked by the peripherally acting opioid receptor inhibitor naloxone methiodide and the selective delta-2 opioid receptor inhibitor naltriben mesylate, but not by the selective delta-1 inhibitor 7-benzylidene naltrexone maleate. The antagonists alone had no effect on arrhythmogenesis. CONCLUSIONS: Peripheral delta-2 opioid receptor activation by Delt-II, Delt-Dvar, and Delt-E enhanced cardiac tolerance to the arrhythmogenic effects of ischemia.

Intermediate CGG repeat length at the FMR1 locus is not associated with hormonal indicators of ovarian age.

OBJECTIVE: Premutation and intermediate CGG repeat length at the fragile X mental retardation 1 (FMR1) locus have been associated with premature ovarian failure. We tested whether intermediate length is associated with indicators of ovarian age in a sample of fertile women. Our primary measures of ovarian age were antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) levels. METHODS: The cross-sectional sample comprised 258 women with karyotyped spontaneous abortions (140 trisomic spontaneous abortions and 118 chromosomally normal spontaneous abortions or spontaneous abortions with anomalies other than trisomy) and 325 women with recent live births (LBs). We analyzed data from the total sample and data from LBs only. We defined CGG repeat length by the length (both continuous and categorical) on the longer allele. RESULTS: CGG repeat length was not significantly associated with either hormone measure. A repeat length of 35 to 54 CGG, versus the modal category of 30 CGG, was associated with an approximately 7% increase in median AMH level and a 3% increase in median FSH level. Results were unaltered when analyses were limited to LBs. Analyses of hormone levels using cutpoints to define older ovarian age showed no associations with repeat length. Among 10 women with repeat lengths of 35 to 54 CGG analyzed for AGG sequences, the uninterrupted CGG length was not significantly longer among women with hormonal indicators of "old" versus "young" ovarian age. CONCLUSIONS: Our data do not support an association between intermediate CGG repeat length and levels of AMH or FSH among fertile women.

To drive or be driven: the path of a mouse model of recurrent pregnancy loss.

This review is an example of the use of an animal model to try to understand the immune biology of pregnancy. A well-known model of recurrent spontaneous pregnancy loss is put in clinical, historical, and theoretical context, with emphasis on T cell biology.

Alveolar macrophages in neonatal mice are inherently unresponsive to Pneumocystis murina infection.

Pneumocystis pneumonia was first diagnosed in malnourished children and has more recently been found in children with upper respiratory symptoms. We previously reported that there is a significant delay in the immune response in newborn mice infected with Pneumocystis compared to adults (Garvy BA, Harmsen AG, Infect. Immun. 64:3987-3992, 1996, and Garvy BA, Qureshi M, J. Immunol. 165:6480-6486, 2000). This delay is characterized by the failure of neonatal lungs to upregulate proinflammatory cytokines and attract T cells into the alveoli. Here, we report that regardless of the age at which we infected the mice, they failed to mount an inflammatory response in the alveolar spaces until they were 21 days of age or older. Anti-inflammatory cytokines had some role in dampening inflammation, since interleukin-10 (IL-10)-deficient pups cleared Pneumocystis faster than wild-type pups and the neutralization of transforming growth factor beta (TGF-ß) with specific antibody enhanced T cell migration into the lungs at later time points. However, the clearance kinetics were similar to those of control pups, suggesting that there is an intrinsic deficiency in the ability of innate immunity to control Pneumocystis. We found, using an adoptive transfer strategy, that the lung environment contributes to association of Pneumocystis organisms with alveolar macrophages, implying no intrinsic deficiency in the binding of Pneumocystis by neonatal macrophages. Using both in vivo and in vitro assays, we found that Pneumocystis organisms were less able to stimulate translocation of NF-κB to the nucleus of alveolar macrophages from neonatal mice. These data indicate that there is an early unresponsiveness of neonatal alveolar macrophages to Pneumocystis infection that is both intrinsic and related to the immunosuppressive environment found in neonatal lungs.

Comparative analysis of the cardioprotective properties of opioid receptor agonists in a rat model of myocardial infarction.

OBJECTIVES: This study was conducted to test the hypothesis that opioid receptor (OR)-mediated cardioprotection is agonist specific when administered prior to coronary artery occlusion and reperfusion in a rat model. METHODS: Anesthetized open-chest male Wistar rats were subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. Opioid agonists were infused 15 minutes prior to coronary artery occlusion. Two control groups and 15 opioid-treated groups were studied. Controls were infused with either saline alone (n = 16) or dimethyl sulfoxide plus hydroxypropyl-ß-cyclodextrin in saline (n = 19). The µ-selective agonist DAMGO was infused at either 150 nmol/kg (n = 15) or 1500 nmol/kg (n = 14), and dermorphin-H was infused at 150 nmol/kg (n = 14). The δ1 -selective agonist d-Pen²(,)5 enkephalin (DPDPE) was infused at 150 nmol/kg (n = 16) or 1500 nmol/kg (n = 14). The δ2 -selective agonists deltorphin II (n = 16), deltorphin-D(variant) (n = 15), and deltorphin-E (n = 14) were infused at 150 nmol/kg. The selective κ1 opioid agonist U-50488 was infused at 240 nmol/kg (n = 14), 1500 nmol/kg (n = 14), and 2,400 nmol/kg (n = 14). The selective κ2 opioid agonist GR-89696 was infused at 150 nmol/kg (n = 14) and 1500 nmol/kg (n = 15). Orphinan FQ (nociceptin), also referred to as OR-like 1 (ORL1), was infused at 220 nmol/kg (n = 15) and 1500 nmol/kg (n = 15). The infarct size/area at risk (IS/AAR) ratio was determined after reperfusion by negative staining with patent blue violet dye. Hemodynamic parameters including heart rate, mean arterial blood pressure (MAP), and rate pressure product (RPP) were determined. RESULTS: Pretreatment with the δ2 OR agonist deltorphin II (150 nmol/kg) significantly reduced the IS/AAR ratio, while deltorphin-D(variant) and deltorphin-E did not exhibit an infarct-sparing effect at that treatment dose. Activation of δ1 OR by DPDPE, κ1 OR by U-50488, κ2 OR by GR-89696, µ OR by DAMGO, dermorphin-H, and nociceptin had no effect on the IS/AAR ratio. U-50488 at 2,400 nmol/L induced a bradycardic effect. All other opioids had no effect on hemodynamic parameters at the doses tested. CONCLUSIONS: Peripheral δ2 OR activation by deltorphin II induces infarct size reduction in this animal model. Agonists of µ, δ1, κ1, κ2, and nociceptin receptors at the doses tested did not induce cardiac tolerance to ischemia/reperfusion injury in vivo.

Pyrrolidine dithiocarbamate (PDTC) blocks apoptosis and promotes ionizing radiation-induced necrosis of freshly-isolated normal mouse spleen cells.

Ionizing radiation (IR) is a pro-oxidant that kills cells by both apoptotic and necrotic mechanisms. Pyrrolidine dithiocarbamate (PDTC) is a thiol-containing compound that may act either as a pro- or anti-oxidant depending on the experimental conditions. This study was designed to determine whether PDTC would reduce or enhance IR-induced cell death of freshly-isolated normal mouse B6/129 spleen cells (NMSC). We determined the effect of increasing doses of IR, PDTC alone and PDTC followed by IR on the viability of NMSC. Annexin V and propidium iodide (Annexin V/PI) staining demonstrated a dose and time-dependent relationship in which PDTC enhanced the percentage of IR-induced apoptotic/necrotic NMSC. Trypan blue dye inclusion confirmed that a loss of membrane integrity was occurring 1 h after incubation with PDTC plus IR. Reduction in the glutathione (GSH)/glutathione disulfide (GSSG) ratio and GSH demonstrated that both IR (8.5 Gy) and PDTC acted as pro-oxidants, but their mechanisms of action differed: In contrast to IR, which promoted p53 activation and caspase 3/7-mediated apoptosis, PDTC inhibited IR-induced p53 and caspase 3/7 activity. However, PDTC increased H(2)O(2) formation and necrosis, resulting in an overall increase in IR-induced cell death. Catalase prevented the PDTC-induced increase in IR cytotoxicity implicating the generation of H(2)O(2) as a major factor in this mechanism. These results demonstrate that in NMSC PDTC acts as pro-oxidant and enhances IR-induced cell cytotoxicity by increasing H(2)O(2)formation and thiol oxidation. As such, they strongly suggest that the use of PDTC as an adjunct to reduce radiation toxicity should be avoided.

The manganese superoxide dismutase mimetic, M40403, protects adult mice from lethal total body irradiation.

Over-expression of manganese superoxide dismutase (MnSOD) protects tissues from radiation. M40403 is a stable non-peptidyl mimetic of MnSOD that crosses cell membranes and is effective in reducing experimental inflammation. Male BALB/c mice were injected intraperitoneally (i.p.) and subcutaneously (s.c.) with M40403, 30 min before 6.5, 7.5 and 8.5 Gy total body irradiation (TBI). Whereas all control injected mice died after receiving 8.5 Gy TBI by day 17, 30 day survival of mice pre-treated i.p. with 40, 30, 20 or 10 mg/kg was 100%, 90%, 81% and 25%, respectively. The Dose Reduction Factor 50/30 for animals treated with 30 mg M40403 s.c. 30 min prior to TBI was 1.41. Decreased apoptosis of the large and particularly the small bowel and marked recovery of both lymphoid and hematopoietic tissues occurred in the M40403 pre-treated animals. M40403 is effective in reducing TBI-induced tissue destruction and has potential as a new radioprotective agent.

T10B9 monoclonal antibody: a short-acting nonstimulating monoclonal antibody that spares gammadelta T-cells and treats and prevents cellular rejection.

T10B9.1A-31/MEDI-500 is a nonmitogenic immunoglobulin M kappa murine monoclonal antibody (mAb) directed against the alpha-beta (alphabeta) heterodimer of the T-lymphocyte receptor complex. The hybridoma was first produced by fusing spleen cells from BALB/C mice immunized with human peripheral blood T-lymphocytes with SP2/O-Ag14 mutant myeloma cells. The mAb is produced and purified using multistep ion exchange and molecular sieve chromatography protocols. T10B9 has been used successfully to treat acute cellular rejection in renal transplantation and as an immunosuppression induction agent in heart and simultaneous kidney-pancreas transplantation. Because T10B9 is nonmitogenic and causes minimal cytokine release, both treatment of rejection and induction of immunosuppression were accomplished with significantly fewer and milder untoward effects (cytokine release syndrome) than its comparator OKT3. Since T10B9 is directed against the alphabeta heterodimer of the CD3 epitope, it spares the gamma delta (gammadelta) region. These gamma delta (gammadelta) T cells have a unique role in the immune response controlling many serious human diseases and perhaps facilitating the development of immunologic tolerance. T10B9 has a relatively short duration of action, depleting T cells for only 10 to 14 days, unlike the protracted depletion seen with thymoglobulin and Campath-1H. There is no B-lymphocyte depletion with T10B9 as there is with both of the aforementioned reagents. The lack of prolonged lymphocyte depletion may account for less infection observed with T10B9 treatment.

Activation of peripheral delta2 opioid receptors increases cardiac tolerance to ischemia/reperfusion injury Involvement of protein kinase C, NO-synthase, KATP channels and the autonomic nervous system.

AIMS: This study aims to investigate the role of peripheral delta(2) opioid receptors in cardiac tolerance to ischemia/reperfusion injury and to examine the contribution of PKC, TK, K(ATP) channels and the autonomic nervous system in delta(2) cardioprotection. MAIN METHODS: Deltorphin II and various inhibitors were administered in vivo prior to coronary artery occlusion and reperfusion in a rat model. The animals were monitored for the development of arrhythmias, infarct development and the effects of selected inhibitors. KEY FINDINGS: Pretreatment with peripheral and delta(2) specific opioid receptor (OR) antagonists completely abolished the cardioprotective effects of deltorphin II. In contrast, the selective delta(1) OR antagonist 7-benzylidenenaltrexone (BNTX) had no effect. The protein kinase C (PKC) inhibitor chelerythrine and the NO-synthase inhibitor L-NAME (N-nitro-L-arginine methyl ester) also reversed both deltorphin II effects. The nonselective ATP-sensitive K+ (K(ATP)) channel inhibitor glibenclamide and the selective mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoic acid only abolished the infarct-sparing effect of deltorphin II. Inhibition of tyrosine kinase (TK) with genistein, the ganglion blocker hexamethonium and the depletion of endogenous catecholamine storage with guanethidine reversed the antiarrhythmic action of deltorphin II but did not change its infarct-sparing action. SIGNIFICANCE: The cardioprotective mechanism of deltorphin II is mediated via stimulation of peripheral delta(2) opioid receptors. PKC and NOS are involved in both its infarct-sparing and antiarrhythmic effects. Infarct-sparing is dependent upon mitochondrial K(ATP) channel activation while the antiarrhythmic effect is dependent upon TK activation. Endogenous catecholamine depletion reduced antiarrhythmic effects but did not alter the infarct-sparing effect of deltorphin II.

Radiation mitigation effect of cultured mushroom fungus Hirsutella Sinensis (CorImmune) isolated from a Chinese/Tibetan herbal preparation -Cordyceps Sinensis.

PURPOSE: This study was carried out to test the hypothesis that the anti-oxidant and growth promoting properties of the cultured mushroom fungus Hirsutella sinensis (CorImmune) of Cordyceps sinensis mitigate radiation injury in mice. MATERIALS AND METHODS: BALB/c mice received total body irradiation (TBI) followed by treatment with CorImmune. The effect of CorImmune on lymphoid tissue, spleen and blood cells as well as survival and hematopoietic recovery was compared to normal saline treated controls. RESULTS: CorImmune administered beginning 2 hours after a lethal dose of TBI significantly improved survival: 55% in the CorImmune group vs. 0% in the saline control (p < 0.0001). It increased normal leukocyte levels in a dose-dependent fashion. Animals treated with sub-lethal TBI and monitored for blood leukocyte recovery exhibited a return to normal baseline 3 weeks after TBI injury. In contrast, only 50% returned to normal baseline in the saline control group (p < 0.01). CorImmune also stimulated immune lymphocyte proliferation by nearly two-fold in a (3)H-thymidine incorporation assay compared to controls (p < 0.01). CONCLUSIONS: CorImmune significantly increased animal survival after a lethal dose of radiation, accelerated leukocyte recovery and stimulated immune lymphocyte proliferation. We conclude that CorImmune is effective as a radiation mitigator when administered after radiation injury.

P53 status influences regulation of HSPs and ribosomal proteins by PDTC and radiation.

Pyrrolidine dithiocarbamate (PDTC) is a thiol-containing compound that can act under varying conditions as an anti-oxidant or pro-oxidant. Utilizing microarrays, we determined the effect of PDTC +/- ionizing radiation (IR) on the expression of heat shock protein (HSP) genes in isolated B6/129 wild-type (WT) and p53-/- spleen cells. Extremely significant microarrays demonstrated that PDTC, but not IR, markedly up-regulated the expression of the majority of detectable HSP genes in WT and many to a significantly greater degree in p53-/- deficient cells. Determination of the glutathione/glutathione disulfide ratio indicated that PDTC was acting as a pro-oxidant under these conditions. From these data we conclude that the clinical use of "antioxidants" with radiotherapy or chemotherapy must be very carefully based on knowledge of the p53 status of their intended normal and tumor target cells.

Use of a T cell-specific monoclonal antibody, T10B9, in a novel allogeneic stem cell transplantation protocol for hematologic malignancy high-risk patients.

To reduce the toxicity of traditional conditioning regimens for allogeneic stem cell transplantation (allo-SCT), we used single-agent chemotherapy conditioning with either busulfan (total cumulative dose, 16 mg/kg) or melphalan (200 to 240 mg/m 2 ), followed by the anti-T cell-specific monoclonal antibody T10B9 (MEDI-500) daily for 3 days. T cell-replete SCT was performed from HLA-identical sibling donors. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of 7 additional days of T10B9 and delayed onset of cyclosporine (ie, on day +4 or +5). Twenty-six high-risk hematologic malignancy patients were entered onto this study. All 24 patients who survived longer than 8 days engrafted, although 1 patient experienced late graft failure. Deaths occurred in 21 of 26 patients because of infection (n = 7), progression/recurrence of primary disease (n = 6), aGVHD (n = 4), regimen-related toxicity (n = 1), and other causes (n = 3). Five of these patients are enjoying disease-free survival with a median survival of 1193 days after allo-SCT. The conditioning regimen induced modulation of surface expression of CD3 (but not CD4 or CD8) and was associated with decreasing tumor necrosis factor-alpha (but not interleukin-6) serum levels. In conclusion, single-agent chemotherapy conditioning with T10B9 produced durable engraftment and long-term survival in some patients who would not have qualified for a traditional allo-SCT.