Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management.

BACKGROUND AND OBJECTIVE: Older oncology patients with multiple comorbidities are at risk for adverse drug events associated with polypharmacy and drug-drug interactions due to patients' altered pharmacokinetic/pharmacodynamic status and the narrow therapeutic windows associated with anti-neoplastic agents. This study addresses the issue of polypharmacy and potential drug-drug interactions in outpatients in a community setting in the USA, and the prescribing behaviour of oncologists after being made aware of potential drug-drug interactions. METHODS: We performed a retrospective cohort study in patients with multiple comorbidities exposed to chemotherapy to profile the potential for adverse drug reactions and to define physicians' responses to risks arising from drug interactions. The medical records of 100 patients aged >or=70 years receiving chemotherapeutic agents at a community-based, university-affiliated medical practice were randomly selected and reviewed. Drug class usage was quantified, and potential drug-drug interactions were assessed and categorized. Treating oncologists were encouraged to modify their prescriptions on the basis of potential interactive drug evaluation reports. Physicians' responses were catalogued. RESULTS AND DISCUSSION: The mean age of the study population was 78 years (range, 70-90 years). Patients had an average of three comorbid conditions. Each patient received an average of 9 x 1 medications. Cardiovascular drugs were the most common medications that patients used to treat chronic conditions. Carboplatin and paclitaxel were the most frequently used chemotherapeutic agents. Inspite of the potential for drug-drug interactions, physicians made no adjustments to prescriptions. CONCLUSION: Given that polypharmacy and the chronic use of multiple drugs are a reality for older patients with cancer and polymorbidities, outcome data need to be generated and motivations/incentives provided for physicians to optimize safe and effective supportive oncologic therapeutics.

Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene.

The serine/threonine kinase Akt has been implicated in the control of cell survival and metabolism. Here we report the disruption of the most ubiquitously expressed member of the akt family of genes, akt1, in the mouse. Akt1(-/-) mice are viable but smaller when compared to wild-type littermates. In addition, the life span of Akt1(-/-) mice, upon exposure to genotoxic stress, is shorter. However, Akt1(-/-) mice do not display a diabetic phenotype. Increased spontaneous apoptosis in testes, and attenuation of spermatogenesis is observed in Akt1(-/-) male mice. Increased spontaneous apoptosis is also observed in the thymi of Akt1(-/-) mice, and Akt1(-/-) thymocytes are more sensitive to apoptosis induced by gamma-irradiation and dexamethasone. Finally, Akt1(-/-) mouse embryo fibroblasts (MEFs) are more susceptible to apoptosis induced by TNF, anti-Fas, UV irradiation, and serum withdrawal.

A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death.

Tuberculous meningitis (TBM) is a devastating form of tuberculosis that occurs predominantly in children and in immunocompromised adults. To study the pathogenesis of TBM, a rabbit model of acute mycobacterial central nervous system infection was set up (8-day study). Inoculation of live Mycobacterium bovis Ravenel intracisternally induced leukocytosis (predominantly mononuclear cells), high protein levels, and release of tumor necrosis factor-alpha (TNF-alpha) into the cerebrospinal fluid within 1 day. Histologically, severe meningitis with thickening of the leptomeninges, prominent vasculitis, and encephalitis was apparent, and mortality was 75% by day 8. In animals treated with antituberculous antibiotics only, the inflammation and lesions of the brain persisted despite a decrease in mycobacteria; 50% of the rabbits died. When thalidomide treatment was combined with antibiotics, there was a marked reduction in TNF-alpha levels, leukocytosis, and brain pathology. With this combination treatment, 100% of the infected rabbits survived, suggesting a potential clinical use for thalidomide in TBM.

TRAF2 is essential for JNK but not NF-kappaB activation and regulates lymphocyte proliferation and survival.

TRAF2 is believed to mediate the activation of NF-kappaB and JNK induced by the tumor necrosis factor receptor (TNFR) superfamily, which elicits pleiotropic responses in lymphocytes. We have investigated the physiological roles of TRAF2 in these processes by expressing a lymphocyte-specific dominant negative form of TRAF2, thereby blocking this protein's effector function. We find that the TNFR superfamily signals require TRAF2 for activation of JNK but not NF-kappaB. In addition, we show that TRAF2 induces NF-kappaB-independent antiapoptotic pathways during TNF-induced apoptosis. Inhibition of TRAF2 leads to splenomegaly, lymphadenopathy, and an increased number of B cells. These findings indicate that TRAF2 is involved in the regulation of lymphocyte function and growth in vivo.

Oligosaccharides interfere with the establishment and progression of experimental pneumococcal pneumonia.

Oligosaccharides that block the adherence of bacteria to epithelial cells in vitro--lacto-N-neotetraose (LNnT) and its alpha2-3- and alpha2-6-sialylated derivatives--were tested for their abilities to attenuate the course of pneumococcal pneumonia and to prevent colonization of the nasopharynx in animal models. Intratracheal administration of these agents concurrently with bacteria dramatically decreased pneumococcal load in the lungs of rabbits and conferred protection from bacteremia. The oligosaccharides ameliorated pneumonia and bacteremia when given therapeutically 24 h after infection was established. When administered intranasally, neoglycoconjugates of the active oligosaccharides prevented colonization of the nasopharynx of infant rats. In addition to in vitro anti-adherence properties, LNnT acted directly on cultured lung epithelial cell lines to induce changes such that pneumococcal adherence was prevented for prolonged periods. These activities encourage continued development of oligosaccharides as a class of potentially preventive and therapeutic agents for infectious diseases.

Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development.

We recently have shown that mice deficient for the 86-kDa component (Ku80) of the DNA-dependent protein kinase exhibit growth retardation and a profound deficiency in V(D)J (variable, diversity, and joining) recombination. These defects may be related to abnormalities in DNA metabolism that arise from the inability of Ku80 mutant cells to process DNA double-strand breaks. To further characterize the role of Ku80 in DNA double-strand break repair, we have generated embryonic stem cells and pre-B cells and examined their response to ionizing radiation. Ku80(-/-) embryonic stem cells are more sensitive than controls to gamma-irradiation, and pre-B cells derived from Ku80 mutant mice display enhanced spontaneous and gamma-ray-induced apoptosis. We then determined the effects of ionizing radiation on the survival, growth, and lymphocyte development in Ku80-deficient mice. Ku80(-/-) mice display a hypersensitivity to gamma-irradiation, characterized by loss of hair pigmentation, severe injury to the gastrointestinal tract, and enhanced mortality. Exposure of newborn Ku80(-/-) mice to sublethal doses of ionizing radiation enhances their growth retardation and results in the induction of T cell-specific differentiation. However, unlike severe combined immunodeficient mice, radiation-induced T cell development in Ku80(-/-) mice is not accompanied by extensive thymocyte proliferation. The response of Ku80-deficient cell lines and mice to DNA-damaging agents provides important insights into the role of Ku80 in growth regulation, lymphocyte development, and DNA repair.

Role of the pharmacist in childhood immunizations.

OBJECTIVE: Fewer than half of the 2-year-old children in the United States are fully immunized. This article reviews the literature on barriers to immunization in children and examines how pharmacists can promote childhood immunizations by acting as an educational resource and providing increased access to vaccines. DATA SOURCES: Published data were collected from the literature. Anecdotal data were collected from unstructured interviews with parents and health care professionals at two childhood immunization clinics in Des Moines, Iowa. DATA SYNTHESIS: Data from the literature were compared with data informally collected in the clinics. Both the literature and interviews indicated a variety of structural and personal barriers that may prevent parents from having children vaccinated. CONCLUSION: By collecting and documenting adequate vaccination histories, pharmacists can be a resource for parents and health care professionals who are unsure of a child's immunization status. Pharmacists may wish to establish immunization clinics in their pharmacies as a method to increase access to vaccines.

Requirement for Ku80 in growth and immunoglobulin V(D)J recombination.

The DNA-dependent protein kinase (DNA-PK) is a mammalian serine/threonine kinase that is implicated in the repair of DNA double-strand breaks, DNA replication, transcription, and V(D)J recombination. To determine the role of the DNA-binding subunit of DNA-PK in vivo, we targeted Ku80 in mice. In mutant mice, T and B lymphocyte development is arrested at early progenitor stages and there is a profound deficiency in V(D)J rearrangement. Although Ku80-/- mice are viable and reproduce, they are 40-60% of the size of littermate controls. Consistent with this growth defect, fibroblasts derived from Ku80-/- embryos showed an early loss of proliferating cells, a prolonged doubling time, and intact cell-cycle checkpoints that prevented cells with damaged DNA from entering the cell-cycle. The unexpected growth phenotype suggests a new and important link between Ku80 and growth control.

apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-I transport rates in heterozygotes.

apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes.

Effect of thalidomide on the inflammatory response in cerebrospinal fluid in experimental bacterial meningitis.

In experimental bacterial meningitis in rabbits, the inflammatory process is largely mediated by cytokines such as IL-1 and TNF-alpha. Since thalidomide has been shown to inhibit TNF-alpha production, experiments were carried out to determine whether the drug can modulate the inflammatory response to either lysates of H. influenzae (gram negative) or heat killed S. pneumoniae (gram positive) in rabbits. The introduction of a lysate of H. influenzae into the CSF of rabbits causes a very acute inflammatory response, as indicated by a rapid increase in TNF-alpha levels in the CSF and a concomitantly rapid leukocytosis. In contrast, the introduction of heat killed S. pneumoniae, induces a more indolent inflammatory response which also wanes more slowly. Thalidomide treatment reduces TNF-alpha production in both experimental systems, but has a greater effect on the more indolent gram positive inflammatory response in which peak TNF-alpha levels in the CSF are reduced by > 50%. Also, a sustained inhibition of leukocytosis is observed in the inflammatory response to heat-killed gram positive bacteria. In meningeal inflammation induced by the Gram negative lysate, treatment with thalidomide results in only a 29% inhibition of TNF-alpha release into the CSF. In contrast to the drug effect on TNF-alpha, thalidomide treatment does not significantly affect IL-1 levels in these models of rabbit bacterial meningitis.

Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor.

An immature v-abl-transformed mast cell line (V3-MC) was derived from a mouse that developed systemic mastocytosis after transplantation of v-abl-infected bone marrow cells. V3-MCs injected intravenously into adult BALB/c mice infiltrated the liver, spleen, and intestine by day 6 and underwent progressive differentiation and maturation, eventually resembling indigenous mast cells. In terms of their protease content, the V3-MCs that localized in the liver and spleen differed from those in the intestine, and both differed from the cultured V3-MCs. The acquired expression of certain proteases and the loss of expression of other proteases in these tissue V3-MCs defines particular phenotypes and indicates that the differentiation and maturation of mast cell-committed progenitor cells are primarily regulated by factors in the different tissue microenvironments.

Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase.

Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock. iNOS-/-mice failed to restrain the replication of Listeria monocytogenes in vivo or lymphoma cells in vitro. Bacterial endotoxic lipopolysaccharide (LPS) caused shock and death in anesthetized wild-type mice, but in iNOS-/-mice, the fall in central arterial blood pressure was markedly attenuated and early death averted. However, unanesthetized iNOS-/-mice suffered as much LPS-induced liver damage as wild type, and when primed with Propionobacterium acnes and challenged with LPS, they succumbed at the same rate as wild type. Thus, there exist both iNOS-dependent and iNOS-independent routes to LPS-induced hypotension and death.

TCR selection and allelic exclusion in RAG transgenic mice that exhibit abnormal T cell localization in lymph nodes and lymphatics.

RAG-1 and RAG-2 are developmentally regulated genes that are essential for V(D)J recombination and lymphocyte development. Expression of RAG-1 and RAG-2 by thymocytes is normally limited to cells that have not completed selection. We have previously documented that persistent expression of the recombinase activating genes (RAG) in transgenic mice results in aberrant thymic development, altered lymphatic microanatomy, and a profound immunodeficiency. Here we further document the pathologic changes found in TG.RAG-1,2 mice and examine the role of TCR recombination and positive and negative thymic selection, as well as allelic exclusion, in the etiology of the phenotype. We find that neither selection nor TCR allelic exclusion can be overcome by transgenic expression RAG-1 and RAG-2 under the control of an lck promoter.

A regulatory role for recombinase activating genes, RAG-1 and RAG-2, in T cell development.

RAG-1 and RAG-2 are developmentally regulated genes that are essential for the assembly of antigen receptors in lymphoid cells. Here we describe transgenic mice that carry RAG-1 and RAG-2 under the control of the proximal lck promoter. Persistent expression of RAG-1 and RAG-2 was associated with incomplete thymopoiesis and profoundly compromised cellular immunity. In addition, RAG transgenic mice rapidly developed lymphadenopathy, splenomegaly, and lymphocytic perivascular infiltrates. These effects required both RAG-1 and RAG-2, since mice that carried either gene exclusively were indistinguishable from wild-type controls. We propose that in addition to a previously documented role in V(D)J recombination, RAG-1 and RAG-2 expression must be properly regulated for completion of normal T cell development

Overcoming unit dose drug distribution system logistical problems on a 32-acre campus.

The literature contains numerous articles regarding the implementation of unit dose drug distribution systems, but little has been written concerning the logistical problems sometimes encountered with such systems. This article describes the implementation of a drug distribution system at a psychiatric institution at which the inpatient units are scattered throughout a 32-acre campus.

Evaluation of commercially available antibodies to cytokeratin intermediate filaments and laminin in normal cat pinna.

The pattern of distribution of cytokeratin (CK) intermediate filaments can be used to characterize subsets of epithelial tissues. The purpose of the study was to examine the CK expression of feline pinna skin. Six normal feline pinnae were routinely processed in formalin. An immunohistochemical method was used to stain the pinnae with 8 commercially available anti-human CK antibodies (Abs) (PKK1, CAM 5.2, UCD 10/11, 35BH11, 34BE12, AE1/AE3, MAK 6, A575) and an anti-human laminin Ab. All the CK Abs selectively localized to epithelium except 35BH11, which did not react with any part of the pinna. Some epithelial subsets were identified by their unique staining pattern with CK Abs. Basal cells but not suprabasal cells of the epidermis stained with PKK1; basal but not lumenal cells of apocrine glands stained with 34BE12. Apocrine glands stained with all CK Abs except 35BH11. All epithelial structures were stained with A575. Basal lamina of epithelial and mesenchymal tissues was clearly identified by the anti-laminin Ab. The results indicate that in cat pinna some commercially available anti-human CK Abs selectively stain subsets of epithelium and adnexa. PKK1, 34BE12, and A575 were the CK Abs with the most consistent staining patterns, the other Abs stained more variably from pinna to pinna. The pattern of epithelial and adnexal staining was similar but not identical to that reported for humans.