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Biomedical subjects

Richard E Kast

Publications and source records attributed to Richard E Kast.

At least 19 recordsLinked to original sources
PubMed2006

How influenza's neuraminidase promotes virulence and creates localized lung mucosa immunodeficiency.

Neuraminidase (NA) is an enzyme coded for by the genome of influenza critical for its pathogenicity and survival. Three currently accepted roles for this NA in promoting influenza virulence are: 1. NA cleaves newly formed virus particles from the host cell membrane. Without NA, newly formed virus would remain attached to the cell within which it was produced. 2. NA prevents newly released virus particles from aggregating to each other, preventing clumping that would reduce dissemination. 3. NA promotes viral penetration of sialic acid-rich mucin that bathes and protects respiratory epithelium through which the virus must spread and replicate. We outline here previous research evidence of two further, albeit hypothetical, functions of NA that together could cause disruption the mucosa-IgA axis, creating localized partial immunosuppressed state, enhancing both influenza infection itself and secondary bacterial pneumonia: 4. IgA provides primary immunoglobulin defense of mucosal surfaces. The hinge region of IgA is normally sialylated. IgA denuded of sialic acid is recognized, bound, and cleared by hepatic asialoglycoprotein receptor (ASGPR). Thus, IgA exposed to free NA would be so denuded and have increased hepatic clearance. 5. NA removes sialic acid moieties from mucosa-residing gamma/delta T cells or IgA producing B cells. Previous work indicates desialylation of these lymphocytes' outer cell membrane results in altered homing, to bone marrow, away from mucosa. Currently marketed NA inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) are FDA approved in USA for influenza prophylaxis and treatment. These NA inhibitors lower incidence of secondary bacterial infection in cases where an influenza infection occurs despite their use. Moreover, they are ameliorative in patients with secondary bacterial infections treated with antibiotics, a benefit that surpasses the treatment of antibiotics alone. We interpret these last two points as indicating our ascription of localized immunosuppression to influenza's NA could be correct and lead to new treatments of infections generally.

Animals↗
PubMed2006

Co-administration of ramelton and fluvoxamine to increase levels of interleukin-2.

Ramelton is a medication recently approved by the FDA for treatment of insomnia. Ramelton is an analogue of melatonin with a higher affinity even than that of the natural ligand. Clinically this potentially strong effect of the ligand is blunted by the fact that upon oral ingestion there is first pass metabolism of greater than 95%. This liver metabolism is mediated by the CYP1A2 enzyme. It turns out that the medication fluvoxamine approved by the FDA for the treatment of obsessive compulsive disorder is a potent inhibitor of the CYP1A2 enzyme, with the effect that co-administration of ramelton and fluvoxamine increases blood levels of ramelton by 100-200 fold. It turns out that lymphocytes bear the melatnonin receptors and stimulation of these receptors on lymphocytes cause the lymphocytes to elaborate the pro-inflammatory cytokine interleukin-2 (Il-2). Thus, here we point out that co-administration of ramelton and modest doses of fluvoxamine may be able to smoothly produce increased levels of Il-2, this may be useful in diseases and conditions such as metastatic cancer and maintenance of suppression of the HIV virus.

Adjuvants, Immunologic↗
PubMed2006

Evidence that amphotericin B mediates reactivation of latent Epstein-Barr virus in Hodgkin's lymphoma allowing cytotoxicity by acyclovir.

This brief communication focuses on aspects of a recent case report (Yonsei Med J 2005;46:425-30) on a full and sustained remission of Hodgkin's lymphoma (HL) after a single day of chemotherapy. A septic episode required stopping chemotherapy and starting amphotericin B and acyclovir. Remission evidence was seen within days of starting these. A review of research supporting the notion that amphotericin B can reactivate latent Epstein-Barr virus and thus allow acyclovir to kill infected HL cells is given. Experimental work is required to confirm or refute this possibility. If successful, amphotericin B and acyclovir treatment could be extended to other EBV-driven cancers such as Burkitt's lymphoma, nasopharyngeal carcinoma and the occasional EBV-related epithelial cancer of the breast, colon, prostate, and others.

Acyclovir↗
PubMed2006

Bupropion: pharmacology and therapeutic applications.

A total of 17 years after its introduction, bupropion remains a safe and effective antidepressant, suitable for first-line use. Bupropion undergoes metabolic transformation to an active metabolite, 4-hydroxybupropion, through hepatic cytochrome P450-2B6 (CYP2B6) and has inhibitory effects on cytochrome P450-2D6 (CYP2D6), thus raising concern for clinically-relevant drug interactions. Common side effects are nervousness and insomnia. Nausea appears slightly less common than with the SSRI drugs and sexual dysfunction is probably the least of any antidepressant. Bupropion is relatively safe in overdose with seizures being the predominant concern. The mechanism of action of bupropion is still uncertain but may be related to inhibition of presynaptic dopamine and norepinephrine reuptake transporters. The activity of vesicular monoamine transporter-2, the transporter pumping dopamine, norepinephrine and serotonin from the cytosol into presynaptic vesicles, is increased by bupropion and may be a component of its mechanism of action. Bupropion is approved for use in major depression and seasonal affective disorder and has demonstrated comparable efficacy to other antidepressants in clinical trials. Bupropion is also useful in augmenting a partial response to selective serotonin reuptake inhibitor antidepressants, although bupropion should not be combined with monoamine oxidase inhibitors. It may be less likely to provoke mania than antidepressants with prominent serotonergic effects. Bupropion is effective in helping people quit tobacco smoking. Anecdotal reports indicate bupropion may lower inflammatory mediators such as tumor necrosis factor-alpha, may lower fatigue in cancer and may help reduce concentration problems.

Antidepressive Agents, Second-Generation↗
PubMed2005

H1-antihistamines.

Explore the source record for details and available documents.

Antipsychotic Agents↗
PubMed2005

Bupropion for fatigue and as a tumor necrosis factor-alpha lowering agent in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease which can often be severe, progressive and necessitate liver transplantation. The cause of PBC is not known, and treatments other than liver transplantation are often not effective. Among the more common and troublesome symptoms of PBC is fatigue. The etiology of fatigue in PBC is not well-understood, and there is no known treatment for it. Here, we suggest that for a number of reasons that the safe and commonly used oral antidepressant bupropion might be effective for fatigue in PBC: (1) increased monoaminergic and dopaminergic tone to combat fatigue, (2) treatment of concomitant depression, (3) in general for PBC as a tumor necrosis factor-alpha (TNF) lowering agent, if TNF is eventually found to play a role in PBC pathogenesis.

Fatigue↗
PubMed2005

Proposal for using small molecule tumor necrosis factor-alpha lowering agents, possibly bupropion, in aplastic anemia.

Aplastic anemia (AA) is associated with non-trival mortality. Although diagnostic boarders with other myelodysplastic syndromes are unclear, AA is thought, at some point in the chain of events that destroy marrow hematopoiesis, to involve overproduction of tumor necrosis factor-alpha (TNF) and that TNF is the proximal death programming signal the stem cells receive. Thus agents that lower TNF may be of benefit in AA. In preliminary studies we have found that the commonly used antidepressant bupropion lowers TNF. Thus, bupropion is a potential initial small molecule TNF inhibitor to consider for AA.

Anemia, Aplastic↗
PubMed2005

Using histamine (H1) antagonists, in particular atypical antipsychotics, to treat anemia of chronic disease via interleukin-6 suppression.

Anemia of chronic disease (ACD) is a condition of decreased red cell mass secondary to some other chronic inflammatory condition. In ACD total body iron stores are normal, though serum iron is typically low secondary to iron sequestration by macrophages, and often iron supplementation is not an effective treatment for ACD for the same reason. The pathogenesis of ACD had been poorly understood, but recently there has been important progress: upregulation of interleukin-6 (Il-6) secondary to the underlying chronic inflammatory disease upregulates expression of the protein hepcidin. Upregulation of hepcidin causes anemia by a number of mechanisms: decreased intestinal absorption of iron from the duodenum, increased sequestration of iron by macrophages. Thus, downregulation of Il-6 may represent a most important treatment avenue for ACD. Anti-Il-6 antibodies might be a way to lower Il-6 levels, but such antibodies besides being expensive would have to be given intravenously or intramuscularly, and such large immunogenic molecules may not be appropriate in patients already with a chronic inflammatory condition. Here, we note that an immediately available and potentially effective treatment for ACD is to decrease Il-6 levels by histamine (H1) receptor antagonism, given that histamine acting through the H1 receptor is known to be a potent positive regulator of Il-6. Among the classes of medications that are H1 antagonists we point out that atypical antipsychotic medications such as olanzapine and quetiapine are among the most potent H1 antagonists, and can have simple daily dosing schedules and thus may be particularly useful in ACD.

Anemia↗
PubMed2005

The atypical antipsychotic agents ziprasidone [correction of zisprasidone], risperdone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is an unremitting, advancing disease of central nervous system white matter. PML is caused by infection of the JC polyoma virus, most always in patients with immunosupression due to, for example, cancer, anti-rejection transplant medications or HIV. There is no specific treatment or cure for PML, and untreated it has a median life expectancy is less than four months. Highly active antiretroviral treatment (HAART) has greatly reduced the incidence and prevalence of PML in HIV+ patients likely, however, even in the best case scenario of an HIV+ patient with PML and taking HAART, a significant mortality remains. Novel treatments for PML are needed. Recently Atwood and colleagues have found that the cellular receptor for JC virus is the serotonin 5HT2A receptor. In vitro they used the older antipsychotic medications chlorpromazine and clozapine to block the serotonin 5HT2A receptor and block JC virus cell entry. Unfortunately, however, chlorpromazine and clozapine have such significant side effects and toxicities, e.g., extrapyramidal symptoms and the possibility of bone marrow dyscrasias - that they may be problematic to use clinically. Here, we point out that some newer atypical antipsychotics such as zisprasidone, risperidone and olanzapine--medicines with much better side effect and toxicity profiles than the older antipsychotics--in vitro are significantly more potent 5HT2A receptor antagonists than chlorpromazine or clozapine by in some cases more than a factor of 10, and thus may be useful as treatment for or prophylaxis against PML.

Antipsychotic Agents↗
PubMed2004

Paroxetine for hepatopulmonary syndrome?

Hepatopulmonary syndrome (HPS) is a severe pulmonary sequela which can affect up to 15% of patients with cirrhotic liver disease. There is no treatment for HPS other than liver transplantation. The cause of HPS is incompletely understood, but the pulmonary vasodilation in HPS is thought to be related to increased levels of nitric oxide. We therefore suggest that, the extremely safe and commonly used antidepressant medication paroxetine (Paxil) which is a potent nitric oxide synthase (NOS) inhibitor be considered for use in HPS.

Hepatopulmonary Syndrome↗
PubMed2004

Combination of bupropion, paroxetine and quetiapine as adjuvant treatment for multiple myeloma.

Multiple myeloma is a severe plasma dyschrasia with no known treatment or cure, even bone marrow transplantation. Cytokines such as tumor necrosis factor-alpha (TNF) and interleukin-6 (Il-6) are thought to be important trophic factors for the malignant plasma cells. In turn, histamine and nitric oxide are positive regulatory factors for Il-6. Here we note that the safe, approved and commonly used psychiatric medicines bupropion (Wellbutrin), paroxetine (Paxil) and quetiapine (Seroquel) are respectively potent TNF, nitric oxide and histamine antagonists and thus might find some use in treatment of multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Bupropion for Blau syndrome.

Blau syndrome (BS) is an autosomal dominantly inherited disease characterized by granulomas and arthritis. The gene mutated in BS was recently found to be CARD15. Mutations in this gene also occur in about 20% of patients with Crohn's disease (CD), though with different mutations than in the Crohn's patients. We are not aware of any cure or specific treatment for BS. We have found that bupropion is effective for CD, and we now suggest that bupropion be considered for treatment of BS.

Arthritis↗
PubMedDate not supplied

Review of evidence that posttransplantation psychiatric treatment commonly affects prolactin levels and thereby influences graft fate.

Delirium, depression and other psychiatric difficulties are commonly encountered by posttransplantation patients, and antipsychotic medicines are frequently used to treat these difficulties. This article reviews previous research data concerning the immunological effects of these medicines, with particular focus on the consequences of prolactin elevation. Unproven but of concern is that these effects may influence graft fate. Older antipsychotic medicines such as haloperidol and chlorpromazine have a high likelihood of elevating prolactin. Prolactin is an immunologically active molecule generally promoting bone marrow function. This may be of benefit post-stem-cell transplant, helping engraftment, but could further rejection of solid-organ transplants. Elevated prolactin is implicated in the facilitation of graft-versus-host disease. Aripiprazole is the antipsychotic medicine least likely to increase prolactin (and may actually decrease prolactin); risperidone, the most likely to increase prolactin. Olanzapine, quetiapine and ziprazadone are antipsychotic medicines with a lower likelihood of elevating prolactin. Older ("neuroleptic") antipsychotics, such as chlorpromazine, droperidol and haloperidol, perphenazine and many others, are likely to elevate serum prolactin. Among antidepressants, most serotonin reuptake inhibitors, with the exception of sertraline, can slightly elevate prolactin. The atypical (i.e., alone in their class) antidepressants bupropion and mirtazapine are prolactin neutral. The immunological consequences of psychiatric medicines should be considered when treating transplant patients for delirium, depression and thought disorders; in addition, if elevation of prolactin is thought to be of immunological importance during psychiatric treatment, then it should be monitored and treated. The dopamine agonists used to treat Parkinson's disease--bromocriptine, pergolide, pramipexole, ropinerole--usually reverse antipsychotic-induced prolactin increases without compromising psychiatric effectiveness.

Antipsychotic Agents↗
PubMedDate not supplied

Ribavirin in cancer immunotherapies: controlling nitric oxide augments cytotoxic lymphocyte function.

Either ribavirin (RBV) or cyclophosphamide (CY) can shift an immune response from Th2 toward a Th1 cytokine profile. CY is used in this role in various current cancer immunotherapy attempts but with mixed success. More potent and reliable immunoadjuvants and Th1 response biasing methods are needed. RBV is used today mainly to augment interferon-alpha treatment of hepatitis C. RBV shifts an immune response from Th2 toward Th1 more effectively than CY and may be a safe and useful adjuvant for current cancer immunotherapeutic efforts. RBV is thought to act by inhibition of tetrahydrobiopterin synthesis. Tetrahydrobiopterin is an essential cofactor for all known isoforms of nitric oxide synthase. Lowered nitric oxide favors Th1 development as high levels favor Th2 weighting.

Animals↗