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Biomedical subjects

R E Kast

Publications and source records attributed to R E Kast.

At least 19 recordsLinked to original sources
PubMed2006

Some fibrocystic breast change may be caused by sexually transmitted H. pylori during oral nipple contact: supporting literature and case report of resolution after gut H. pylori eradication treatment.

OBJECTIVES: To briefly review previously published evidence for Helicobacter pylori (Hp), colonization of extra-intestinal sites and suggest an hypothesis that breast acini and ducts be added to this list, concluding such breast colonization is not rare and is a sexually transmitted infection. METHODS: PubMed literature search and review with a case report. CONCLUSIONS: (1) Evidence indicates oral Hp is common and can remain in the mouth after successful eradication in stomach and duodenum. (2) Evidence indicates that the breast is also occasionally colonized by Hp. (3) Hp may be injected retrograde up into ducts of the breast during oral nipple stimulation during sexual activity and this Hp may give rise to some cases of fibrocystic breast change. (4) A case of painful fibrocystic change that had been present for two years in a 27 year old female, resolved after gastrointestinal Hp treatment.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2006

A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice.

In a wide range of human diseases of inflammatory nature like Crohn's disease, pathology is mediated in part by pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF) or interferon-gamma. We show here that a commonly used generic antidepressant bupropion, in wide use worldwide to treat depression in humans for a decade now, profoundly lowers levels of TNF, interferon-gamma, and interleukin-1 beta in vivo, in a mouse lipopolysaccharide (LPS) induced inflammation model. Mice challenged with an otherwise lethal dose of LPS were protected by bupropion and levels of the anti-inflammatory cytokine interleukin-10 were increased. Previous data in rodents and humans indicate antidepressant effects of bupropion are mediated by its weak reuptake inhibition of norepinephrine and dopamine. Concordant with this, TNF suppression by bupropion in our mouse LPS model was largely abrogated by beta-adrenergic or dopamine D1 receptor antagonists but not by a D2 antagonist. TNF synthesis is controlled by an inverse relationship with intracellular cyclic adenosine monophosphate (cAMP) and stimulation of either beta-adrenoreceptors or D1 dopaminergic receptors result in increased cAMP but stimulation of D2 receptors lowers cAMP. We conclude that bupropion may suppress TNF synthesis by mediating increased signaling at beta-adrenoreceptors and D1 receptors, resulting in increased cAMP that inhibits TNF synthesis. Bupropion is well tolerated also in non-psychiatric populations and has less risk with long term use than current anti-inflammatory, immunosuppressive or TNF suppressive treatments such as prednisone, azathioprine, infliximab, or methotrexate. New anti-inflammatory treatments are needed. We believe a new chapter in antiinflammatory, TNF lowering treatment of disease has been opened. Bupropion's use for this in humans should be explored.

Adrenergic beta-Antagonists↗
PubMed2006

Aspirin, TNF-alpha, NFkB, and survival in multiple myeloma: the importance of measuring TNF-alpha.

Aspirin and other cyclooxygenase inhibitors can increase levels of tumor necrosis factor-alpha and engage pro-apoptosis paths and/or anti-apoptosis paths. Seemingly conflicting data are briefly reviewed. Aspirin has been shown to slightly increase survival duration in multiple myeloma. In this brief note caution is raised about use of aspirin and COX inhibitors generally in inflammatory states and specifically in myeloma. Should they increase tumor necrosis factor-alpha they could exacerbate disease. A figure is presented showing the tendency for interleukin-6 and tumor necrosis factor-alpha, both demonstrated to be growth factors in myeloma, to be counter-regulated. Since both are now easily measured by specialty labs, it would be reasonable to monitor these during myeloma treatment generally, and particularly when using aspirin, COX inhibitors, or any other drug with potential to increase these growth factors.

Apoptosis↗
PubMed2005

Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: new insights into the biology of TNF-alpha giving new treatment opportunities--the role of bupropion.

Etanercept is a commercially available pharmaceutical protein approved for treatment of rheumatoid arthritis, RA. Given subcutaneously, etanercept binds and inactivates soluble tumor necrosis factor-alpha, TNF. Etanercept has a good safety record and is of benefit in lowering pain, inflammation, and joint destruction in RA. RA is mediated by many factors, TNF among them. Malignant myeloma, MM, is a malignant clonal expansion of a post-germinal center B lymphocyte. Since TNF is a necessary growth factor for expansion and maintenance of MM cells, and etanercept binds soluble TNF and is of clinical benefit in RA, etanercept was tried experimentally in MM. Contrary to expectations, etanercept resulted in increased levels of TNF and possibly shortened survival. This paper presents an hypothesis of how this happened. There are two cognate receptors for TNF, termed R1 and R2 and two forms of TNF, soluble and transmembrane. Soluble TNF has greater affinity for TNF-R1 than for TNF-R2. Transmembrane TNF has equal affinity for the two receptors. Since TNF-R2 signaling tends to be more anti-apoptotic and activating of nuclear factor kappa B, NFkB, than is TNF-R1, and TNF-R1 tends to be more pro-apoptotic than is TNF-R2, by inactivating soluble TNF while leaving transmembrane TNF signaling relatively unchanged, etanercept changed the balance in TNF signaling from TNF-R1 towards TNF-R2 weighting. Anti-apoptosis and TNF synthesis would have been up-regulated by that shift. Early data indicates that the common generic antidepressant bupropion may ameliorate Crohn's disease course by down regulating TNF synthesis, maybe it will slow the course of MM as well.

Bupropion↗
PubMed2005

Tiagabine may reduce bruxism and associated temporomandibular joint pain.

Tiagabine is an anticonvulsant gamma-aminobutyric acid reuptake inhibitor commonly used as an add-on treatment of refractory partial seizures in persons over 12 years old. Four of the 5 cases reported here indicate that tiagabine might also be remarkably effective in suppressing nocturnal bruxism, trismus, and consequent morning pain in the teeth, masticatory musculature, jaw, and temporomandibular joint areas. Tiagabine has a benign adverse-effect profile, is easily tolerated, and retains effectiveness over time. Bed partners of these patients report that grinding noises have stopped; therefore, the tiagabine effect is probably not simply antinociceptive. The doses used to suppress nocturnal bruxism at bedtime (4-8 mg) are lower than those used to treat seizures.

Adult↗
PubMed2003

Tenofovir, COX inhibitors and zileuton during cancer immunotherapies: up-regulated TNF-alpha increases antigen driven lymphocyte proliferation.

Current attempts at active immunization of patients to their adenocarcinomas have heretofore met with a curiously little success. The carrier antigens, viral vector proteins, and other co-administered antigens typically elicit strong cell-mediated or humoral responses while the relevant cancer antigen elicits undetectable or feeble responses and often minimal if any retardation of malignant tissue growth is seen. There are exceptions but clearly more effective cancer antigen immunization strategies are needed. Adenylate cyclase, AC, catalyses the conversion of ATP to cyclic adenosine monophosphate (cAMP). Increased cAMP down regulates tumor necrosis factor-alpha, TNF, and decreased cAMP reliably up-regulates synthesis and release of TNF. TNF enhances dendritic cell (DC) maturation processes started by other stimuli. TNF promotes antigen responding CD4+ and CD8+ lymphocytes' proliferation, and suppresses suppressor T cells during primary immunization. Tenofovir is an oral antiviral drug currently used in anti-HIV treatments. It is an acyclic nucleoside analogue of adenosine monophosphate that also happens to increase TNF. The mechanism has not been established but antagonism of cAMP's inhibition of TNF is the likely path. Prostaglandin E (PGE) is a stimulatory allosteric modifier of AC and thus suppresses TNF via the resultant increase of cAMP. Since cyclooxygenase, COX, is the rate-controlling enzyme in PGE production, COX inhibitors, otherwise known as non-steroidal anti-inflammatory drugs (NSAID), increase TNF synthesis and release by depriving AC of PGE. Indomethacin, diclofenac and ketorolac are COX inhibitors that have been on the market for many years that would be well suited for use to increase TNF levels. This paper reviews the data on TNF up-regulation by tenofovir and COX inhibitors and the consequent augmented antigen driven lymphocyte proliferation secondary to increased TNF and suggests exploration of tenofovir and COX inhibitors like indomethacin, diclofenac or ketorolac in augmentation of current cancer immunotherapy attempts. Profound COX inhibition can lead to a compensatory leukotriene increase and leukotrienes have been identified as growth and survival factors in various gastrointestinal cancers. Therefore, zileuton, an orally active 5-lipooxygenase inhibitor that prevents leukotriene synthesis, should be added whenever profound COX inhibition is undertaken in cancer immunotherapies.

Adenine↗
PubMed2002

Acarbose related diarrhea: increased butyrate upregulates prostaglandin E.

The alpha-glucosidase inhibitor acarbose is a drug used to treat type II diabetes mellitus. It occasionally causes diarrhea. Acarbose related colitis has been reported. This note explains how such side effects may occur. Because of small intestine alpha-glucosidase inhibition, increased starch reaches the colon. Increased colonic starch allows the flora to generate increased butyrate. Absorbed butyrate causes up-regulation of prostaglandin E series production and the latter generates water and electrolyte loss. A colitis results when this acarbose driven process is extreme. Acarbose should be avoided in pregnancy until above can be disproved due to teratogenic and labor inducing potential of prostaglandin E. A theoretical reason for avoiding acarbose in Crohn's disease is presented. Despite these considerations, acarbose remains a safe medicine and may even have salutary intestinal consequences stemming from the same physiology as outlined here.

Acarbose↗
PubMed2001

Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy.

Mirtazapine is an antidepressant that has a receptor-binding profile that may suit it for use in controlling the nausea and insomnia of highly emetic cancer chemotherapy. Mirtazapine binds to and is antagonistic at the 5HT3 receptor, as are the group of medicines related to ondansetron. Mirtazapine is anxiolytic by virtue of its antagonism of the 5HT2 receptor, and is strongly sleep inducing. The resulting sleep quality tends to be superior to that induced by benzodiazapines. There has been concern about mirtazapine's potential to suppress bone marrow function, so that further study is required before routine use in chemotherapy can be adopted.

Antidepressive Agents, Tricyclic↗
PubMed2001

Borage oil reduction of rheumatoid arthritis activity may be mediated by increased cAMP that suppresses tumor necrosis factor-alpha.

Recent double blind studies have shown some benefit of borage oil in treatment of rheumatoid arthritis. Tumor necrosis factor-alpha has been shown to be a central mediator of inflammatory and joint destructive processes in rheumatoid arthritis. In this paper, evidence from published research is reviewed that indicates gamma linolenic acid component of borage oil increases prostaglandin E levels that increase cAMP levels that in turn suppress tumor necrosis factor-alpha synthesis. If this biochemical path of borage oil is correct then (1) concomitant non-steroidal anti-inflammatory drug use would tend to undermine borage oil effects, and (2) borage oil would be contraindicated in pregnancy given the teratogenic and labor inducing effects of prostaglandin E agonists.

Abortion, Spontaneous↗
PubMed2000

Tumor necrosis factor has positive and negative self regulatory feed back cycles centered around cAMP.

This paper reviews data that allow recognition of, (1) two opposing intracellular chains of events occurring subsequent to an increase in tumor necrosis factor, TNF, and (2) that these two chains have opposing effects on intracellular cyclic adenosine monophosphate, cAMP. The two chains - attenuation cycle, where TNF results in prostaglandin E mediated increased cAMP and, consequent to this, suppression of TNF levels; and an amplification cycle, where increased TNF increases intracellular cyclic adenosine phosphodiesterase, lowering cAMP, thereby raising TNF levels further. TNF is a central mediator in several inflammatory diseases. Understanding TNF control systems will allow better delineation of pathophysiology and clinical care.

Animals↗