Triazolobenzodiazepines Exert Immunopotentiating Activities on Normal Human Peripheral Blood Lymphocytes

Jirillo, Emilio; Maffione, Angela Bruna; Greco, Béatrice; Cannuscio, B; Calvello, Rosa; Covelli, Venusia

doi:10.3109/08923979309026001

Cited by 14 publications

(5 citation statements)

References 22 publications

(10 reference statements)

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“…Speculation linking benzodiazepines to infections originally began when multiple in vivo pharmacology studies demonstrated immune dysfunction and bacterial infections of greater frequency among rodents exposed to diazepam [ 88 – 90 ]. Despite these results, the immunopharmacology of peripheral and central benzodiazepine GABA A receptors remains complex as other in vitro studies have shown potentiation of immune response from triazolo-benzodiazepines such as alprazolam and triazolam [ 91 – 93 ]. This begs the question as to whether there is a true ‘class effect’ of these agents or if there are indeed indisputable immunopharmacological differences between them.…”

Section: Infectionsmentioning

confidence: 99%

Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research

2017

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Various adverse events resulting from, or associated with, benzodiazepine and/or Z-drug use have been extensively reported on and discussed in great detail within the biomedical literature. It is widely accepted that motor vehicle accidents and falls leading to fractures in older adults are major adverse events that have been shown to occur more frequently in users of sedative-hypnotic medication, especially of the benzodiazepine and related Z-drug variety. However, the last few years have seen increasing reports in the literature raising the issue of benzodiazepine and Z-drug exposure in the development of other serious medical issues including dementia, infections, respiratory disease exacerbation, pancreatitis, and cancer. This article provides an overview and interpretation on the current state of evidence regarding each of these associations and proposes what gaps in the evidence for drug-exposure–harm associations need to be addressed in the future for the purpose of evaluating causality of harm as it relates to these drugs.

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Section: Infectionsmentioning

confidence: 99%

Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research

2017

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“…Alprazolam could up-regulate the depressed phagocytosis and killing in these patients, also leading to a substantial amelioration of clinical manifestations [72,73]. In these patients, the effects of Alprazolam on TNF-α release was not verified, even if this benzodiazepine has been shown to reduce LPS-induced release of TNF-α in mice [74].…”

Section: Stress-induced Modulation Of the Immune Responsementioning

confidence: 99%

“…Patients with MWA take therapeutical advantage from the use of alprazolam, a BDZ endowed with immunomodulating activities, in terms of either inhibition [71] or enhancement [72,73] of responses. Alprazolam could up-regulate the depressed phagocytosis and killing in these patients, also leading to a substantial amelioration of clinical manifestations [72,73].…”

Section: Stress-induced Modulation Of the Immune Responsementioning

confidence: 99%

Drug Targets in Stress-Related Disorders

Covelli¹,

Passeri²,

Leogrande³

et al. 2005

CMC

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Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-alpha (TNF- alpha), and interleukin- 1 beta] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients. In MWA patients, a beta-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-alpha serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients. Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-gamma in these patients, thus indicating a predominance of T helper (h)1 response in CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation o...

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“…On the contrary, the same drug does not interfere with the antibacterial activity exerted by normal human peripheral blood lymphocytes (PBL) (7). On the other hand, alprazolam and triazolarn, two triazolobenzodiazepines, markedly enhance lymphocyte-dependent antibacterial activity from normal donors, while they do not influence polymorphonuclear cell (PMN) and monocyte phagocytosis and killing (7,8).…”

Section: Introductionmentioning

confidence: 99%

In Vivo Effects of Alprazolam and Lorazepam on the Immune Response in Patients With Migraine Without Aura

Covelli¹,

Maffione²,

Greco³

et al. 1993

Immunopharmacology and Immunotoxicology

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Over the past few years, the immunomodulating role of benzodiazepines (BDZ) has been reported in literature. In particular, diazepam is an inhibitory BDZ with regard to its effects on the phagocytic and metabolic activities of polymorphonuclear cells (PMN) and monocytes, while triazolobenzodiazepines (alprazolam and triazolam) upregulate normal human peripheral blood T lymphocyte function. On these grounds, the administration of alprazolam (1 mg/per day for 1 month) in 13 patients with migraine without aura (MWA) and of lorazepam (2 mg/per day for 1 month) in 10 matched MWA subjects has been evaluated in terms of immune response. Results show that before administration of BDZ in both groups of patients phagocytosis and killing of PMN and monocytes were profoundly depressed and the same was true for the lymphocyte-dependent antibacterial activity. After one month treatment lorazepam further decreased lymphocyte function without modifying phagocytic capabilities. On the contrary, alprazolam increased PMN phagocytosis and killing and monocyte phagocytosis without modifying antibacterial activity values. Taken together, these results further support the existence of different classes of BDZ in terms of their immunomodulating capacities. Moreover, alprazolam seems to be a more appropriate BDZ for treating immunocompromised patients, even including MWA patients.

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Triazolobenzodiazepines Exert Immunopotentiating Activities on Normal Human Peripheral Blood Lymphocytes

Cited by 14 publications

References 22 publications

Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research

Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research

Drug Targets in Stress-Related Disorders

In Vivo Effects of Alprazolam and Lorazepam on the Immune Response in Patients With Migraine Without Aura

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