Dose-related Effects Research Articles

Anabolic androgen use in the management of hereditary angioedema: Not so cheap after all

BackgroundHereditary angioedema due to C1 inhibitor deficiency (HAE) is a rare, life-threatening disease that imposes a significant burden on affected patients. 17α-alkylated androgens (anabolic androgens) decrease attack frequency and severity but carry the risk of potentially serious dose-related adverse effects. Despite the emergence of targeted therapies for HAE, continued anabolic androgen use has been driven in part by their low cost. ObjectiveTo examine the hidden cost of anabolic androgen use related to the risk of developing non-HAE comorbidities. MethodsPatients with HAE were identified in the Southern California Kaiser Permanente database using clinical and laboratory findings compatible with HAE. These patients were stratified into anabolic androgen exposed and nonexposed groups. Matched controls were selected from the Kaiser database who did not have HAE or anabolic androgen exposure. Using multivariate analysis, we determined the number of non-HAE comorbidities linked to anabolic androgen use. We next determined the association between dosing and increasing exposure to anabolic androgens and the likelihood of having various comorbidities. ResultsPatients with HAE exposed to anabolic androgens had a 28% increase (P = .04) in non-HAE comorbidities when compared with their matched (nonexposed) controls. With each gram per month increase in exposure, a 12% increase in non-HAE comorbidities is observed (P < .01). The most commonly occurring non-HAE comorbidities were psychiatric, muscle cramps, obesity, and hyperlipidemia. ConclusionOur data suggest that long-term anabolic androgen use enhances the risk of developing comorbid health conditions, thus amplifying the cost of care. Our report provides additional support for the preferred use of newer, targeted therapies for the management of HAE.

Enhancing Effects of NMDA-Receptor Blockade on Extinction Learning and Related Brain Activation Are Modulated by BMI.

A distributed network including prefrontal and hippocampal regions is involved in context-related extinction learning as well as in renewal. Renewal describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Animal studies have demonstrated that prefrontal, but not hippocampal N-methyl-D-aspartate receptor (NMDAR) antagonism disrupted extinction learning and processing of task context. However, human studies of NMDAR in extinction learning are lacking, while NMDAR antagonism yielded contradictory results in other learning tasks. This fMRI study investigated the role of NMDAR for human behavioral and brain activation correlates of extinction and renewal. Healthy volunteers received a single dose of the NMDAR antagonist memantine prior to extinction of previously acquired stimulus-outcome associations presented in either identical or novel contexts. We observed better, and partly faster, extinction learning in participants receiving the NMDAR antagonist compared to placebo. However, memantine did not affect renewal. In both extinction and recall, the memantine group showed a deactivation in extinction-related brain regions, particularly in the prefrontal cortex, while hippocampal activity was increased. This higher hippocampal activation was in turn associated with the participants' body mass index (BMI) and extinction errors. Our results demonstrate potentially dose-related enhancing effects of memantine and highlight involvement of hippocampal NMDAR in context-related extinction learning.

Re-evaluation of glycerol (E422) as a food additive.

The ANS Panel provides a scientific opinion re‐evaluating the safety of glycerol (E 422) used as a food additive. In 1981, the Scientific Committee on Food (SCF) endorsed the conclusion from the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1976 of ‘acceptable daily intake (ADI) for man not specified’. The Panel concluded that glycerol has low acute toxicity and that local irritating effects of glycerol in the gastrointestinal tract reported in some gavage studies was likely due to hygroscopic and osmotic effects of glycerol. Glycerol did not raise concern with respect to genotoxicity and was of no concern with regard to carcinogenicity. Reproductive and prenatal developmental studies were limited to conclude on reproductive toxicity but no dose‐related adverse effects were reported. None of the animal studies available identified an adverse effect for glycerol. The Panel conservatively estimated the lowest oral dose of glycerol required for therapeutic effect to be 125 mg/kg bw per hour and noted that infants and toddlers can be exposed to that dose by drinking less than the volume of one can (330 mL) of a flavoured drink. The Panel concluded that there is no need for a numerical ADI and no safety concern regarding the use of glycerol (E 422) as a food additive at the refined exposure assessment for the reported uses. The Panel also concluded that the manufacturing process of glycerol should not allow the production of a food additive, which contains genotoxic and carcinogenic residuals at a level which would result in a margin of exposure below 10,000. The Panel recommended modification of the EU specifications for E 422. The Panel also recommended that more information on uses and use levels and analytical data should be made available to the Panel.

Antinociceptive and immunosuppressive effect of opioids in an acute postoperative setting: an evidence-based review

### Key points Opioids remain the mainstay of perioperative pain management for many surgical procedures and settings. However, they are well known to cause side-effects, including nausea, vomiting, hallucinations, urinary retention, constipation, somnolence, and respiratory depression. More recently, there have been some concerns regarding their long-term antinociceptive effects due to the development of tolerance or hyperalgesia.1 There have also been reports of suppression of the immune system by opioids.1 In this review, the evidence and the possible mechanisms for the occurrence of acute tolerance, hyperalgesia, and immunosuppression in the perioperative setting will be explored. Evidence-based opioid-sparing treatments may be used in the perioperative setting to diminish the dose-related adverse effects of opioids. ### Opioid tolerance and hyperalgesia Tolerance occurs when a patient's response to a drug reduces over time and necessitates an increase in dose to maintain the desired result. This results from desensitization of opioid receptors due to a number of mechanisms as outlined below. Opioid-induced hyperalgesia (OIH) is a state of pain receptor sensitization caused by exposure to opioids. Clinically, this is recognized by a paradoxical response to opioid analgesics. While opioids are being used to manage the pain, they may actually result in an increase in sensitivity to painful stimuli. Therefore, any further increase in the opioid dose could result in an increased perception of painful stimuli.2 There is strong positive evidence from animal studies, …

Safety assessment of medium- and long-chain triacylglycerols containing 30% (w/w) medium-chain fatty acids in mice and rats

A novel medium- and long-chain triacylglycerols (MLCT), with 30% (w/w) medium-chain fatty acids (MCFA) was evaluated for its safety as a dietary fat in mice and rats. The subacute oral toxicity study showed that the maximum tolerated dose exceeded 54.33 g/kg body weight (kg bw)/day. In the 90-day feeding study, no dose-related adverse effects were observed in rats administered diets formulated with different levels of MLCT (2.0, 4.0, and 8.0 g/kg bw/day) as compared to the rapeseed oil control diet. Further safety assessment in pregnant rats did not reveal any significant difference relative to the control at a treatment level up to 8.0 g MLCT/kg bw/day. The results from this study indicated the safe use of MLCT with high contents of MCFA in food products for improving human health.

Tolerability and Safety of Commonly Used Antiepileptic Drugs in Adolescents and Adults: A Clinician's Overview.

This paper discusses the issues surrounding the tolerability and safety of the commonly used antiepileptic drugs (AEDs) in adolescents and adults. The content includes dose-related adverse effects, idiosyncratic reactions, behavioural and psychiatric comorbidities, chronic problems, enzyme induction and teratogenesis. Twenty-one AEDs are discussed in chronological order of their introduction into the UK, starting with phenobarbital and ending with brivaracetam. Wherever possible, advice is given on anticipating, recognising and managing these issues and thereby improving the lives of people with epilepsy, most of whom will need to take one or more of these agents for life. Avoidance of side effects will increase the possibility of achieving and maintaining long-term seizure freedom. Alternatively, adverse events from AEDs will substantially reduce quality of life and often result in higher healthcare costs.

Effects of hydroxyl-functionalized multiwalled carbon nanotubes on sperm health and testes of Wistar rats.

Carbon nanotubes (CNTs) are promising candidates for various applications including biomedical purposes. Owing to their remarkable physical, mechanical, electrical and chemical properties, CNTs have become an area of intense research and industrial activity in recent years. Therefore, toxicity and risk assessment studies are becoming increasingly important. The present study was designed to assess the effects of hydroxyl-functionalized multiwalled CNTs (OH-f MWCNTs) on sperm health and testes of adult Wistar rats. Animals were treated with different doses of OH-f MWCNTs (0.4, 2.0 and 10.0 mg/kg) along with a control group receiving only vehicle. Assessments after 15 alternate intraperitoneal doses revealed dose-related adverse effects on many endpoints tested. Results of the study showed significant impairment of sperm health at 2.0 and 10.0 mg/kg. Histology of testes demonstrated degeneration of germinal epithelium and loss of germ cells in the treatment groups. The exposure resulted in increased oxidative stress in testes in a dose-dependent manner. The findings of the study demonstrate that CNTs are potentially harmful for male reproductive health.

The antioxidant role of agomelatine and gallic acid on oxidative stress in STZ induced type I diabetic rat testes.

Diabetes is a multisystem disorder and its effects are observed on the reproductive system. One of the main causes of testicular tissue damage is diabetes-induced overproduction of reactive oxygen species and glycated end products. The main objectives of this study were to investigate the possible effects of agomelatine (AG) and gallic acid (GA) in suppressing oxidative stress in Type I diabetes induced testicular damage. A total of 28 adult male rats were included in the study. Diabetes was induced by intraperitoneal injection of streptozocin (STZ, 55mg/kg) to 21 rats, which were then randomly assigned to 3 groups; 1mL saline solution was given to the diabetes+saline group by oral gavage, 20mg/kg/day oral AG was given to the diabetes+AG group, and 20mg/kg/day oral GA was given to the diabetes+GA group for 4 weeks. Tumor necrosis factor α (TNFα), nitric oxide synthase 2 (NOS2), fibronectin and vascular endothelial growth factor (VEGF) were used for the investigation of inflammation, fibrosis and vascular structures. The terminal-deoxynucleoitidyl-transferase mediated nick end-labeling assay (TUNEL) was used to detect apoptosis. Testicular tissue total antioxidant capacity values were tested by biochemical analysis. AG treatment showed an improvement on biochemical parameters and histopathological appearance on the rat testes. GA showed dose-related regenerative effects on biochemical parameters. Histologically, a minimal healing effect was determined on the testes damage. In conclusion, it was observed that AG is a potentially beneficial agent for reducing testicular damage by decreasing oxidative stress level. However, GA was seen to have a poor therapeutic effect.

Synergistic Effects of Serotonin or Dopamine Combined With Lidocaine at Producing Nociceptive Block in Rats.

The purpose of this experiment was to investigate the interactions of the local anesthetic lidocaine combined with an agent (serotonin or dopamine) as infiltrative anesthetics. Cutaneous analgesia was characterized by the blockade of the cutaneous trunci muscle reflex following 6 skin pinpricks on the rat back. Serotonin or dopamine at producing cutaneous analgesia in a dosage-dependent fashion was compared with lidocaine. Drug-drug interactions were calculated using the isobolographic analysis. We revealed that serotonin, dopamine, and lidocaine provoked dose-related cutaneous analgesic effects. On the 50% effective dose basis, the rank of drugs' potency was found to be serotonin (1.70 [1.56-1.85] μmol) > lidocaine (5.18 [4.67-5.75] μmol) > dopamine (43.0 [40.9-45.2] μmol) (P < 0.01). At doses equivalent to their 25%, 50%, and 75% effective doses, serotonin or dopamine elicited a longer duration of action than lidocaine (P < 0.01) on producing cutaneous analgesia. Coadministration of serotonin or dopamine with lidocaine produced a synergistic effect. The preclinical data showed that serotonin and dopamine produce dose-related cutaneous analgesic effects as an infiltrative anesthetic. Serotonin has a better potency with a much longer duration of action compared with lidocaine at provoking cutaneous analgesia. Serotonin or dopamine as an adjuvant increases the quality of lidocaine in cutaneous analgesia.

Design, Development and Evaluation of Buccal Tablets of Pregabalin

The present investigation is concern with formulation and evaluation of mucoadhesive buccal tablets containing anti convulsant drug. Pregabalin to circumvent the first pass effect and to improve its bioavailability with reduction in dosing frequency and dose related side effects. The tablets were prepared by direct compression method. Nine formulations were prepared with different polymers like carbopol, HPMC, Xanthan gum with varying concentration. The tablets were tested for weight variation, hardness, drug content uniformity, swelling index and in vitro drug dissolution study. FTIR studies showed no evidence on interactions between drug and polymer. The in vitro release of Pregabalin was performed under sink conditions (Phosphate buffer PH 7.2, 37 ± 0.5°C) using dissolution apparatus USP type II. The best in vitro drug release profile was achieved with the formulation F6 which contains the drug, HPMC (30 mg). The formulation F6 containing 50 mg of Pregabalin exhibited 8 hrs sustained drug release i.e. 99.01%. The in vitro release kinetics studies reveal that formulation fits with Korsmeyer-Peppas model and mechanism of drug release is anolomus diffusion.

Formulation and Evaluation of Sustained Release Matrix Tablet of Anti-Amoebic Drug by Natural Polymers

The present study was to formulate Metronidazole sustained release matrix tablet using Xanthan gum, and guar gum as natural polymers and to elucidate the effect of type of polymers and its concentration on release pattern of drug from sustained release matrix tablets. Metronidazole matrix tablets were prepared in two batches (batch number F1 to F2) by direct compression method using xanthan gum and guar gum as natural polymers and Microcrystalline cellulose as a binder and pyrolidone as a water soluble polymer. The in vitro drug release studies of all the batches indicated that optimized formulation pertaining to Batch no. F2 was a promising system to provide sustained release effect of drug. The release pattern of the above formulation was best fitted to zeroorder model and first order model. Mechanism of drug release followed was non-Fickian (super case-II) transport mechanism. Based on the above studies it can be concluded that this type of Anti-ameobic drug can be effectively formulated using different classes of natural polymers which can have greater bioavailability with less dose related side effects having better patient compliance.

Dose Related Psychiatric Adverse Effect of Lamotrigine in Management of Bipolar Disorder

Lamotrigine is increasingly being used as an effective maintenance treatment in bipolar disorders to control mood swings. This medication is generally well tolerated with most of its adverse reactions being well documented. However there are some reports of certain psychiatric symptoms associated with the use of Lamotrigine for treatment of mental disorders, but there is a paucity of data to support such findings. Here we discuss the case of a Caucasian female who presented to us with a history of bipolar disorder which was well controlled with Lithium. However the patient was advised to taper the use of Li due to long term Li induced damage to kidneys. She was started on Lamotrigine as an add-on, on a cross taper model. Initially she tolerated Lamotrigine well with mild-moderate physical side effects of nausea, warm flashes and constipation. After the dose was titrated to 100 mg/day of Lamotrigine, the patient demonstrated some psychiatric side effects such as vivid dreams and nightmares, which was resolved on reducing the dose of Lamotrigine to 50 mg/daily. However over the long term, she had a relapse of bipolar symptoms as Lamotrigine seemed not to be tolerated at high enough dose to prevent such a relapse. This case is consistent with some previous reports of occurrence of dose related psychiatric adverse side effect of Lamotrigine.

Weight and content uniformity study of captopril half-tablets

Dose-related adverse effects of medications are a major problem in modern medical practice. The dose, based on drug company guidelines in package inserts, may not be correct for many patients. Tablet splitting or dividing has been an accepted practice for many years as a means of obtaining the prescribed dose of medication. As model tablets for this investigation, three brands of captopril scored tablets labeled to contain 50 mg were used. Tablets were split by hand, tablet splitter, or knife. The percentages by which each whole tablet’s or half-tablet’s drug content and weight difference from sample mean values were compared with Ph. Eur. specification ranges for drug weight and content. Using tablet splitter, the results showed that 13.3% and 5.83 % of half-tablets fell outside of the proxy Ph. Eur specification for weight and content respectively. In case of hand and knife splitting, the percentage of half-tablets that fell outside of the proxy Ph. Eur specification increased to 62.5% (weight) and 20% (content).

The Therapeutic Effect of Vitamin C in an Animal Model of Complex Regional Pain Syndrome Produced by Prolonged Hindpaw Ischemia-Reperfusion in Rats.

Objectives: It is known that increased free radicals from oxidative stress are one of the major causes of complex regional pain syndrome (CRPS). In this study, we tested the hypothesis that vitamin C has a dose-related treatment effect in a chronic post-ischemic pain (CPIP) model.Methods: A total of 49 male rats weighing 250 to 350 g were used. The 4 treatment groups were control (no medication), group 1.0 (administration of 1 mg/day for vitamin C for 5 days), group 2.5 (administration of 2.5 mg/day vitamin C for 5 days), and group 7.5 (administration of 7.5 mg/day vitamin C for 5 days). The 50% mechanical withdrawal threshold and total blood antioxidant status (TAS) were measured before and after administration of vitamin C.Results: Twenty-eight CPIP model rats were generated from 49 rats. Seven rats were randomly allocated to each group. The 50% mechanical withdrawal threshold of group 2.5 (after the administration of vitamin C) was higher than that of the control group and group 1.0 (P < 0.05). At 1 day of the administration of vitamin C, the 50% mechanical withdrawal threshold of group 1.0 was higher than that of the control group and the blood levels of TAS in groups 2.5 and 7.5 were higher than that in control group (P < 0.05). Twelve days after the administration of vitamin C, the blood levels of TAS in groups 2.5 and 7.5 were lower than that of the control group (P < 0.05).Discussion: The administration of a proper dose of vitamin C can reduce oxidative stress, increase antioxidants, and recover the threshold for mechanical allodynia in the CPIP model.

The effects of intra-cerebroventricular administered rocuronium on the central nervous system of rats and determination of its epileptic seizure-inducing dose

The aim of this study was to investigate the effects of intracerebroventricularly administered rocuronium bromide on the central nervous system, determine the seizure threshold dose of rocuronium bromide in rats, and investigate the effects of rocuronium on the central nervous system at 1/5, 1/10, and 1/100 dilutions of the determined seizure threshold dose. A permanent cannula was placed in the lateral cerebral ventricle of the animals. The study was designed in two phases. In the first phase, the seizure threshold dose of rocuronium bromide was determined. In the second phase, Group R 1/5 (n=6), Group 1/10 (n=6), and Group 1/100 (n=6) were formed using doses of 1/5, 1/10, and 1/100, respectively, of the obtained rocuronium bromide seizure threshold dose. The rocuronium bromide seizure threshold value was found to be 0.056±0.009μmoL. The seizure threshold, as a function of the body weight of rats, was calculated as 0.286μmoL/kg-1. A dose of 1/5 of the seizure threshold dose primarily caused splayed limbs, posturing, and tremors of the entire body, whereas the dose of 1/10 of the seizure threshold dose caused agitation and shivering. A dose of 1/100 of the seizure threshold dose was associated with decreased locomotor activity. This study showed that rocuronium bromide has dose-related deleterious effects on the central nervous system and can produce dose-dependent excitatory effects and seizures.

The effect of hydro-alcoholic extract of Achillea millefolium on appetite hormone in rats.

Achillea millefolium (A. millefolium) is known as an orexigenic herb in Iranian traditional medicine. In this study, the possible orexigenic effect of hydro-alcoholic extract of A. millefolium was investigated by measuring plasmaghrelin level. Thirty male Wistar rats were divided into five groups. Control group received water. Treatment groups received 50, 100 or 150 mg/kg of A. millefolium extract for 7 days via gavage. Before the intervention, daily amount of the food eaten by each rat was measured for 10 days. During the investigation, the amount of energy intake of each rat was also estimated 1, 2, 4, 6 and 24 hr after each intake, for 7 days. Later, the orexigenic dose of extract and distilled water was fed to two separate groups of 6 male Wistar rats. Plasma ghrelin level was measured 0.5, 1, 2 and 4 hrafter extract intake. The change in energy intake after treatment by 50and 100mg/kg of the extract was significantly higher than other groups (p<0.001).Administration of Achillea 100mg/kg significantly (p<0.05) decreased ghrelin level one hrafter intervention but there was no significant (p>0.05) difference among control and treated group. This study indicated that A. millefolium had positive dose-related effects on appetite in rats. It seems that the orexigenicactivity of extract was not related to changes in plasma ghrelin levels.

Antioxidant-induced reductive stress has untoward consequences on the brain microvasculature.

Antioxidant-induced reductive stress has untoward consequences on the brain microvasculature.

Pharmacological Properties of Riparin IV in Models of Pain and Inflammation.

Riparins, natural alkaloids of the alkamide group, can be synthesized by simple methods, enhancing their potential application in pharmaceutical development. Here, the pharmacological properties of riparins were investigated in in vitro and in vivo assays of pain and inflammation in Swiss mice. Inflammatory mediators were measured by radioimmunoassay and Real-Time PCR. Riparins I, II, III and IV (1.56–100 mg/kg; ip) produced dose-related antinociceptive effects in the formalin test, exhibiting ED50 values of 22.93, 114.2, 31.05 and 6.63 mg/kg, respectively. Taking the greater potency as steering parameter, riparin IV was further investigated. Riparin IV did not produce antinociceptive effect on the tail flick, suggesting that its antinociception is not a centrally-mediated action. In fact, riparin IV (1.56–25 mg/kg) produced dose-related antinociceptive and antiedematogenic effects on the complete Freund’s adjuvant (CFA)-induced paw inflammation in mice. During CFA-induced inflammation, riparin IV did not modulate either the production of cytokines, TNF-α and IL-10, or COX-2 mRNA expression. On the other hand, riparin IV decreased the PGE2 levels in the inflamed paw. In in vitro assays, riparin IV did not exhibit suppressive activities in activated macrophages. These results indicate, for the first time, that riparin IV induces antinociceptive and anti-inflammatory effects, possibly through the inhibition of prostanoid production.

M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.

The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.

The In Vitro Effect of Acidic-Pepsin on Nuclear Factor KappaB Activation and Its Related Oncogenic Effect on Normal Human Hypopharyngeal Cells.

BackgroundExtra-esophageal carcinogenesis has been widely discussed in relation to the chronic effects of laryngopharyngeal reflux and most prominently with pepsin historically central to this discussion. With refluxate known to include gastric (pepsin) and duodenal (bile) fluids, we recently demonstrated the mechanistic role of NF-κB in mediating the preneoplastic effects of acidic-bile. However, the role of pepsin in promoting hypopharyngeal premalignant events remains historically unclear. Here, we investigate the in vitro effect of acidic-pepsin on the NF-κB oncogenic pathway to better define its potential role in hypopharyngeal neoplasia.MethodsHuman hypopharyngeal primary cells (HHPC) and keratinocytes (HHK) were repetitively exposed to physiologic pepsin concentrations (0.1 mg/ml) at pH 4.0, 5.0 and 7.0. Cellular localization of phospho-NF-κB and bcl-2 was determined using immunofluorescence and western blotting. NF-κB transcriptional activity was tested by luc reporter and qPCR. Analysis of DNA content of pepsin treated HHK and HHPC was performed using Fluorescence-activated-cell sorting assay. To explore a possible dose related effect, pepsin concentration was reduced from 0.1 to 0.05 and 0.01 mg/ml.ResultsAt physiologic concentration, acidic-pepsin (0.1 mg/ml at pH 4.0) is lethal to most normal hypopharyngeal cells. However, in surviving cells, no NF-κB transcriptional activity is noted. Acidic-pepsin fails to activate the NF-κB or bcl-2, TNF-α, EGFR, STAT3, and wnt5α but increases the Tp53 mRNAs, in both HHPC and HHK. Weakly acidic-pepsin (pH 5.0) and neutral-pepsin (pH 7.0) induce mild activation of NF-κB with increase in TNF-α mRNAs, without oncogenic transcriptional activity. Lower concentrations of pepsin at varying pH do not produce NF-κB activity or transcriptional activation of the analyzed genes.ConclusionOur findings in vitro do not support the role of acidic-pepsin in NF-κB related hypopharyngeal carcinogenesis.