A connectivity mapping approach predicted acetylsalicylic acid (aspirin) to induce osteo/odontogenic differentiation of dental pulp cells.

AIM: To use connectivity mapping, a bioinformatics approach, to identify compounds that could induce odontogenic differentiation of dental pulp cells (DPCs) and to experimentally validate this effect. A subsidiary aim was to investigate the anti-inflammatory effect of any identified compound. METHODOLOGY: The Gene Expression Omnibus (GEO) database was searched for microarray data sets assessing odontogenic differentiation of human DPCs. An odontogenic gene expression signature was generated by differential expression analysis. The statistical significant connectivity map (ssCMap) method was used to identify compounds with a highly correlating gene expression pattern. DPCs were treated with the compound identified, and osteo/odontogenic differentiation was assessed by Alizarin red staining, alkaline phosphatase activity and expression of osteo/odontogenic genes ALPL, RUNX2, COL1A1, DSPP, DMP1 and SPP1 by RT-PCR. The anti-inflammatory effect of the compound was assessed using an ex vivo pulpitis model, and cytokine levels were measured with multiplex assay. Means were compared using the t-test or ANOVA followed by a Bonferroni post hoc test with the level of significance set at P ≤ 0.05. RESULTS: The GEO database search identified a specific gene expression signature for osteo/odontogenic differentiation. Analysis using ssCMap found that acetylsalicylic acid [(ASA)/aspirin] was the drug with the strongest correlation with that gene signature. The treatment of DPCs with 0.05 mmol L-1 ASA showed increased alkaline phosphatase activity (P < 0.001), mineralization (P < 0.05), and increased the expression of the osteo/odontogenic genes, DMP1 and DSPP (P < 0.05). Low concentration (0.05 mmol L-1 ) ASA reduced inflammatory cytokines IL-6 (P < 0.001), CCL21 (P < 0.05) and MMP-9 (P < 0.05) in an ex vivo pulpitis model. CONCLUSIONS: Connectivity mapping, a web-based informatics method, was successfully used to identify aspirin as a candidate drug that could modulate the differentiation of DPCs. Aspirin was shown to induce odontogenic differentiation in DPCs in vitro and this, together with its anti-inflammatory effects, makes it a potential candidate for vital pulp therapies.

Association between oral health status and future dietary intake and diet quality in older men: The PRIME study.

OBJECTIVES: This study investigated whether oral health status, defined as number of natural teeth and subsequent prosthodontic rehabilitation, was associated with future dietary intake and diet quality in older adults in The Prospective Epidemiological Study of Myocardial Infarction (PRIME). METHODS: PRIME was originally established to explore cardiovascular risk factors in 50-59 year old men in Northern Ireland (1991-1994). A rescreening phase assessed oral health (2001-2004), while diet was assessed in 2015. Diet quality was characterised by the Dietary Diversity Score and Mediterranean Diet Score. In the current analysis, associations between oral health status, dietary intake and quality were assessed using regression models in 1096 participants. RESULTS: Amongst study participants, the overall mean number of teeth was 18.5, 51.5 % had ≥21 natural teeth and 49.6 % wore dentures. Oral health status was categorised into five groups: 21-28 teeth with (n = 111) and without (n = 453) dentures, 1-20 teeth with (n = 354) and without (n = 99) dentures and edentate with dentures (n = 79). After full adjustment, men with ≥21 teeth and dentures had a higher future intake of fruit, vegetables, and nuts, and diet quality scores, compared to those with <21 teeth with dentures. Edentate men with dentures were less likely to achieve the future fruit dietary recommendation. CONCLUSIONS: Having ≥21 natural remaining teeth positively affected the future intake of fruit, vegetables, and nuts, as well as diet quality. Dentures may be beneficial in men with ≥21 natural remaining teeth, as they were associated with an increased future intake of fruit, vegetables, and nuts and better diet quality. CLINICAL SIGNIFICANCE: Oral health status is associated with dietary intake, after an average time period of 13 years, with those with a larger number of natural teeth having a better diet quality. Further research is required to investigate this relationship in larger, diverse populations with more detailed dietary assessment.

[Prevalence and recognition of bipolarity in patients with a treatment-resistant depressive disorder: a systematic review]. / Prevalentie en herkenning van bipolariteit bij patiënten met een therapieresistente depressieve stoornis; een systematische review.

BACKGROUND: Studies have indicated an association between treatment refractoriness in unipolar depression and unrecognised bipolar spectrum disorder (bsd). If confirmed, this may have implications for diagnosis and treatment.
AIM: To provide an overview on the prevalence and recognition of bsd in treatment resistant depression (trd).
METHOD: A search was made in PubMed concerning the prevalence of bsd in trd and clinical features that may be suggestive of bipolar depression.
RESULTS: Three articles were found that examined the prevalence of bsd in trd; they reported that 26-47% of patients with trd had an underlying bsd. Five cross-sectional studies described the predictors of clinical features in patients with a major depression. The following features occurred significantly more often: positive family history of bsd, young age of onset, higher number of recurrences, and atypical features.
CONCLUSION: There seems to be an association between trd and having an underlying bsd. A few clinical features may help to detect bsd in trd.

Putative periodontal pathogens in the subgingival plaque of Sudanese subjects with aggressive periodontitis.

BACKGROUND AND OBJECTIVES: There has been limited study of the bacterial species associated with aggressive periodontitis (AgP) in high-risk populations in Africa. The aim of this study was to investigate and quantify the presence of four putative periodontal pathogens in the subgingival plaque of Sudanese subjects with AgP. A secondary aim was to investigate the effect of varying the detection threshold on the reported prevalence of the bacterial species investigated. MATERIALS AND METHODS: Subgingival plaque samples were collected from AgP cases (n=73) and healthy controls (n=71). Bacterial DNA was extracted and analyzed by quantitative polymerase chain reaction for the detection and quantification of four putative periodontal pathogens: Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Treponema denticola and Tannerella forsythia. RESULTS: At the lowest detection threshold (>101 cells), P. gingivalis (p<0.0001) was more prevalent in AgP cases than controls. T. forsythia and T. denticola had a high prevalence (>70%) in AgP cases at all detection levels. While T. forsythia was significantly more frequently identified in AgP than in controls at all detection thresholds, this was only the case for T. denticola at the intermediate threshold (>102 cells). A. actinomycetemcomitans was identified less frequently than the other bacterial species with no difference in its prevalence between AgP cases and controls. CONCLUSION: The prevalence of the putative periodontal pathogens investigated varied considerably in Sudanese subjects with AgP and in periodontally healthy controls depending on the detection thresholds applied. T. forsythia was identified as having the strongest association with AgP.

Matrix metalloproteinase-8 activity in gingival crevicular fluid: development of a novel assay.

BACKGROUND AND OBJECTIVE: The matrix metalloproteinases (MMPs) play a role in regulating turnover and metabolism of connective tissues in health but they have also been implicated in a wide variety of pathological conditions, including periodontal disease. MMP-8 has been extensively studied in periodontal health and disease using ELISA, although this technique is limited by its inability to determine enzyme activity. The aim was to develop an assay specifically to measure MMP-8 activity and to demonstrate its use in the analysis of gingival crevicular fluid samples. MATERIAL AND METHODS: A specific antibody was used to coat black 96-well microtitre plates to capture MMP-8 selectively. The activity of bound MMP-8 was measured using a fluorogenic substrate. Gingival crevicular fluid samples, from healthy and periodontally diseased sites, were collected using PerioPaper strips and tested for MMP-8 activity. RESULTS: Significantly higher MMP-8 activity was demonstrated in gingival crevicular fluid from periodontally diseased sites compared with healthy sites that exhibited basal or no MMP-8 activity. No cross-reactivity with other MMPs was noted. CONCLUSION: We show, for the first time, that MMP-8 activity can be specifically detected and quantified in gingival crevicular fluid samples. Measurement of MMP-8 activity could prove to be useful in monitoring periodontal disease progression.

Periodontitis, cardiovascular disease and pregnancy outcome--focal infection revisited?

Over the last two decades there has been a renewed interest around the possible effects of periodontal disease on both cardiovascular health and pregnancy outcome (among other diseases), a topic which has interested science for hundreds of years. These have led to a range of studies, workshops and consensus documents being published, with corresponding coverage in general and professional media. In this article the authors summarise the history and supporting theories behind such associations, whether clinical studies have been able to confirm these and what this might mean for general practitioners who are questioned on this topic by patients.

Mechanisms governing the responses to anthracnose pathogen in Juglans spp.

Juglans nigra and Juglans regia are two highly economically important species for wood and fruit production that are susceptible to anthracnose caused by Gnomonia leptostyla. The identification of genotypes resistant to anthracnose could represent a valid alternative to agronomic and chemical management. In this study, we analyzed 72 walnut genotypes that showed a variety of resistance phenotypes in response to natural infection. According to the disease severity rating and microsatellite fingerprinting analysis, these genotypes were divided into three main groups: (40) J. nigra resistant, (1) J. nigra susceptible, and (31) J. regia susceptible. Data on leaf emergence rates and analysis of in vivo pathogenicity indicated that the incidence of anthracnose disease in the field might be partially conditioned by two key factors: the age and/or availability of susceptible leaves during the primary infection of fungus (avoidance by late flushing) and partial host resistance. NBS profiling approach, based on PCR amplification with an adapter primer for an adapter matching a restriction enzyme site and a degenerate primer targeting the conserved motifs present in the NBS domain of NBS-LRR genes, was applied. The results revealed the presence of a candidate marker that correlated to a reduction in anthracnose incidence in 72 walnut genotypes.

PAR-2 regulates dental pulp inflammation associated with caries.

Protease-activated receptors (PARs) are G-protein-coupled receptors that are activated enzymatically by proteolysis of an N-terminal domain. The cleavage and activation of PARs by serine proteases represent a novel mechanism by which such enzymes could influence the host inflammatory response. The aim of this study was to determine whether PAR-2 expression and activation were increased in dental caries. Using immunohistochemistry, we showed PAR-2 to be localized to pulp cells subjacent to caries lesions, but minimally expressed by healthy pulp tissue. Trypsin and the PAR-2 agonist (PAR2-AP) activated PAR-2 in an in vitro functional assay. Endogenous molecules present in pulp cell lysates from carious teeth specifically activated PAR-2, but those from healthy teeth failed to do so. The activation of PAR-2 in vitro was shown to increase the expression of the pro-inflammatory mediator cyclo-oxygenase-2 (COX-2), providing a mechanism whereby PAR-2 could modulate pulpal inflammation.

Neuropeptide Y Y1 receptor in human dental pulp cells of noncarious and carious teeth.

AIM: To determine the distribution of the NPY Y1 receptor in carious and noncarious human dental pulp tissue using immunohistochemistry. A subsidiary aim was to confirm the presence of the NPY Y1 protein product in membrane fractions of dental pulp tissue from carious and noncarious teeth using western blotting. METHODOLOGY: Twenty two dental pulp samples were collected from carious and noncarious extracted teeth. Ten samples were processed for immunohistochemistry using a specific antibody to the NPY Y1 receptor. Twelve samples were used to obtain membrane extracts which were electrophoresed, blotted onto nitrocellulose and probed with NPY Y1 receptor antibody. Kruskal-Wallis one-way analysis of variance was employed to test for overall statistical differences between NPY Y1 levels in noncarious, moderately carious and grossly carious teeth. RESULTS: Neuropeptide Y Y1 receptor immunoreactivity was detected on the walls of blood vessels in pulp tissue from noncarious teeth. In carious teeth NPY Y1 immunoreactivity was observed on nerve fibres, blood vessels and inflammatory cells. Western blotting indicated the presence and confirmed the variability of NPY Y1 receptor protein expression in solubilised membrane preparations of human dental pulp tissue from carious and noncarious teeth. CONCLUSIONS: Neuropeptide Y Y1 is expressed in human dental pulp tissue with evidence of increased expression in carious compared with noncarious teeth, suggesting a role for NPY Y1 in modulation of caries induced pulpal inflammation.

Medical and social prognoses of non-specific building-related symptoms (Sick Building Syndrome): a follow-up study of patients previously referred to hospital.

OBJECTIVES: The aim of this study was to describe and analyse the medical and social prognoses of patients with non-specific building-related symptoms. METHODS: A follow-up questionnaire focusing on current medical and social status, care, treatment, other actions taken and personality traits was sent to 239 patients with non-specific building-related symptoms assessed during the period between 1986 and 1998 at University Hospital in Umeå, Sweden. The response rate was 79%. RESULTS: Fatigue, irritation of the eyes, and facial erythema were the most common weekly symptoms reported at follow-up. As females constituted 92% of the respondents, statistical analyses were restricted to women. The level and severity of symptoms decreased over time, although nearly half of the patients claimed that symptoms were more or less unchanged after 7 years or more, despite actions taken. Twenty-five percent of the patients were on the sick-list, and 20% drew disability pension due to persistent symptoms at follow-up. The risk of having no work capabilities at follow-up was significantly increased if the time from onset to first visit at the hospital clinic was more than 1 year. This risk was also significantly higher if the patient at the first visit had five or more symptoms. All risk assessments were adjusted for length of follow-up. Symptoms were often aggravated by different situations in everyday life. CONCLUSIONS: Long-lasting symptoms aggravated by environmental factors exist within this group of patients. The results support that early and comprehensive measures for rehabilitation are essential for the patients.

A comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder.

INTRODUCTION: The serotonin specific reuptake inhibitor (SSRI) citalopram and the reversible mono-amine oxidase-A inhibitor (RIMA) moclobemide have both been used successfully for the treatment of social anxiety disorder (SAD). In this study we investigate the effects of these compounds on resting brain function using single photon emission computed tomography (SPECT). METHODS: Subjects meeting DSM-IV criteria for SAD underwent regional cerebral blood flow (rCBF) SPECT using Tc-HMPAO at baseline and after 8 weeks of treatment with either citalopram or moclobemide. Using statistical parametric mapping brain SPECT studies were analysed to determine the effects of treatment on rCBF, to compare the effects of citalopram and moclobemide, and to detect correlations between changes in rCBF and clinical response. RESULTS: Subjects received citalopram (n=17) or moclobemide (n=14) as therapy. Subjects in both treatment groups demonstrated a significant improvement of SAD symptoms as measured by the Liebowitz Social Anxiety Scale total score. All subjects demonstrated a decrease in rCBF in the insulae post therapy. Subjects receiving citalopram had decreased superior cingulate rCBF after therapy compared to those receiving moclobemide. CONCLUSION: Both SSRI's and RIMA's decreased rCBF in the insulae during treatment of SAD; an effect that may be consistent with the role of these regions in processing internal somatic cues evoked by emotional stimuli. Citalopram had a greater effect on superior cingulate perfusion, an effect that is consistent with evidence of high levels of 5-HT transporters in this region.

Changes in health over time in patients with symptoms allegedly caused by their dental restorative materials.

OBJECTIVES: In Sweden, many patients with symptoms allegedly caused by their dental materials have exchanged their restorations, but the effects of the exchange have been insufficiently investigated. Therefore, the aim of the study was to describe the change in health over time for these patients and the hypothesis was that the patients could be divided based on their symptoms and that the ability to recover differs between these groups. Furthermore, we also examined if other factors such as replacement of dental restorative materials and follow-up time had any impact on the perceived health status. METHODS: A questionnaire was sent to 614 patients who had been referred to the School of Dentistry, Umeå, Sweden, with symptoms allegedly caused by dental restorative materials. The response rate was 55%. RESULTS: The risk of having any further complaints was higher for patients with complex symptoms (P = 0.03) and these patients had exchanged their restorations to a significantly larger extent than the others (P = 0.03). The remaining complaints was more frequent among men (P = 0.02). Exchange of dental restorative materials had no significant impact on the ability to recover completely. However, the patients who had exchanged their restorations completely perceived a significantly larger alleviation of their symptoms than the others (P < 0.01), although the frequency of most of the symptoms had increased. CONCLUSIONS: Patients with complex symptoms had a more unfavorable long-term prognosis concerning persistent complaints than those with localized symptoms only. Furthermore, the results indicate that the patients might experience health improvements after removal of their dental restorative materials. The reason for this improvement, however, is unclear. Further analyses regarding other possible explanations than the 'odontological/medical' are needed.

Detection of individual human neutrophil alpha-defensins (human neutrophil peptides 1, 2 and 3) in unfractionated gingival crevicular fluid--a MALDI-MS approach.

The role of antimicrobial peptides is particularly important in the oral cavity where there is constant challenge by microorganisms. The alpha-defensins are a group of cationic peptides that comprise 30-50% of the total protein in azurophilic granules of human neutrophils. They include the human neutrophil peptides (HNP) 1, 2 and 3 which have almost identical amino acid sequences but differ in their biological activities. The amino acid sequence similarities of the defensins have made it difficult to unequivocally determine the presence of individual defensins using antibody-based techniques. However, by virtue of their cationic nature we postulated that the defensins would fly particularly well in mass spectrometry and that this characteristic would allow facile identification of individual HNPs in unfractionated gingival crevicular fluid (GCF) from periodontitis patients and healthy controls. Although there was variability in levels of defensins detected in periodontal health and disease, HNP-1 was always identified as the major peak in the triad and HNP-3 as the minor peak, lending support to the hypothesis that HNP-2 may arise by post-translational proteoyltic cleavage of HNP-3 rather than HNP-1. The finding that the defensins were more abundant in a higher proportion of the healthy sites studied could be linked to a more intact defensin barrier in periodontal health.

Coping and self-image in patients with visual display terminal-related skin symptoms and perceived hypersensitivity to electricity.

OBJECTIVES: The aim of the present study was to measure coping resources and self-image in patients with visual display terminal (VDT)-related skin symptoms and hypersensitivity to electricity (HE). METHODS: From 1980 to 1998, 350 patients with electrical sensitivity were registered. The patients were subdivided into two groups: patients with skin symptoms evoked by VDTs, television screens, and fluorescent-light tubes and patients with so-called hypersensitivity to electricity with multiple symptoms evoked by exposure to different electrical environments. A questionnaire was sent to all patients and contained the coping resources inventory (CRI) and the structural analysis of social behaviour (SASB) in order for us to measure coping resources and self-image, respectively. The CRI and SASB scores were compared with those of control groups. Two hundred and fifty respondents (73%) returned the questionnaire, 200 (78.5% women) in the VDT group and 50 (62% women) in the HE group. RESULTS: The patient group rated high on the CRI spiritual/philosophical scale and high on the SASB spontaneous, positive and negative clusters but low on the controlled cluster. The female patients scored high on the CRI emotional scale. The VDT group rated lower than the controls on the SASB controlled cluster and higher on both the positive and negative cluster. The HE group scored higher than the control group on the SASB spontaneous and positive clusters. The women in the HE group scored higher on the CRI cognitive and CRI total scale than the VDT group and control group and higher on the CRI emotional scale than the controls. The women in the HE group rated higher than both the women in the VDT and control groups on the SASB spontaneous and positive clusters. CONCLUSIONS: The deviant self-image found in these patients, especially the female HE patients, support the view that VDT and HE symptoms can be stress related. In the clinic, a trustful alliance should be established with the patient in order for a more realistic view to be achieved of the capacity.

NEUROPEPTIDES AND NEUROGENIC MECHANISMS IN ORAL AND PERIODONTAL INFLAMMATION.

It is generally accepted that the nervous system contributes to the pathophysiology of peripheral inflammation, and a neurogenic component has been implicated in many inflammatory diseases, including periodontitis. Neurogenic inflammation should be regarded as a protective mechanism, which forms the first line of defense and protects tissue integrity. However, severe or prolonged noxious stimulation may result in the inflammatory response mediating injury rather than facilitating repair. This review focuses on the accumulating evidence suggesting that neuropeptides have a pivotal role in the complex cascade of chemical activity associated with periodontal inflammation. An overview of neuropeptide synthesis and release introduces the role of neuropeptides and their interactions with other inflammatory factors, which ultimately lead to neurogenic inflammation. The biological effects of the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY) are summarized, and evidence for their involvement in the localized inflammatory lesions which characterize periodontitis is presented. In this context, the role of CGRP in bone metabolism is described in more detail. Recent research highlighting the role of the nervous system in suppressing pain and inflammation is also discussed.

[Dental treatment anxiety. A review of useful anxiety-measuring instruments]. / Angst voor tandheelkundige behandelingen. Een overzicht van de bruikbare meetinstrumenten.

Dental anxiety is a common problem. Different tests have been developed to measure the nature and the severity of dental anxiety or phobia. These tests can help to identify highly anxious patients who need special dental care. In this article, the dental anxiety tests useful in The Netherlands are reviewed.

Extraction and radioimmunoassay quantitation of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) from human dental pulp tissue.

The measurement of neuropeptides in complex biological tissue samples requires efficient and appropriate extraction methods so that immunoreactivity is retained for subsequent radioimmunoassay detection. Since neuropeptides differ in their molecular mass, charge and hydrophobicity, no single method will suffice for the optimal extraction of various neuropeptides. In this study, dental pulp tissue was obtained from 30 human non-carious teeth. Of the three different neuropeptide extraction methods employed, boiling in acetic acid in the presence of protease inhibitors yielded the highest levels of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP). High pressure liquid chromatography (HPLC) analysis of dental pulp tissue verified the authenticity of the neuropeptides extracted.

Quantitative analysis of substance P, neurokinin A and calcitonin gene-related peptide in pulp tissue from painful and healthy human teeth.

AIM: The purpose of this study was to investigate the levels of substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP) in painful and healthy human dental pulps. METHODOLOGY: Forty-six samples of pulp tissue were collected from extracted or endodontically treated painful teeth and 20 from clinically healthy teeth extracted for orthodontic reasons. All pulp samples were boiled in 0.5 m acetic acid for 10 min, centrifuged and the supernatant collected. SP, NKA and CGRP levels were measured using radioimmunoassay. RESULTS: Substance P and CGRP were present in all samples and NKA was detected in 96% of the pulps. CGRP was present in much higher concentrations than SP and NKA in both painful and non-painful teeth. The painful teeth had significantly higher concentrations of SP (P = 0.02), NKA (P < 0.001) and CGRP (P = 0.03) than non-painful teeth. The concentration of CGRP was significantly higher in the pulps of smokers compared with non-smokers (P = 0.02). CONCLUSIONS: Elevated levels of these neuropeptides in pulps from painful teeth indicate that they may play an important role in the process of pulpal inflammation and pain. Further investigation of the association between these neuropeptides and pulpal status may help to improve our understanding of pulpal inflammation and dental pain.

Quantitative analysis of MRP-8 in gingival crevicular fluid in periodontal health and disease using microbore HPLC.

BACKGROUND: The protein components of GCF can be separated by reverse-phase microbore HPLC on a C18 column with detection on the basis of 214 nm absorbance. A single major symmetrical protein peak eluting with a retention time of 26 min (50% acetonitrile) was evident in gingival crevicular fluid (GCF) from periodontitis patients but not in healthy GCF. This protein was identified as human MRP-8 by N-terminal amino acid sequencing and liquid chromatography quadropole mass spectrometry. AIMS: To quantify the amount of MRP-8 detectable in GCF from individual healthy, gingivitis and periodontitis affected sites and to study the relationship, if any, between the levels of this responsive protein and periodontal health and disease. METHODS: GCF was sampled (30 s) from healthy, gingivitis, and periodontitis sites in peridontitis subjects (n=15) and from controls (n=5) with clinically healthy gingiva and no periodontitis. Purified MRP-8 was sequenced by Edmann degradation and the phenylthiohydantoin (PTH) amino acid yield determined (by comparison of peak area with external PTH amino acid standards). This value was subsequently used to calculate the relative amount of protein in the peak eluting with a retention time of 26.0 min (MRP-8) in individual GCF chromatograms. RESULTS: Higher levels of MRP-8 were detected in inflammatory sites: periodontitis 457.0 (281.0) ng; gingivitis 413.5 (394.5) ng compared with periodontally healthy sites in diseased subjects 14.6 (14.3) ng and in controls 18.6 (18.5) ng, p=0.003. There was at least 20-fold more MRP-8 in the inflammatory compared with the healthy sites studied. CONCLUSIONS: The preliminary data indicate that MRP-8 is present in GCF, with significantly greater amounts present at diseased than healthy sites. A systematic study of the relationship of this protein to periodontal disease could prove useful in further clarifying whether MRP-8 could be a reliable GCF biomarker of gingivitis and periodontitis.

Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy.

In view of the similarity in chemical structure of the available 5HT(3)-receptor antagonists it is assumed, whilst these agents all act at the same receptor, that failure to one agent would predict subsequent failure to all 5HT(3)-receptor antagonists. We conducted a randomized double blind trial of granisetron 3 mg plus dexamethasone 10 mg versus continued treatment with ondansetron 8 mg plus dexamethasone 10 mg in patients with protection failure on ondansetron 8 mg plus dexamethasone 10 mg during the first 24 hours following highly emetogenic chemotherapy. Of 40 eligible patients, 21 received ondansetron + dexamethasone and 19 received granisetron + dexamethasone. We found a significant benefit from crossing-over to granisetron after failure on ondansetron. Of the 19 patients who crossed over to granisetron, 9 patients obtained complete protection, whereas this was observed in 1 of the 21 patients continuing ondansetron, P = 0.005. These results indicate that there is no complete cross-resistance between 5HT(3)-receptor antagonists, and that patients who have acute protection failure on one 5HT(3)-receptor antagonist should be offered cross-over to another 5HT(3)-receptor antagonist.