Biomedical subjects

M York

Publications and source records attributed to M York.

At least 19 recordsLinked to original sources

PubMed2002

Haemotoxicity of thiamphenicol in the BALB/c mouse and Wistar Hanover rat.

Chloramphenicol (CAP) is haemotoxic in man, inducing two forms of toxicity. First, a commonly-occurring, dose-related, reversible bone marrow depression, which develops during treatment. Second, a rarer aplastic anaemia (AA), developing after treatment, is irreversible, and often fatal. Thiamphenicol (TAP) was developed as a replacement for CAP; however, there are no toxicological investigations in the mouse or rat on the dose-related haemotoxicity of TAP, in repeat dose gavage studies. Therefore, we have conducted a comprehensive investigation in these species, administering TAP for 7-17 days, to define haematological changes. Female BALB/c mice were gavaged with TAP, daily for 7-17 days at 400-1500 mg/kg; female Wistar Hanover rats were dosed with TAP daily at 50-375 mg/kg for 9 or 10 days. Haematological changes were studied at 1, 7 and 14 days post-dosing. In mice at day 1, TAP caused decreases in RBC, HCT and Hb; reticulocytes and platelets were reduced; changes were dose-related and reversible. Marrow cell counts were reduced; marrow was hypocellular, with erythroid depletion and progenitor cell vacuolation; the myeloid/erythroid (M:E) ratio was increased. In the rat, changes were not as clear-cut; there was anaemia with indications of reduced reticulocyte and platelet counts, and evidence of decreased neutrophils and lymphocytes. Marrow erythroid cells were decreased, precursor cells vacuolated, and the M:E ratio increased. We conclude that TAP induced haematological changes in the mouse and rat, parallelling the dose-dependent, reversible marrow depression reported in man; TAP is more haemotoxic in the rat than in the mouse.

Anemia, Aplastic↗

PubMed2000

Eye irritation responses in rabbit and man after single applications of equal volumes of undiluted model liquid detergent products.

A criticism of the use of the rabbit low-volume eye test to determine eye irritation hazard for man is the lack of comparative data in man and rabbit with undiluted products. To address this, such a study has been performed in man and rabbit using undiluted model liquid detergents. The hypothesis tested was that if, under identical test conditions, the effects in the rabbit were the same or greater than the response in man, then it is valid to use the low-volume eye test to assess eye irritation hazard for man. The studies were carried out using 29 human volunteers and 12 rabbits. The effects in the rabbit were unequivocally greater than the effects observed in man, but clearly less than the expected response from these types of product in the Draize test. The results from this study confirm the sensitivity of the rabbit as a test species, and support the use of the low-volume eye test to assess eye irritation hazard for man. Any in vitro/ex vivo alternative to assess eye irritation should be developed against the rabbit low-volume eye test or human data where available.

Animals↗

PubMed2000

A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis.

BACKGROUND: Brain derived neurotrophic factor (BDNF) is a potent survival factor for motoneurons. This study investigated the safety and tolerability of recombinant methionyl human BDNF (r-metHuBDNF) infused intrathecally by means of an implanted pump in patients with ALS. METHODS: Twenty-five patients with probable or definite ALS were treated with either r-metHuBDNF (25, 60, 150, 400 or 1000 microg/day) or placebo in a 12-week, randomized, double-blinded, sequential, dose-escalation study. Test treatment was interrupted by a washout period from days 11 to 25 to allow the evaluation of laboratory safety measures. In each dose cohort four patients received r-metHuBDNF and one received placebo. On completion of the double-blind period of the study all patients continued to receive r-metHuBDNF in an open-label extension for up to 60 weeks. Lumbar cerebrospinal fluid (CSF) samples were taken periodically from all patients for the measurement of r-metHuBDNF levels and in a minority of patients these were supplemented by cistemal samples. RESULTS: Within days after the initiation of infusion the majority of patients receiving r-metHuBDNF reported mild sensory symptoms, including paraesthesias or a sense of warmth, which were usually confined to the lower limbs and were frequently exacerbated by neck flexion. In most instances these symptoms decreased or even disappeared over several weeks. Sleep disturbance, dry mouth, agitation and other behavioural effects were encountered at higher doses (>150 microg/day) and necessitated dose reductions. The spinal CSF levels of r-metHuBDNF were directly related to dose, with a lumbar to cervical ratio of approximately 4:1. CONCLUSIONS: The intrathecal delivery of r-metHuBDNF in doses of up to 150 microg/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment.

Adult↗

PubMed1999

Structure-activity relationships in the murine local lymph node assay for skin sensitization: alpha,beta-diketones.

The biological activity of skin-sensitizing chemicals is related to their ability to react, either directly or after metabolic activation, with appropriate skin proteins. For direct acting electrophilic compounds, this ability can be modelled, using the RAI (relative alkylation index) approach, by a combination of electrophilicity and hydrophobicity parameters. Several structure-activity relationships based on this approach have been reported, but most of them cover guinea pig sensitization test data on what chemists would classify as relatively soft electrophilic chemicals. In the present work, an electrophilicity parameter based on Taft substituent constants is derived for hard electrophiles having a reactive carbonyl group, and is used to calculate RAI values for the analysis of sensitization test data obtained in the murine local lymph node assay (LLNA) for a series of alpha, beta-diketones. The sensitization potential of these reactive hard electrophilic carbonyl compounds in the LLNA shows a good correlation with the RAI. Overall, the findings reaffirm our view that physical organic chemistry is the key to understanding why some chemicals sensitize more strongly than others, while some do not sensitize at all, and provide further evidence of the value of the LLNA for SAR studies.

Animals↗

PubMed1999

Haemotoxicity of chloramphenicol succinate in the CD-1 mouse and Wistar Hanover rat.

1. Chloramphenicol has been widely used in the treatment of serious infections including typhoid fever and meningitis. However, the drug is haemotoxic in man inducing firstly, a reversible, dose-dependent anaemia which develops during treatment, secondly, an often fatal aplastic anaemia with pancytopenia and acellular marrow, and thirdly, leukaemia. 2. We investigated the haemotoxicity of chloramphenicol succinate (CAPS) in female CD-1 mice in repeat dose studies, to compare the response with the reversible anaemia reported in man. Studies in male Wistar Hanover rats were also carried out. 3. CAPS was gavaged daily to mice at dose levels from 800 - 2000 mg/kg for seven days. Values were significantly reduced for reticulocytes at 1700 and 2000 mg/kg, and for erythrocytes (RBC), haematocrit (HCT), and haemoglobin (Hb) at 2000 mg/kg. Platelet and white blood cell (WBC) counts were unaffected. 4. Mice were dosed with CAPS at 1400 mg/kg for 10 days and sampled at 1, 4 and 15 days after the last dose. At day 1 post dosing, RBC, HCT and Hb values were significantly reduced, but returned to normal (or above normal) by day 4 or 15. 5. CAPS from 2000 - 4000 mg/kg was gavaged to rats daily for 19 days. Hb values were significantly lower at 3600 and 4000 mg/kg; reticulocytes were not reduced. WBC and platelet counts, in general, were unaffected. 6. Levels of apoptosis in marrow mononuclear cells were increased in CAPS-treated mice, but not in CAPS-treated rats. Serum biochemistry parameters, in general, showed few changes of toxicological significance. 7. We conclude that the administration of CAPS to CD-1 mice induced haematological changes showing close parallels with the chloramphenicol-induced reversible anaemia seen in man.

Anemia, Aplastic↗

PubMed1998

Stereotactic pallidotomy for the treatment of Parkinson's disease. Efficacy and adverse effects at 6 months in 26 patients.

We evaluated the safety and efficacy of microelectrode-guided stereotactic pallidotomy in patients with advanced Parkinson's disease (PD). Using diagnostic criteria and evaluations outlined in the Core Assessment Programme in Transplantation (CAPIT) protocol, we studied unilateral pallidotomy in 26 patients with advanced idiophatic PD, motor fluctuations, and peak dose dyskinesias. All underwent unilateral stereotactic pallidotomy. Assessments conducted in the "practically defined off" and "best on" states at baseline and at 1 and 6 months postoperatively included Unified Parkinson's Disease Rating Scale (UPDRS) parts II, III, and IV and timed motor testing as outlined in CAPIT. Motor UPDRS in the "off" state improved at 1 and 6 months after surgery (p = 0.002, p = 0.008) Likewise, the sum of individual "off" contralateral motor UPDRS items improved (p = 0.0002, p = 0.0005). The duration (p = 0.0001 at 1 and p = 0.001 at 6 months) and severity (p = 0.003 at 1 and p = 0.0005 at 6 months) of dyskinesia improved, but other aspects of the "on" function were unchanged. Serious adverse effects occurred in eight patients and included one fatal deep and three nonfatal frontal lobe hemorrhages with resultant language or behavioral deficits. Nonhemorrhagic complications included one hemiparesis and three frontal lobe syndromes. Pallidotomy improves PD motor disability in the "off" state. Peak dose dyskinesias are reduced, although other aspects of "on" motor function are unchanged. Although morbidity may limit its use, pallidotomy is effective in targeting particular symptoms such as unremitting dyskinesia and severe "off" motor disability in advanced PD.

Activities of Daily Living↗

PubMed1997

Interlaboratory evaluation of a human patch test for the identification of skin irritation potential/hazard.

The human 4 hr patch test provides an opportunity to identify substances with significant skin irritation potential without recourse to the use of animals. To demonstrate the validity of the method it must be relevant and reliable. It is self-evident that the method is relevant to the identification of skin irritation hazards to humans. However, it is essential that the results be reproducible. This paper presents data on a number of substances tested by different laboratories. Eight substances were tested by two or more laboratories and the data compared with a standard positive control, 20% sodium dodecyl sulfate. In almost all cases, the outcome of this comparison was identical. Thus, despite the fact that there is known variability among human subjects in terms of skin reactivity to irritants, this simple method showed good reproducibility for the classification of acute skin irritation potential. Therefore, it is argued that this human 4-hr patch test is a valid alternative to the equivalent rabbit test for the assessment of skin irritation hazard to humans.

Adult↗

PubMed1997

The classification of skin irritants by human patch test.

The human 4 hour patch test provides an opportunity to identify substances with significant skin irritation potential without recourse to the use of animals. The protocol is designed to avoid the production of more than mild irritant reactions and meets the highest ethical standards. This paper provides the background to the development of the method and comments on its performance in the light of recent intra- and inter-laboratory investigations. In particular, the value of the method in providing 'gold standard' data for the identification of those substances (or preparations) which should, or should not, be classified as irritant to skin in European legislation is discussed. On the basis of the published data and supplementary investigations, recommendations are made on both the conduct and interpretation of the human 4 hour patch test. Finally, the lack of any necessity for formal validation of this assay is addressed.

Health Planning Guidelines↗

PubMed1997

Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

PURPOSE: To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS: Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS: The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION: DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

Aged↗

PubMed1997

Oral ondansetron 8 mg twice daily is as effective as 8 mg three times daily in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. S3A-376 Study Group.

The efficacy and safety of ondansetron 8 mg BID compared with 8 mg TID for 3 days in the prevention of nausea and vomiting in 402 patients on cyclophosphamide (> or = 500 mg/m2)-based chemotherapy were evaluated in a multicenter, randomized, double-blind, stratified study. The percentage of patients with no emetic episodes over the 3-day study period was 61% in the ondansetron BID group compared with 58% in the ondansetron TID group. Among patients with at least one emetic episode, the mean time to emesis was 14 hr and 17 min in the ondansetron BID group compared with 12 hr and 48 min in the ondansetron TID group. Patients' daily appetite ratings and nausea scores were not significantly different between groups. Clinical laboratory and adverse event profiles were similar between groups. This study is the first large-scale, double-blind trial to demonstrate that ondansetron 8 mg BID for 3 days, a dosing regimen that may enhance patient convenience and compliance, is as effective as ondansetron 8 mg TID for 3 days in the prevention of nausea and vomiting associated with cyclophosphamide-based chemotherapy.

Administration, Oral↗

PubMed1996

Evaluation of a human patch test for the identification and classification of skin irritation potential.

Current regulations require that the skin irritation/corrosion potential of new chemicals is assessed in the rabbit Draize test, although there are opportunities to use alternative methods to identify the most aggressive materials. Previously, we have proposed that it is possible to employ a strategy that avoids the use of animals and at the same time delivers a more relevant assessment of skin irritation/corrosion potential. The approach is to identify corrosive materials in vitro and then proceed to human volunteer testing for skin irritation. In this study, the human 4-h patch test, its interpretation, and results with 29 test materials are presented. Using 14 materials not classified as "Irritating to skin" by EU criteria, 13 classified as "Irritating to skin" by suppliers, and 2 as "Corrosive - causes burns", it is demonstrated that, by evaluating these on human skin in vitro and in vivo, a significant proportion are either over-classified or under-classified. In conclusion, we are convinced that by application of the approach described in detail here, it is possible to avoid the use of animals, whilst at the same time obtaining an assessment of skin irritation/corrosion potential that is more relevant to man, and which, if required, may be used directly for classification and labelling of substances and preparations within the European Union.

Acyclic Monoterpenes↗

PubMed1996

Phase III randomized study to compare interferon alfa-2a in combination with fluorouracil versus fluorouracil alone in patients with advanced colorectal cancer.

PURPOSE: To compare the efficacy and toxicity profiles of a combination of fluorouracil (5-FU) and recombinant human interferon alfa-2a ([IFN alpha 2a] Roferon-A; Hoffmann-LaRoche, Basel, Switzerland) versus 5-FU alone in the treatment of advanced colorectal cancer (ACC). PATIENTS AND METHODS: A total of 245 previously untreated ACC patients were randomized to receive either IFN alpha 2a (9 million IU) subcutaneously (SC) three times weekly with 5-FU (750 mg/m2/d) by continuous intravenous (CIV) infusion on days 1 to 5 and then, after a 1-week hiatus, as a weekly IV bolus at the same dose (IFN/ 5-FU), or 5-FU alone at the same dose schedule (5-FU). RESULTS: There were no significant differences between IFN/5-FU and 5-FU alone in the overall response rate (24% v 17%, P = .2), duration of response (median, 6.4 v 8.1 months), time to response (plateau at 3 months), time to progressive disease ([PD] median, 4.8 v 4.9 months), or survival duration (median, 13.9 v 13.2 months). Toxicity profiles were not statistically different except for constitutional symptoms, which were more frequent and more severe with IFN/5-FU. More patients interrupted treatment for adverse events (AEs) with IFN/ 5-FU (34%) than with 5-FU alone (21%) (P = .03). The number of deaths (mostly unrelated to drug treatment) during the study (8%) was similar with both regimens. CONCLUSION: The combination IFN/5-FU produced a response rate, response duration, and survival duration similar to that of 5-FU alone. The addition of IFN to 5-FU in the doses and schedules used in this study did not provide any further benefit over 5-FU alone and cannot be recommended for patients with metastatic ACC. This study confirms the value of large prospective randomized clinical trials to determine the clinical value of regimens that emerge from smaller single-center phase II studies.

Adult↗

PubMed1996

Harmonization of animal clinical pathology testing in toxicity and safety studies. The Joint Scientific Committee for International Harmonization of Clinical Pathology Testing.

Ten scientific organizations formed a joint international committee to provide expert recommendations for clinical pathology testing of laboratory animal species used in regulated toxicity and safety studies. For repeated-dose studies in rodent species, clinical pathology testing is necessary at study termination. Interim study testing may not be necessary in long-duration studies provided that it has been done in short-duration studies using dose levels not substantially lower than those used in the long-duration studies. For repeated-dose studies in nonrodent species, clinical pathology testing is recommended at study termination and at least once at an earlier interval. For studies of 2 to 6 weeks in duration in nonrodent species, testing is also recommended within 7 days of initiation of dosing, unless it compromises the health of the animals. If a study contains recovery groups, clinical pathology testing at study termination is recommended. The core hematology tests recommended are total leukocyte (white blood cell) count, absolute differential leukocyte count, erythrocyte (red blood cell) count, evaluation of red blood cell morphology, platelet (thrombocyte) count, hemoglobin concentration, hematocrit (or packed cell volume), mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. In the absence of automated reticulocyte counting capabilities, blood smears from each animal should be prepared for reticulocyte counts. Bone marrow cytology slides should be prepared from each animal at termination. Prothrombin time and activated partial thromboplastin time (or appropriate alternatives) and platelet count are the minimum recommended laboratory tests of hemostasis. The core clinical chemistry tests recommended are glucose, urea nitrogen, creatinine, total protein, albumin, calculated globulin, calcium, sodium, potassium, total cholesterol, and appropriate hepatocellular and hepatobiliary tests. For hepatocellular evaluation, measurement of a minimum of two scientifically appropriate blood tests is recommended, e.g., alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, glutamate dehydrogenase, or total bile acids. For hepatobiliary evaluation, measurement of a minimum of two scientifically appropriate blood tests is recommended, e.g., alkaline phosphatase, gamma glutamyltransferase, 5' -nucleotidase, total bilirubin, or total bile acids. Urinalysis should be conducted at least once during a study. For routine urinalysis, an overnight collection (approximately 16 hr) is recommended. It is recommended that the core tests should include an assessment of urine appearance (color and turbidity), volume, specific gravity or osmolality, pH, and either the quantitative or semiquantitative determination of total protein and glucose. For carcinogenicity studies, only blood smears should be made from unscheduled sacrifices (decedents) and at study termination to aid in the identification and differentiation of hematopoietic neoplasia.

Animal Welfare↗

PubMed1995

The effects of oral sumatriptan, a 5-HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man.

1. The effects of oral sumatriptan (50, 100 and 200 mg), a 5-HT1 receptor agonist, and placebo, on circulating adrenocorticotrophic hormone (ACTH) and cortisol concentrations were determined over 24 h after dosing, in 26 healthy male subjects. ACTH was measured by immunoradiometric assay and cortisol by radioimmunoassay. 2. After sumatriptan all subjects displayed a normal diurnal rhythm for circulating ACTH and cortisol compared with placebo. 3. There was a reduction in the trough circulating ACTH concentration over 0-4 h which was 18% with 100 mg (P = 0.002), and 25% with 200 mg (P < 0.001). The 5 h, post-prandial, peak ACTH concentration was reduced by 21% with 100 mg (P = 0.018) and by 20% with 200 mg (P = 0.024). The weighted mean ACTH over 24 h was reduced by 8% with 100 mg (P = 0.029) and by 8% with 200 mg (P = 0.018). The nadir concentration of ACTH over the 24 h and the ACTH concentration 24 h after sumatriptan were not, however, significantly reduced. All results are compared with placebo. 4. There was a reduction in the trough circulating cortisol concentration over 0-4 h which was 15% with 50 mg (P = 0.015), 14% with 100 mg (P = 0.022) and 24% with 200 mg (P < 0.001). The 5 h, post-prandial, peak cortisol concentration was reduced by 16% with 100 mg (P = 0.012) and by 15% with 200 mg (P = 0.017).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1995

A stepwise procedure for evaluating irritant materials in normal volunteer subjects.

1. The cutaneous response to a known irritant has been assessed in human volunteer subjects using both clinical scoring and two non-invasive instrumental methods; erythema measurement using an erythema meter and capillary blood flow using a laser Doppler device. 2. Aqueous solutions (0.5% and 1%) of sodium hydroxide were applied to back skin for 3, 15 and 60 min with assessments immediately after removal and at 1, 24 and 48 hours. 3. Increased erythema was seen with increasing duration of exposure and an increase was also seen at 1 h, 24 h and 48 h after removal of the patch. The results obtained with the erythema meter paralleled the clinical erythema scores. However, the laser Doppler device showed the greatest changes immediately after removal of the patch with subsequent readings showing a gradual decrease. 4. Statistical analysis of the data has been carried out to determine the accuracy and precision of the assessment procedures and to determine the minimum test panel size for detecting irritant reactions. 5. Comparison between back and forearm skin indicated a greater sensitivity to sodium hydroxide on the back. 6. The results of this study define an ethical approach to testing irritant materials in human subjects and provide the basis for the development of a classification system for cutaneous irritants.

Adolescent↗

PubMed1995

Skin irritation testing in man for hazard assessment--evaluation of four patch systems.

1. The limitations of the Draize rabbit skin irritation test for hazard evaluation for man are widely documented. Nevertheless it remains the prescribed method for determining acute skin irritations hazard. 2. While the use of human testing for risk assessment of irritants is well established, the use of predictive testing in man for hazard identification has not been explored widely, and this is the object of the research programme. 3. The experiment described in this report evaluates the sensitivity of four patch testing systems (Finn chamber, Hill Top patch, Van der Bend chamber, and Webril patch) using a total of six irritant substances. 4. Following preliminary range-finding experiments, test materials were applied to the upper outer arm for up to 4 h. Assessments were performed immediately after patch removal and at 1, 24, 48, and 72 h. 5. Webril and Hill Top patches generated the greatest levels of response, although responses with Finn and Van der Bend were observed. Hill Top patches are recommended for future development work. 6. The use of very small preliminary panels to predict the effects in larger panels using different volunteers was only of limited value as each volunteer was found to have different irritant thresholds.

Acetates↗

PubMed1994

The identification and classification of skin irritation hazard by a human patch test.

There exist various regulatory instruments the purpose of which is to ensure that the intrinsic toxic hazards associated with substances and preparations are identified. In the context of identification of skin irritation potential, the method is normally the Draize test. Guidance notes provided by the OECD and the EEC expect that corrosive substances will have been screened out by a variety of methods. Substances or preparations which cause a sufficient degree of skin irritation will be classified as skin irritants. The primary motivation behind the present work was to introduce the concept that it is possible to assess the hazard potential of a substance or preparation to produce skin irritation in a human study. In the example presented here, 20% sodium lauryl sulfate (SLS) has been chosen as the positive control. With the protocol currently devised, occluded patch treatment with 20% SLS for up to 4 hr produces an irritant response in just over half of the panel. An irritant response is taken as a clinically evident and significant increase in erythema, oedema or dryness--a minimum of a+ reaction on the ICDRG scale. At such a level of response with the positive control (both in terms of intensity and in proportion of the panel), it is then possible to judge and/or to determine statistically, whether the test material has produced a level of skin irritation which is similar to, greater, or lower than the positive control. In this way a human patch test protocol can form a fundamental component of a strategy for the replacement of animals in determination of skin irritation and corrosion potential. By use of a careful and progressive protocol and by comparison of test data against a positive control it is both possible and practical to classify substances and preparations in terms of their skin irritation potential using that endpoint in the species of concern, man.

Adult↗

PubMed1994

Efficacy of oral ondansetron, a selective antagonist of 5-HT3 receptors, in the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapies. Ondansetron Study Group.

We evaluated the efficacy and safety of oral ondansetron, a selective antagonist of 5-HT3 receptors, for the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapy (> 500 mg/m2). In this trial 324 chemotherapy-naive cancer patients, mostly females with breast cancer, were randomized to receive either placebo or ondansetron 1 mg, 4 mg, or 8 mg three times per day for 3 days. There were no differences in the doses of cyclophosphamide, doxorubicin, and methotrexate between the study groups. All ondansetron dose groups were superior to the placebo control group (p < .001) for all measured efficacy parameters (complete response, number of emetic episodes, therapeutic failures, need of rescue antiemetics). No emetic episodes were reported by 9 (12%), 29 (37%), 48 (64%), and 47 (66%) of the placebo patients and the 1-mg, 4-mg, and 8-mg dose of ondansetron patients, respectively. Nausea was reduced and food intake was improved for all the ondansetron groups. A more severe emetic response was observed in patients receiving cyclophosphamide and doxorubicin combination chemotherapy. In this subgroup of patients, 66%, 38%, 25%, and 16% of the placebo group and 1-mg, 4-mg, and 8-mg ondansetron patients, respectively, required rescue antiemetics. No significant toxic effects were observed in this study. A higher incidence of headaches and gastrointestinal complaints (constipation, abdominal pain) were observed in the three ondansetron groups. In conclusion, oral ondansetron is an effective and well-tolerated antiemetic treatment in the management of cancer patients receiving ambulatory cyclophosphamide-based chemotherapy. These results support the view that serotonin and 5-HT3 receptors play an important role in cyclophosphamide-induced nausea and vomiting.

Administration, Oral↗