A triple-dose protocol was evaluated in the rat bone-marrow micronucleus test using azobenzene and 1,2-dibromo-3-chloropropane (DBCP) as test compounds. Dosing with 250 mg/kg azobenzene over 3 consecutive days led to an accumulation of micronucleated polychromatic erythrocytes. The magnitude of the effect was the same as that obtained after a single dose of 750 mg/kg in a previous study. In the single-dose study the effect was only detected at the 48 h sampling time. With the triple-dose protocol the effect was apparent 24 h after the last dose--thus eliminating the need for more than one sampling time. In the case of DBCP, the positive effect observed after a single dose diminished with increasing number of doses for the low dose but plateaued for the high dose, accompanied by a marked cytotoxic effect. It is therefore concluded, that for one of the compounds, azobenzene, the triple-dose protocol provided an advantage whereas for the other, DBCP, it failed to do so and led to results which are rather difficult to interpret. Furthermore, the number of animals necessary to select an appropriate dose level appears to be higher than in the single-dose protocol.

Animals↗

PubMedDate not supplied

Development of a high throughput in vitro toxicity screen predictive of high acute in vivo toxic potential.

At an early stage of drug discovery high throughput screens are an invaluable tool to de-select compounds with undesirable properties. A high throughout in vitro toxicity screen has been developed and validated to identify compounds that have a high potential to be acutely toxic in vivo. This screen is based on treating Chinese hamster ovary (CHO) cells with test compounds for 24 h and then determining the degree of cytotoxicity by the reduction of Resazurin. Twenty-six structurally unrelated compounds were chosen that spanned a range of acute LD(50) values and mechanisms of toxicity. The acute LD(50) values (intraperitoneal and intravenous routes) from rat and mouse were taken from the RTECS database. Experimentally derived in vitro IC(35) results were compared to the 'most toxic' (lowest) LD(50) values for each compound. The resulting correlation was statistically significant (r=0.8475). However, due to the scatter of the data points, it was considered not appropriate to rank compounds according to their degree of in vivo toxicity on the basis of the in vitro result. However, by defining cut-off concentrations for both the in vivo (LD(50)) and the in vitro (IC(35)) values it was possible, using the in vitro result (IC(35) <10 microM), to identify compounds that had a high potential to be acutely toxic in vivo ('most toxic' LD(50) <25 micromol/kg). Further development led to a high throughput screen capable of giving a 'Yes', 'No' or 'Borderline' classification as to whether a compound has a high acute in vivo toxic potential. This screen is highly specific (no false positive classifications) and has a sensitivity of approximately 80%. This is deemed acceptable for a first tier toxicity screen at an early stage in the drug discovery process. Transfer of this screen from GlaxoSmithKline UK to sites in Italy, Spain and the USA resulted in very similar findings indicating the inter-laboratory robustness of this screen and therefore the ability to compare results across the GlaxoSmithKline sites.

Animal Testing Alternatives↗

PubMedDate not supplied

Nine days post-thawing red cell conservation in a synthetic medium. Biochemical studies.

The expiration of thawed red cells (RBC) currently is 24 hours. This leads to problems in current transfusion practice, and often wastes rare and costly products. To remedy this situation, we developed a synthetic medium containing 0.085 g per l adenine, 5 g per l glucose, 48.0 g per l sucrose, 0.75 g per l NaH2PO4.H2O, 4 g per l Na2HPO4.2H2O, and 2.5 g per l NaCl, with a pH of 7.40, and an osmolarity of 320 mOsm. After 15 days post-thawing storage at 4 degrees C in our medium, the viability and function of RBC were maintained. We propose the storage of thawed RBC at 4 degrees C in our medium for up to 9 days: sterility was maintained, pH was 6.80, and 2,3-diphosphate glycerate was 50 percent, and adenosine triphosphate 100 percent of the original values. Free hemoglobin was 122 mg per unit, adenylate energy charge was 0.90, and RBC labeled 7 days after thawing showed 89 percent survival 24 hours after transfusion and a one-half disappearance of 22 days.

Adenosine Triphosphate↗

PubMedDate not supplied

Sharp foreign bodies in the tracheobronchial tree.

Aspiration and/or ingestion of foreign bodies is a common occurrence. Six cases of scarf pin aspiration are described. Scarf pin inhalation as a cultural and ethnic hazard in an Arab woman is highlighted. [Editorial comment: The authors illustrate the dangers of holding a straight pin in the mouth. Management of these sharp, potentially penetrating foreign bodies is described.]

Adolescent↗

PubMedDate not supplied

In vitro toxicology in the light of new technologies.

Explore the source record for details and available documents.

Animal Testing Alternatives↗

PubMedDate not supplied

A portable system for monitoring physiological responses to hypoglycaemia.

Hypoglycaemia is the most common complication affecting people with Type 1 insulin dependent diabetes mellitus. Its onset is characterized by symptoms which include sweating, tremor, palpitations, loss of concentration and tiredness. As part of a research project to investigate the mechanisms of hypoglycaemia we have developed an ambulatory system to monitor and record pulsatile changes in blood flow, pulse interval, body temperature and skin impedance. The system uses a pocket computer (Atari Portfolio) to collect and store the data on a memory card. The analogue system consists of two thermocouples, an infrared photoplethysmograph and skin impedance monitoring circuit. To conserve power the system is programmed to make measurements for 2 min every 10 min: using this regimen over 16 h of data can be stored. Data collected during a spontaneous overnight hypoglycaemic episode are presented and also a comparison between continuous and intermittent data collection during a period of induced hypoglycaemia. The system is being used to investigate the physiological responses to hypoglycaemia but could easily be adapted for monitoring other physiological signals.

Arrhythmias, Cardiac↗

PubMedDate not supplied

Treatment of acute myocardial infarction: does the type of hospital make a difference? PPAMI Study Group.

There is sparse data on the treatment practices being followed for acute myocardial infarction at various hospitals that differ in their financial infrastructure, availability of facilities and attachment to a medical college. In this prospective observational study, we evaluated the treatment practices for acute myocardial infarction, its appropriateness based on ACC/AHA guidelines and possible influence by type of hospital and certain patient characteristics. Thrombolysis, beta-blockers and angiotensin-converting enzyme-I inhibitors were used in 674 (63%), 506 (47%) and 413 (38%) respectively of 1072 patients. However, when evaluated according to ACC/AHA guidelines, appropriate use was noted in 83 percent, 78 percent and 99.3 percent, respectively. Thrombolysis was inappropriately denied to 14.7 percent patients whereas in 2.4 percent it was used contrary to recommendations. The most common reason for ineligibility for thrombolysis was late arrival. Beta-blockers were denied to 25.1 percent patients. Decision on use of angiotensin-converting enzyme-I was appropriate in most patients. Aspirin was used in 1027 (95.8%) patients. Government hospitals were least likely to thrombolyse a patient as compared to private, industrial and voluntary hospitals; however, this difference was not seen with the use of beta-blockers and angiotensin-converting enzyme-I. Hospitals attached to medical colleges follow guidelines for use of thrombolysis and beta-blockers more closely than non-teaching hospitals. To conclude, evaluation of appropriateness of a therapeutic modality is of greater clinical significance than mere absolute use. Benefits of thrombolytic therapy can be extended by minimising pre-hospital delay; and there is scope for improved utility of beta-blockers which are cost-effective. In addition, the hospital type also has an impact on the treatment practice being followed for acute myocardial infarction.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Eosinophilia-myalgia syndrome and giant cell myocarditis: a case report and therapeutic approach.

Eosinophilia-myalgia syndrome and giant cell myocarditis are rare and unrelated inflammatory conditions. Both may result in intense inflammatory infiltrates with eosinophilic predominance. A case involving a patient in whom both conditions occurred and who required intensive, prolonged immunosuppressive therapy is presented.

Cyclosporine↗

PubMedDate not supplied

Decreased P-glycoprotein in a tamoxifen-tolerant breast carcinoma model.

The initial benefits of antiestrogen treatment in mammary cancer tend to decrease with time as antiestrogen resistant subpopulations of cancer cells predominate. The role of P-glycoprotein in this phenomenon is not known. In the tumour model investigated, estradiol increased this efflux pump, while prolonged Tamoxifen exposure resulted in cell populations tolerant to the drug and with decreased P-glycoprotein expression. While Tamoxifen resistance is clinically undesirable, selective pressure by this drug may result in cancer cell lines with increased vulnerability to other chemotherapeutic modalities.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Ethyl alcohol: experimental agent for interventional therapy of neurovascular lesions.

Perfusion of absolute ethyl alcohol into the middle cerebral artery of six rhesus monkeys was performed using the Pevsner miniballoon catheter system. The animals were sacrificed by thoracotomy and intracardiac perfusion of a mixed aldehyde solution for fixation. Preliminary angiography and electron microscopy suggest absolute ethyl alcohol is a good neurovascular occlusive agent, and a possible replacement for isobutyl 2-cyanoacrylate in the treatment of angiomas and tumors.

Animals↗

PubMedDate not supplied

Management of chronic left ventricular assist device percutaneous lead insertion sites.

Patients with ventricular assist devices must necessarily have percutaneous leads linking the internal device to the external console. In the chronic circumstance, the percutaneous lead insertion site may become the location of irritation or infection. At the University of Pittsburgh, a procedure has been developed for care of this site. Since the institution of the procedure, 30 patients have been mechanically supported, representing a total of 1688 patient days of support. Positive cultures were obtained from the lead insertion sites of four patients in this series, whose length of support ranged from 72 to 144 days. All four patients were hemodynamically unstable requiring support with the intraaortic balloon pump before institution of the ventricular assist device, and two patients had significant risk factors for infection development at the lead insertion site before implementation. Two of the infections were considered minor, and posttransplantation sequelae developed in only one patient. With current therapeutic protocols and the defined procedure for care of the lead insertion site, the occurrence of positive cultures associated with clinical signs and symptoms of site infection appears to be infrequent.

Anti-Infective Agents, Local↗