Recrudescent cryptococcosis, caused by Cryptococcus gattii (molecular type VGII), over a 13-year period in a Birman cat.

A 17-year-old desexed male Birman cat presented with a fleshy mass protruding from the left ear canal. A culture from the mass revealed a heavy growth of Cryptococcus gattii (molecular type VGII, serotype B). The lesion resolved with antifungal therapy over 8 weeks. Itraconazole was continued indefinitely due to persistent high serum cryptococcal antigen titres. The cat was euthanased 12 months later due to the acute development of hindlimb ataxia and collapse which may or may not have been attributable to cryptococcosis. This cat had first presented when 4 years of age with a 3-week history of inappetance, sneezing and serous nasal discharge. Culture of swabs from both nostrils were positive for C. gattii (VGII). Fluconazole therapy produced steady improvement over a 6 month period, at which time therapy was discontinued. The cat presented 9 months later for sneezing, again with a positive culture of C. gattii from the nasal cavity. Antifungal therapy was continued for 8 months, after which time cultures were negative and symptoms resolved. Three episodes of cryptococcosis in a cat over a 13-year period were thus documented. Importantly, the two C. gattii isolates, obtained 13 years apart, were identical using DNA fingerprinting and random amplification of polymorphic DNA (RAPD) analysis.

Concurrent Fusarium chlamydosporum and Microsphaeropsis arundinis infections in a cat.

A 7-year-old cat was presented initially with multiple draining sinuses on the metatarsal region of its right hindlimb. Another lesion had appeared at the same time on the fifth proximal interphalangeal joint of the left forelimb. Histopathological examination of a biopsy from the right hindlimb lesion revealed chronic pyogranulomatous inflammation associated with yeast-like bodies and septate mycelia; a fungus was cultured on conventional media but not identified further. Culture of a swab collected from the left forelimb lesion demonstrated a pigmented fungus, also not characterised further. Although there was initially a favourable response to ketoconazole (Nizoral, Janssen-Cilag Pty. Ltd) and beta-lactam therapy, the infection in the hind limb relapsed subsequently, and Fusarium chlamydosporum was cultured from deep biopsy specimens. Clinical improvement followed debridement and itraconazole (Sporanox, Janssen-Cilag Pty. Ltd; 100 mg orally once daily), however amputation of the limb represented the best chance for a cure. The cat made an uncomplicated recovery following surgery and remained well for five months until the lesion on the left forelimb recurred. Amputation of the distal fourth digit was then performed, and the resected tissue submitted for culture. The dematiaceous fungus Microsphaeropsis arundinis was subsequently cultured. The cat remained well for several months, until a further F. chlamydosporum infection developed on the body wall. This was excised 7 months ago, and no lesions have recurred in this area. Importantly, this is the first reported case of M. arundinis infection in a mammalian host.

Animal behaviour learning environment: software to facilitate learning in canine and feline behavior therapy.

Interactive software has been developed on CD-ROM to facilitate learning of problem formulation, diagnostic methodology, and therapeutic options in dog and cat behavior problems. Students working in small groups are presented with a signalment, a case history, and brief description of the problem behavior as perceived by the client. Students then navigate through the case history by asking the client questions from an icon-driven question pad. Animated video responses to the questions are provided. Students are then required to rate the significance of the questions and answers with respect to the development of the unwelcome behavior. Links to online self-assessments and to resource materials about causation and treatment options are provided to assist students in their decision-making process. The activity concludes with a software-generated e-mail submission that includes the recorded history, diagnosis, and recommended treatment for assessment purposes.

PNU-159548, a novel cytotoxic antitumor agent with a low cardiotoxic potential.

PURPOSE: PNU-159548 (4-demethoxy-3'-deamino-3'aziridinyl-4'-methylsulphonyl-daunorubicin), a derivative of the anticancer idarubicin, has a broad spectrum of antitumoral activity in vitro and in vivo attributable to its DNA intercalating and alkylating properties. The present study was conducted to determine the cardiotoxic activity of PNU-159548 relative to doxorubicin in a chronic rat model sensitive to anthracycline-induced cardiomyopathy. METHODS: Young adult male rats were allocated to the following treatment groups: group 1, PNU-159548 vehicle control (colloidal dispersion); group 2, doxorubicin control (saline); groups 3, 4, 5, 6, and 7, PNU-159548 at 0.12, 0.25, 0.50, 0.75, and 1.0 mg/kg, respectively; and group 8, 1.0 mg/kg doxorubicin. Treatments were administered intravenously once weekly for 4 weeks (first sacrifice time) or for 7 weeks (rats killed at weeks 8, 12, 22, 27, or 35). Body weights, organ weights, serum chemistry, hematology, serum troponin-T, and cardiac histopathology were followed throughout the study. RESULTS: Doxorubicin caused irreversible cardiomyopathy evident at week 4 in some rats and progressing in severity in all rats by week 8. There were also marked myelotoxicity, increased liver and kidney weights, testicular atrophy, and about 20% mortality by week 27 in doxorubicin-treated rats. The deaths were attributed to cardiomyopathy and/or nephropathy. PNU-159548 caused a dose-dependent myelotoxicity, with the dose of 0.5 mg/kg per week being equimyelotoxic to 1.0 mg/kg per week doxorubicin. PNU-159548 also caused an increase in liver weight that was reversible and a non-reversible testicular atrophy but, unlike doxorubicin, had no effect on kidney weight. At equimyelotoxic doses, the cardiotoxicity caused by PNU-159548, expressed as the mean total score, was less than one-twentieth of that induced by doxorubicin, and much less than that predicted on the basis of its content of idarubicin, which is in turn markedly less cardiotoxic than doxorubicin. CONCLUSIONS: The novel cytotoxic antitumor derivative, PNU-159548, is significantly less cardiotoxic than doxorubicin at equimyelosuppressive doses. The combination of intercalating and alkylating activities within the same molecule without the cardiotoxic side effects of anthracyclines makes PNU-159548 an excellent candidate for clinical development in oncology.

Pharmacological and toxicological aspects of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548): a novel antineoplastic agent.

4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548) belongs to a novel class of antitumor compounds (termed alkycyclines) and is currently undergoing Phase II clinical trial. In the present study, we investigated the in vitro and in vivo antitumor activity, the pharmacokinetics, and the toxicological profile of this compound. PNU-159548 showed good cytotoxic activity in murine and human cancer cells growing in vitro, with an average concentration for 50% growth inhibition of 15.8 ng/ml. The drug showed strong antitumor efficacy in vivo after i.v. and p.o. administration against rapidly proliferating murine leukemias and slowly growing transplantable human xenografts. At non-toxic doses, PNU-159548 produced complete regression and cures in ovarian, breast, and human small cell lung carcinomas. Fourteen of 16 models studied, including colon, pancreatic, gastric, and renal carcinomas, astrocytoma and melanoma, were found to be sensitive to PNU-159548. In addition, PNU-159548 was effective against intracranially implanted tumors. Toxicological studies revealed myelosuppression as the main toxicity in both mice and dogs. The maximum tolerated doses, after a single administration, were 2.5 mg/kg of body weight in mice, 1.6 mg/kg in rats, and 0.3 mg/kg in dogs. In the cyclic studies, the maximum tolerated doses were 0.18 mg/kg/day (cumulative dose/cycle: 0.54 mg/kg) in rats and 0.05 mg/kg/day (cumulative dose/cycle: 0.15 mg/kg) in dogs. PNU-159548 showed minimal cardiotoxicity, when compared with doxorubicin in the chronic rat model at a dose level inducing similar myelotoxicity. Animal pharmacokinetics, carried out in mice, rats, and dogs, was characterized by high volumes of distribution, plasma clearance of the same order of the hepatic blood flow, and short terminal half-life. These findings support the conclusion that PNU-159548 is an excellent candidate for clinical trials in the treatment of cancer.

Echocardiographic measurements in greyhounds, whippets and Italian greyhounds--dogs with a similar conformation but different size.

OBJECTIVE: To determine the effect of body size on various echocardiographic measurements in dogs of widely differing size, but identical body conformation. DESIGN: A randomised echocardiographic study of healthy sighthounds. ANIMALS: 60 dogs comprising an equal number (20) of racing Greyhounds, Whippets and Italian Greyhounds. PROCEDURE: Following sedation with acepromazine and morphine, and acclimatization, a thorough echocardiographic examination was performed on each dog using standard methods. RESULTS: Dimensions measured echocardiographically were highly correlated with body size. These data were subsequently examined using analyses of variance and regression. Body surface area was the best overall predictor of dimensional measurements. In comparison to previous studies using dogs of differing size and conformation, the spread of values for measurements plotted against body surface area showed substantially narrower ranges. Thus, the relationship between echocardiographic measurements and body surface area was much closer for dogs with an identical somatotype than for dogs of differing size and conformation. Commonly used ejection phase indices (fractional shortening, ejection fraction and velocity of circumferential fibre shortening) were negatively correlated with body size. In contrast, the thickening fraction of the left ventricular posterior wall, another ejection phase index, was independent of body weight and body surface area for all three breeds and when the data were pooled. CONCLUSION: Taken in consideration with previous work, this study demonstrates that body conformation and body size both influence canine echocardiographic measurements. Commonly used ejection phase indices are significantly affected by body size, with larger sighthounds having lower values. A more appropriate method of quantitating left ventricular function may be the determination of the thickening fraction of the left ventricular posterior wall.

An evaluation of the results of two non-surgical methods in the treatment of fractures of the odontoid process.

The authors illustrate the results of a series of 47 fractures of the odontoid process all treated according to two non-surgical methods, among the most diffused and accepted: Minerva plaster and halo-plaster. The various elements used to classify odontoid fractures are examined, as is their importance for prognosis. The conclusions refer to two essential points: 1) fractures with a higher risk of nonunion are Anderson type II, with posterior shifting, in elderly patients; 2) reduction and immobilization with a halo-plaster may be considered the first choice of a method for most of these fractures, in consideration of the limited risk of nonunion involved.

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel.

PURPOSE: Results of several clinical studies suggest that the combination of doxorubicin (DOX) and paclitaxel (PTX) is highly active against solid tumors. Both drugs are known to cause adverse cardiac effects, cardiomyopathy in the case of DOX and acute changes in cardiac rhythm in the case of PTX. It has been suggested that the addition of dexrazoxane (DZR) to this regimen may reduce the risk of cardiotoxicity. A model of chronic cardiomyopathy in the rat was used to determine whether DZR was tolerated and cardioprotective in a DOX + PTX combination. METHODS: Male rats were treated once weekly for 7 weeks with one of the following vehicle and/or drug sequences: Group A, M/6 sodium lactate/saline/Cremophor EL (CEL); Group B, lactate/DOX/CEL; Group C, DZR/DOX/CEL; Group D, lactate/DOX/PTX; and Group E, DZR/DOX/PTX. DZR and DOX or their respective vehicles were given i.v. whilst PTX or CEL were given i.p. DZR, DOX and PTX were administered at 16 mg/kg, 0.8 mg/kg and 2.4 mg/kg, respectively, doses which caused minimal noncardiac toxicities. The hearts were examined histologically 5 weeks following the last treatment. RESULTS: There were no deaths and no signs of overt toxicity during the 12 weeks of study. There was a significant decrease (P < 0.01) in white blood cell count in rats treated with DZR + DOX, DOX + PTX or DZR + DOX + PTX but not in those given DOX alone. Liver and kidney weights were increased in rats given DOX (P < 0.05) but not in those given DZR + DOX. PTX had no effect on the DOX-induced liver and kidney changes and did not interfere with the protective effect of DZR on the kidney. The severity and extent of cardiomyopathy expressed as the mean total score (MTS) for each treatment group, was similar for DOX and DOX + PTX (4.6 and 4.2, respectively). DZR provided significant cardioprotection (P < 0.01) when added to either DOX (MTS 2.0) or to DOX + PTX (MTS 2.1). CONCLUSIONS: The results suggest that PTX does not exacerbate the chronic cardiomyopathy caused by DOX and when added to the DOX + PTX combination, DZR retains its protective activity against DOX-induced cardiotoxicity without increasing noncardiac toxicity.

Effect of acute haemorrhage on QRS amplitude of the lead II canine electrocardiogram.

OBJECTIVE: To examine the effect of acute haemorrhage on the QRS amplitude of the canine lead II surface electrocardiograph (ECG). DESIGN: Ten adult racing Greyhounds were tranquilised, anaesthetised, positioned in right lateral recumbency and connected to recording electrodes of an ECG unit. Baseline six-lead ECG traces were recorded, and further traces were obtained after one unit (460 mL) of blood, and then a second unit, were collected from the femoral artery. RESULTS: There was a consistent and progressive reduction in amplitude of the QRS complex in all leads during acute haemorrhage. QRS amplitude in lead II after removal of two units of blood averaged 74% of the baseline voltage, with individual values of 61 to 91% (P < 0.0001). There were even greater reductions in QRS amplitudes in lead aVL during haemorrhage. In three additional dogs, reductions in QRS voltages were shown to be accompanied by reductions in end-diastolic left ventricular internal dimensions measured echocardiographically. Furthermore, the effects of haemorrhage on the QRS amplitude and echocardiographic measurements were reversed when circulating blood volume was restored by re-infusion of blood removed previously. CONCLUSION: Acute haemorrhage corresponding to an approximately one-third reduction in blood volume caused a substantial reduction in QRS voltage of the surface ECG. It is postulated that this resulted from diminished ventricular distension as a consequence of reduced venous return. A similar mechanism may account for the small-amplitude ECG complexes associated with pericardial effusion, severe dehydration and hypovolaemia.

Influence of mutations associated with familial prion-related encephalopathies on biological activity of prion protein peptides.

In transmissible spongiform encephalopathies (TSEs), an altered form of prion protein (PrP), PrPres, aggregates in amyloid fibrils and accumulates in the brain. Several point mutations of the PrP gene have been associated with the TSEs, so, to investigate how the mutations affect the biological activity of PrP, we analyzed the biological effects and chemicophysical characteristics of the peptide homologous to the wild-type and mutated sequence of PrP fragments. The mutation P102L altered the biological activity of PrP 89-106, which became neurotoxic without changing its fibrillogenic capacity. The mutation (D178N) in the PrP 169-185 strongly increased the neurotoxic activity of the native sequence. In this case, there was also a clear alteration of the structural conformation. None of the other mutations considered, including A117V, seemed to influence the biological activities of the respective peptides. These data identify new neurotoxic fragments of PrP in the mutated form and elucidate their genetic influence on the pathogenesis of TSEs.

Protection against doxorubicin-induced cardiotoxicity in weanling rats by dexrazoxane.

PURPOSE: Dexrazoxane (DZR) protects against anthracycline-induced cardiotoxicity in several laboratory animal species and in patients with breast cancer. Encouraging results have also been obtained in a limited number of pediatric oncology patients. We conducted studies to determine the safety and cardioprotective activity of DZR in the doxorubicin (DOX)-treated weanling rat simulating the rapidly growing immature child. METHODS: Male weanling rats and young adult rats, 20 days old and 7 weeks old, respectively, were given 1 mg/kg DOX i.v., either alone or with 20 mg/kg DZR, once weekly for 7 weeks. Rats were sacrificed at weeks 8, 12 or 26 following blood collection for hematology and serum chemistry. Hearts were weighed and examined histologically. RESULTS: DOX, either alone or with DZR, inhibited growth, and body weight remained below that of controls throughout the 26 weeks of study. There were no biologically significant hematologic changes in either the DOX- or DZR + DOX-treated young rats. DOX caused a slight increase in liver and kidney weights relative to body weight and a slight increase in serum cholesterol and triglycerides in the young rats. These effects were ameliorated or delayed by DZR. DOX, either alone or with DZR, caused a marked atrophy of the testes in the young rats which had recovered by week 26. In the mature rats, DOX caused a significant decrease in the WBC 1 week after the last treatment, and the WBC was significantly lower in the rats given DZR + DOX compared to those given DOX alone. There were marked increases in liver and kidney weight, serum cholesterol and triglycerides in the mature rats given DOX alone but not in those given DZR + DOX. There was also a marked testicular atrophy in the mature rats given either DOX or DZR + DOX but, unlike that observed in the young rats, this had not returned to normal by week 26. DOX-induced cardiotoxicity was less severe in the younger rats than in the mature rats but in both age groups, the lesion progressed rapidly until week 12, 5 weeks after the last dose, and remained relatively stable or progressed slightly thereafter. DZR provided significant cardioprotection in both age groups at all time points examined. Moreover, in both age groups, the severity of the cardiomyopathy in the DZR-treated rats was somewhat less at week 26 than it was at week 12. CONCLUSIONS: The results indicate that the pharmacologic effects of DZR, including its ability to protect against cardiotoxicity, are similar in immature and adult male animals treated with DOX.

Amidation of beta-amyloid peptide strongly reduced the amyloidogenic activity without alteration of the neurotoxicity.

Beta-amyloid accumulates in cerebral deposits in Alzheimer's disease, so to test the correlation between the neurotoxic and fibrillogenic capacity of beta-amyloid, we synthesized a peptide homologous to fragment 25-35 of beta-amyloid (beta25-35) and amidated at the C-terminus (beta25-35-NH2). As the amidation strongly reduced the amyloidogenic capacity of beta25-35, we compared its neurotoxic activity in the amidated (beta25-35-NH2) and nonamidated forms. The viability of primary cultures from fetal rat hippocampus was reduced in a dose-related manner (10-100 microM) similarly by beta25-35 and beta25-35-NH2, whereas a scrambled peptide, amidated or nonamidated, did not alter the neuronal viability. The neurotoxic activity of beta25-35-NH2 is mediated by apoptosis as demonstrated by morphological and biochemical investigations. Electron microscopy examination of culture media with beta25-35 or beta25-35-NH2 incubated with neuronal cells for 7 days confirmed the high level of fibrillogenic activity of beta25-35 and the almost total absence of fibrils in the solution with beta25-35-NH2. Furthermore, staining with thioflavine S was used to identify amyloid fibrils, and only the cultures exposed to beta25-35 exhibited intense staining associated with neuronal membranes. These data indicate that the neurotoxic activity of the beta-amyloid fragment is independent of the aggregated state of the peptide.

Dose-response relationship of dexrazoxane for prevention of doxorubicin-induced cardiotoxicity in mice, rats, and dogs.

Dexrazoxane [(DZR), ADR 529, ICRF-187] ameliorates doxorubicin (DOX)-induced cardiotoxicity in animals, and is recommended as a cardioprotectant in patients receiving cumulative doses of DOX above 300 mg/m2. A DZR:DOX dose ratio of 10:1 is recommended based on studies in patients receiving 50 mg/m2. Since DOX may be used at much higher doses in certain clinical settings, we evaluated the ability of DZR to protect against cardiomyopathy in animals given bolus doses of DOX at varying dose levels. The severity and extent of the cardiomyopathy were evaluated histologically and expressed as the mean total score (MTS). Mice were given 10 doses of DOX (2 or 4 mg/kg) over a 7-week period. Without DZR, the MTS 4 weeks after the last treatment was 3.7 with 4 mg/kg DOX and 1.3 with 2 mg/kg DOX. DZR at 5:1, 10:1, and 20:1 dose ratios caused a dose-dependent decrease in the MTS but was less efficacious with the higher, more cardiotoxic dose of DOX. Rats were given DOX at 0.2, 0.4, and 0.8 mg/kg with a 20:1 ratio of DZR weekly for 13 weeks. Cardiomyopathy was most severe with the highest dose of DOX in the absence of DZR, especially in males, and progressed during the 6 weeks following the last treatment. DZR reduced the MTS in both sexes but in the males given the highest dose of DOX, there was still a significant amount of cardiac damage compared to vehicle-treated controls. Dogs were given 0.1, 0.3, and 0.8 mg/kg DOX with 20:1 DZR for 13 weeks. DZR reduced the MTS significantly (P < 0.05) in males and females but cardiac lesions were still present in each of the DZR-treated dogs. The results indicate that although DZR is highly effective in attenuating the cardiomyopathy caused by DOX, dose ratios of DZR:DOX capable of providing total or nearly complete cardioprotection at low doses of DOX are less efficacious at higher doses of DOX. One possible explanation for this effect is the marked pharmacokinetic difference between DZR and DOX, with DZR undergoing a much more rapid rate of elimination from the body compared to DOX. These findings point to the need for further studies to optimize the dose scheduling of DZR before using it clinically with bolus doses of DOX above those currently recommended.

Long-lasting effect of dexrazoxane against anthracycline cardiotoxicity in rats.

The long-lasting protective effect of dexrazoxane (ADR-529) against doxorubicin- and epirubicin-induced cardiotoxicity was evaluated in the multiple-dose 35-wk rat model. Groups of 36 male Sprague-Dawley rats were given ADR-529 30 min before administration of cardiotoxic doses of doxorubicin (1 mg/kg/wk) or epirubicin (1.13 mg/kg/wk). The compounds were intravenously injected once weekly for 7 consecutive wk at ADR-529; anthracycline ratios ranging from 5:1 to 20:1. These ratios covered the entire chemotherapeutic range in humans and allowed studying the chronic progressive cardiomyopathy in our rat model. Animals were observed for up to 35 wk to follow the time course of the well-characterized cardiomyopathy, which was evaluated through the well-established qualitative/quantitative morphological grading. It was clearly demonstrated in this rat model that ADR-529, at the ratios administered, provided ample cardioprotection for a duration of 35 wk, which corresponds to 25 yr of equivalent human time.

Evaluation of 4'-iodo-4'-deoxydoxorubicin-induced cardiotoxicity in two experimental rat models.

In the present study, 1 single-dose and 1 multiple-dose models were applied in studying 4'-iodo-4'-deoxydoxorubicin (I-DX) cardiotoxicity. Anthracycline cardiotoxicity has been reproduced in several animals including mice, rats, hamsters, rabbits, dogs, and monkeys. Of these species the rat can be considered the most suitable species for the study of anthracycline-induced cardiomyopathy. The cardiotoxicity induced by I-DX in male Sprague-Dawley rats was compared to that of doxorubicin (DX), used as standard positive control. Groups of 36-42 rats were observed for up to 35 wk to follow the progression of the lesions. Cardiomyopathy was evaluated through well-established qualitative/quantitative morphological grading. The new DX derivative proved to be clearly less cardiotoxic than DX with both treatment schedules. Although both models can be considered useful for evaluating and comparing the cardiotoxicity of new anthracycline derivatives and mimicking the transvenous endomyocardial biopsies in humans, the chronic test seems to be more suitable for compounds like I-DX, which possess a low cardiotoxic potential and which could go undetected in the single-dose test.

The histopathology of kidney changes in rats and monkeys following intravenous administration of massive doses of FCE 26184, human basic fibroblast growth factor.

Intravenous administration of human basic fibroblast growth factor up to 100 micrograms/kg/day to Sprague-Dawley rats caused changes in the kidneys that included enlargement, vacuolation, and karyomegaly of podocytes in glomeruli, dilatation and cast formation in tubules, thickening of the media in the lobular arteries, and hyperplasia of the epithelium of the papilla and collecting ducts. In cynomolgus monkeys there was hyperplasia of the parietal epithelium of Bowman's capsule in the glomeruli, tubular dilatation, and minimal arteriopathy. These changes were only seen at 100 micrograms/kg/day. The development and eventual recovery over time were investigated in a sequence of sacrifices. In monkeys the first changes were seen after 7 days of treatment, but in rats only after 16 days. In both species the changes had partially resolved after 30 days of recovery and were considered to return to normal after 60 days without treatment. The morphological changes were accompanied by functional alterations that included proteinuria and raised blood urea. Changes that occurred in other tissues including bone, red blood cells, adrenals, ovaries, liver, gall bladder, spleen, mesenteric lymph nodes, thymus, aorta, salivary glands, and injection site are not described in this paper.

Multinucleated hepatocytes induced by rifabutin in rats.

Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria, including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies. An interesting feature was the occurrence of multinucleated hepatocytes (MNHs) in the rat. In some instances, as many as 25 nuclei occurred in a single cell. Light microscopy revealed a large hepatocyte with normal eosinophilic staining. The multiple nuclei stained like those present in the surrounding normal cells. Electron microscopy showed no abnormalities of the nuclei and no cell membranes within the cytoplasm. The customary organelles were present. MNHs were dose- and sex-related, starting from 10 mg/kg/day and being more evident in males. They began to appear after 5 wk of treatment and persisted over long periods of recovery (12 mo), without showing any tendency for cell proliferation. The life-span of MNHs was similar to that of normal hepatocytes. MNHs were present in the carcinogenicity study, but there was no increase in liver tumors. MNHs did not occur in mice or monkeys treated with rifabutin, nor did they occur in response to treatment with rifampin. The effect appears to be specific to the rat.

Characterization of the toxicity of distamycin derivatives on cancer cell lines and rat heart.

The cytotoxicity and cardiotoxicity of benzoyl mustard (FCE 24517) and epoxamido (FCE 24561) synthetic derivatives of distamycin A were reported in the present study. The 50% inhibiting concentration (IC50) of colony formation of FCE 24517 on human SNB-19 glioblastoma, A2780 ovarian cancer and DU 145 prostate cancer was at least three times lower than that of FCE 24561; on the same cell lines the IC50 of DXR was up to 14 and 240 times higher than that of FCE 24561 and FCE 24517, respectively. Isolated rat hearts perfused with concentrations of both derivatives equivalent to their respective IC50 values did not show any significant change in ECG parameters, contractility and coronary flow. Compared to control hearts, FCE 24517 10(-6) M induced a significant increase in PR interval, reduction in + dF/dtmax, heart rate and coronary flow, while FCE 24561 10(-6) M produced a modest but significant increase in S alpha T segment and decrease in + dF/dtmax. Rats treated with FCE 24561 3, 6 or 12 mg/kg, intravenously (i.v.), once weekly for 3 weeks had a modest increase in S alpha T segment and QRS complex duration, while a slight alteration of S alpha T segment and QRS complex duration were observed in rats given FCE 24517 1 or 2 mg/kg i.v. once weekly for 3 weeks. No cardiac histologic alterations were found in hearts from rats receiving FCE 24517 or FCE 24561. For comparison, the cardiotoxicity of doxorubicin (DXR) was evaluated in the same experimental models; perfusion of hearts with DXR 10(-6) M induced severe alterations in all parameters of the isolated hearts; the administration of DXR 3 mg/kg i.v. once a week for 3 weeks was associated with a widening of the S alpha T segment and QRS complex and cardiac histologic picture was markedly altered. In conclusion, distamycin A derivatives display elevated cytotoxicity while no substantial cardiotoxicity was observed.

In vivo activity of novel sulphonic derivatives of distamycin A.

Solid tumor growth can be modulated through inhibition of vascularization elicited by angiogenic factors. With the objective to complex these factors, new derivatives of distamycin A were synthesized and evaluated in vitro [1] and in vivo for their ability, after i.v. administration, to inhibit bFGF-induced vascularization and the growth of M5076 murine reticulosarcoma implanted i.m. The tested compounds were able to block angiogenesis with inhibition values ranging between 70-100%. Moreover, they were found to be capable of inducing tumor inhibition with values ranging between 40% and 95% at non-toxic doses.

Halo-cast treatment of fractures and dislocations of the cervical spine.

Twenty-eight consecutive patients with dislocated, and often unstable, injuries of the cervical spine were treated by halo-cast stabilisation. One died and 27 were followed up. Twenty had no symptoms and 17 had full movement of the neck. There were only a very few minor complications. Seven patients had initial neurological impairment. They included the single death, but the remaining 6 regained useful muscle function. The halo-cast allows complete reduction in many types of fractures and dislocations, and good immobilisation is maintained.