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Efficacy and safety of the test product imidacloprid 10%+moxidectin 2.5% spot on (Advocate®, Advantage multi®) in the treatment of canine generalized demodicosis were evaluated in a multi–centre, controlled, randomized, blinded field study in Albania, France, and Germany. The study was conducted according to a non–inferiority design to demonstrate that the efficacy of the test product is not inferior to that of a control product containing milbemycin oxime (Interceptor, tablets for oral application). Of the 72 dogs enrolled, all of which expressed clinical signs of generalized demodicosis, 63 completed the study. Of these, 30 dogs were treated 2–4 times, at 4–week intervals, with the test product at the recommended dose of at least 0.1 ml/kg body weight. Thirty–three dogs were treated daily for two to four periods of 4 weeks with the control product according to label instructions (0.5–1 or 1–2 mg/kg body weight). Presence of mites in deep skin scrapings and clinical improvement were assessed 3–6 times at each inspection at 4–week intervals. Treatment was discontinued in dogs negative for mites on two subsequent examinations 4weeks apart or at the last examination on day 84. At the end of the trial, dogs in both groups showed a similar clinical improvement. No Demodexmites were detected in 26 of 30 dogs treated with imidacloprid/moxidectin and in 29 of 33 dogs treated with milbemycin oxime. Statistical evaluation confirmed that the efficacy of the test product in the treatment of generalized canine demodicosis was not inferior to that of milbemycin oxime.

A multicentric, placebo–controlled, randomised, blinded and blocked field study was conducted to evaluate the efficacy and safety of toltrazuril (Baycox®, Bayer AG, Leverkusen, Germany) in the treatment of coccidiosis in first–year grazing calves naturally infected with Eimeria spp. Three–hundred and thirty–one calves were enrolled in the study and allocated to one of two treatments at a ratio of 1:1. One hundred and sixty–seven animals were treated once orally with 15 mg/kg toltrazuril, and 164 animals served as placebo–treated controls. Two treatment regimes were compared, a metaphylactic (treatment on the day, or 1 day after, turn out) and a therapeutic treatment (4 or 7 days after turn out). During an observation period of 14 days after treatment the animals were clinically examined for diarrhoea and faecal samples were regularly assessed for Eimeriaoocysts. Other possible causes of diarrhoea were excluded on the basis of microbiological and virological examination. Animals were predominantly infected with Eimeria alabamensis. Number of days with diarrhoea in animals treated with toltrazuril was significantly lower compared to the placebo–treated group (therapeutic treatment: P=0.0024; metaphylactic treatment: P<0.0001). Furthermore, the number of animals with diarrhoea during the observation period for a minimum of at least 3 days, the number of animals positive for Eimeriaoocysts, and the number of animals with both diarrhoea for a period of at least 3 days and positive for Eimeriaoocysts, were signiflicantly lower (P<0.01), in the toltrazuril– compared to the placebo–treated animals. Body weight in the toltrazuril–treated animals significantly exceeded that of the placebo–treated animals at the end of the observation period. Mean difference in body weight was higher in the metaphylactic (+7.3 kg) compared to the therapeutic treatment group (+3.4 kg). No adverse reactions were observed. The results indicate that toltrazuril is highly efficacious and safe in the metaphylactic and therapeutic treatment of coccidiosis caused by E. alabamensisin first–year grazing calves.

Efficacy and safety of treatment with imidacloprid 10%+moxidectin 2.5% spot-on (Advocate®, Advantage multi®; Bayer AG, Leverkusen, Germany) were tested in dogs naturally infested with Sarcoptes scabieior Otodectes cynotisin a multi–centre, controlled, randomized, blinded field study conducted in France, Germany, Albania and the UK. The study was performed according to a non–inferiority design to demonstrate that the efficacy of imidacloprid/moxidectin spot–on was not inferior to that of a control product containing selamectin (Stronghold spot–on; Pfizer). All Sarcoptes–infested dogs were topically treated twice (days 0 and 28) with the dosage recommended by the respective manufacturer (27 dogs with imidacloprid/moxidectin, 26 with selamectin). All Otodectes–infested dogs were treated on day 0 (35 dogs with imidacloprid/moxidectin, 34 with selamectin), and only those still positive on day 28 received a second treatment. Parasitological cure rate in Sarcoptes–infested dogs was 100% for both treatments, while parasitological cures rates in the Otodectes–infested dogs at day 28 and day 56 were 68.6 and 85.7% with imidacloprid/moxidectin, and 64.7 and 88.2% with Stronghold. Non–inferiority of Advocate was confirmed statistically. Clinical assessment of skin lesion scores at day 56 showed that with either product >96% of the dogs treated against sarcoptic mange were improved or cured, the difference between the groups being non–significant. On the basis of a final clinical assessment of lesion scores, 80% of the dogs treated with imidacloprid/moxidectin against otoacariosis and 85.3% of those treated with selamectin were rated cured or improved. Only three mild, possibly drug–relatedBadverse reactions were observed among alI treated animals (two in the imidacloprid/moxidectin group, one in the selamectin group). It is concluded that imidacloprid/moxidectin spot–on is an effective and safe treatment for sarcoptic mange and otoacariosis in the dog.

Razoxane is one of the few agents which has shown activity in the treatment of advanced colorectal cancer. The drug has therefore been evaluated in a prospective randomized controlled trial as an adjuvant to surgery for resectable colorectal cancer. The results to median follow-up of 5 years are reported here. Accrual has ceased and a total of 272 patients entered the trial (133 control, 139 treatment). Treated patients received razoxane postoperatively on a continuous, long-term basis while control patients received identical clinical care but no adjuvant chemotherapy. Analysis of the results shows a significant prolongation of the time to recurrence for Dukes' C patients. All other groups including the overall analysis show no benefit although there is a consistent trend in favour of the treated patients except in Dukes' group ‘D’. Razoxane is tolerated well by patients and causes minimal side-effects. However acute leukaemia occurred in three patients (2·45 per cent) after prolonged exposure to the drug and further evaluation should be in patients who are at high risk of developing recurrent cancer, in whom such a risk may be acceptable. It is concluded that razoxane is suitable for further evaluation in colorectal cancer and for incorporation into combination chemotherapy regimens.

Biotinylation of chemically glycosylated bovine serum albumin, yielding a panel of neoglycoproteins, and of desialylated, naturally occurring glycoproteins allowed to systematically evaluate presence and distribution of various types of endogenous sugar receptors in the sections of human glioblastomas and gangliocytomas by a routine histochemical procedure. Pronounced cytoplasmic staining with markers, carrying constituents of natural glycoconjugates, e.g. for ß-galactoside-specific receptors, contrasted with the different intensities, noticed for a- and ß-glucosidespecific receptors. Significant qualitative differences between the two tumor types were detected with N-acetyl-D-galactosamine-and sialic acid-carrying probes. Nuclear staining with only a part of the applied panel underscored the specificity of the protein-carbohydrate interaction. Fine structural features of the synthetic neoglycoproteins, e.g. the mode of coupling of the carbohydrate moiety to the protein, were found to exert a significant influence on their suitability as histochemical markers. On the basis of the histochemical results, exemplary biochemical analysis of certain classes of endogenous sugar receptors by affinity chromatography and subsequent gel electrophoresis, namely of ß-galactoside-, a-fucoside-, a-mannoside- and a-glucoside-specific proteins, revealed presence and characteristics of respective sugar receptors that can contribute to the histochemical staining. Similar extent of histochemical staining with the respective probes notwithstanding, the different tumor types exhibited qualitative differences in the expression of individual endogenous sugar receptors. The combined histochemical and biochemical analysis is supposed to be of conspicuous value for biological and clinical investigations on endogenous sugar receptors.

THE antimitotic action of (±)-1,2-bis (3,5-dioxopiperazin-1-yl) propane (ICRF 159) has been extensively studied in vivo in human1and animal tumours2,3, but its mode of action at the cellular and biochemical level has not yet been elucidated. Although it reduces the rates of DNA, RNA and protein synthesis of cells in vitro4, it has also been shown to block the cell generation cycle in the post-DNA synthesis (G2) phase5,6. Tumours whose growth is halted contain many large multinucleate cells not seen in control tumours. An attempt has therefore been made to see if the morphological changes produced by the drug in cells grown in vitro could provide an indication of its intracellular site of action and point towards possible mechanisms of action. The cells used were non-synchronised cultures of non-transformed hamster fibroblasts (Nil 8 cells), HeLa cells and fibroblasts derived from a transplantable fibrosarcoma in Syrian hamsters (T17 cells). They were exposed to single daily doses of ICRF 159 for 3 d.

Important biological functions and cellular recognition phenomena are supposedly governed by specific sugar-protein interactions. Human hematopoietic cell lines offer an excellent model for the study of the expression of endogenous receptors for the carbohydrate part of glycoconjugates with respect to cell lineage and modulation by differentiation. Initially, a panel of fluorescent (neo)glycoproteins was successfully employed to demonstrate cytologically the actual presence of such receptors on different cell lines: the B lymphoblast line, Daudi; the T cell lymphoblastic leukemia line, P 12; the multipotent leukemic line, K 562 and the promyelocytic line, HL 060. Biochemical analyses were performed using affinity chromatography on supports with immobilized lactose and asialofetuin (simple or complex ß-galactosides), melibiose (a-galactoside), fucose, N-acetyl-D-galactosamine, maltose (a-glucoside), the mannose-rich yeast glycoprotein, mannan, glycopeptides containing sialic acid residues and heparin. Subsequently, sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis was used to detect cell lineage-dependent changes in these parameters. Differentiation-dependent changes in the expression of receptors with specificity to galactose, N-acetylgalactosamine, maltose and heparin were similarly uncovered upon dimethyl sulfoxide-induced differentiation of HL 60 cells. Differences in this type of cellular characteristic were also apparent for lymphoma cells from patients with various histological subtypes of lowgrade lymphomas. This initial description of lineage- and differentiation-dependent differences in various human hematopoietic cell lines and in cells from patients with lowgrade lymphomas suggests that advances in the knowledge of the composition of endogenous sugar receptors (lectins) may aid in understanding aspects of the biological behavior of hematopoietic cells and their related malignancies via participation of sugar-protein (lectin) interactions.

At a median follow-up of 5 years, adjuvant razoxane (125 mg b.d.) given 5 days/week indefinitely following resection of colorectal cancer provided no benefit in terms of survival or recurrence for Dukes' A or B patients when compared to untreated controls. However in Dukes' C patients this treatment reduced the recurrence rate (P=0·05) and possibly increased survival time (P=0·08). Analysis now of the development of metastases in this trial which entered 272 patients over 7 years shows that in the Dukes' C group the incidence of liver metastases in the razoxane-treated patients is only about half that of the untreated patients (18 per cent versus 34 per cent) and that the time to first appearance of the liver metastases is twice as long in the razoxane-treated group as it is in the untreated group (80 weeks versus 40 weeks). It is concluded that the benefit of adjuvant razoxane observed in the Dukes' C patients is due to the antimetastatic activity of the drug in reducing and slowing down the development of hepatic secondaries.

One hundred and seventy six patients (81 controls, 95 receiving treatment) have entered a prospective randomized tiral of long-term oral adjuvant razoxane (ICRF-159) following removal of a colorectal cancer. The median follow-up is 34 months. The treated patients in Dukes' groups B and C have a significantly longer disease-free interval than the control patients (P=0.01 ‘as randomized’ and P=0.004 ‘as treated’). The differences in survival for Dukes' groups B and C are not significant, although follow-up is short. In Dukes' groups B and C, however, 24 of 56 of the patients in the control group have died (43%), as against only 17 of 64 in the treatment group (27%). The treatment produces very few side-effects, is well tolerated by patients, and is taken orally.

Istope shift and hyperfine structure measurements have been performed for the242fAm fission isomer with target production rates of only a few per second. The method is based on resonance ionization spectroscopy (RIS) in a buffer gas cell with radioactive decay detection of the ionization process (RADRIS). A relative isotope shift ratioXexp=IS242f,241/ IS243,241=41.7±0.9 has been measured for the 500.02 nm transition corresponding to a nuclear parameter Λ242f,241=5.4±0.3 fm2. The analysis of the quadrupole moment based on the deformed Fermi-model of the nuclear charge distribution including second order corrections results inQ20=38.2 ±1.4(

A single dose of 200 mg/kg razoxane protected mice against the subchronic lethal effects (i.e. within 21 days) of 10 mg/kg daunomycin. When the razoxane dose was split into 2 doses of 100 mg/kg, even better protection against higher doses of daunomycin was obtained. The best protective effect was seen when the razoxane was given 24 h before or simultaneously with the daunomycin, and it was still present, though less, 24 h later. Histopathological examination to determine the site of protection showed it to be in the small bowel. Marrow and cardiac tissue showed no evident changes when examined by light microscopy.

A mixture of gangliosides (Cronassial) protects against the chronic but not the acute lethal toxicity of vincristine in mice and affords some protection against the acute lethal toxicity of vincristine in chicks. The protective effect of Cronassial appears to be greatest near the LD50 of vincristine and then diminishes as the dose of vincristine increases further. Cronassial does not, however, reduce the vincristine antitumour activity, so that the net effect is an improvement in the vincristine therapeutic index. Clinical trials are underway to examine the effect of the combination on the development of neurotoxicity in cancer patients.

In the course of a study of circadian rhythmicity in the number of cells in the S-phase of the cell cycle in mouse kidney, a comparison was made between 2 methods of estimation of DNA synthetic activity. One of the methods used was an autoradiographical analysis of the tritiated thymidine labelling index; the other was a biochemical assay of the DNA content of the tissues coupled with liquid scintillation counting, to obtain an estimate of the incorporation of tritiated thymidine, expressed as dpm per μg of DNA. The correlation between individual estimates of DNA-synthetic activity, using the 2 methods was highly significant, as was the correlation between the 2 data sets with respect to time of zeniths. There was a suggestion that the biochemical assay procedure may be the more sensitive indicator of circadian rhythmicity in relatively homogeneous tissues with low proliferative rates. Estimated over a 3-day period, the time of maximal DNA synthetic activity lay between the hours of 22.00 and 02.00. The nadir of the curve was less well defined and occurred between 02.00 and 14.00 hours. The autoradiographical study took 5 weeks to complete exclusive of histological and autoradiographical preparation. The biochemical assay was completed in 4 days.

A second look at epidural anaesthesia in obstetrics, five years after our first three-year report, confirms the findings that the procedure outlined above is a highly satisfactory one Technical skill can be easily acquired The incidence of potentially serious complications is minimal It seems to be the safest method of obstetrical analgesia known at the present tune Nous présentons les observations associées de huit anesthésiologistes de l’Hôpital New Mount Sinai, Toronto, sur 26, 127 anesthésies épidurales chez des malades en couche Nous avons une technique simple et avons oipservé peu de complications, d’ailleurs, celles-ci peuvjent être prévenues ou traitées efficacement. Nous avons discutè les dangers possibles “du syndrome d’hypotension en position dorsale” et de ’“l’hypofibrinogénémie” A notre avis, actuellement, l’anesthésie épidurale est la méthode qui offre la plus grande sécurité en analgésie obstétricale

The output of urinary adrenocorticoids has been studied in man before, during and immediately after exposure to high environmental temperatures. The results indicate that while there was no significant change in the excretion of 17-hydroxycorticoids, cortisone and cortisol or of tetrahydrocortisone and tetrahydrocortisol there was a significant increase in the output of aldosterone.

Zusammenfassung Die „Chroniker“ haben für die ambulante Praxis eine große Bedeutung, sowohl von der Zahl her als auch wegen der Zusammensetzung dieser Patientengruppe. Man hat ungefähr mit 30000 Chronikern zu rechnen, die ambulant behandelt werden. In dieser Patientengruppe finden sich viele sogenannte „schwierige“ Patienten, disziplinarisch und vorzeitig Entlassene, Therapieversager, ältere Patienten mit mehrfacher Keimresistenz und mit Zweitkrankheiten behaftet. Die Chemotherapie dieser Gruppe richtet sich genau nach den für die Klinik geltenden Richtlinien. Auch für die ambulante Praxis ist zu fordern:

High dose dexamethasone combined with irradiation to the base of the brain achieved a dramatic beneficial effect in two terminal cases of widespread metastatic carcinoma of the prostate involving cranial nerves and the entire skeleton. Pain requiring very large doses of analgesics and anemia requiring blood transfusions every 3–4 weeks were improved rapidly. No further transfusions were needed.

‘ICRF 159’, a new cytostatic agent, blocks the entry of cultured human lymphocytes into mitosis and arrests dividing cells in prophase and early metaphase.

THE aim of cancer chemotherapy to destroy the last malignant cell may be unnecessarily ambitious if inhibition of metastases formation by chemotherapy could convert a malignant to a quasi-benign tumour. Systematic investigations into the experimental chemotherapy of spontaneous metastases have, however, been remarkably few1. This is perhaps not surprising in view of the technical difficulties experienced in the past in obtaining meaningful results. We have for some time attempted to study the effects of potential anticancer agents on the development of metastases by using the Lewis lung (3LL) tumour of mice, a tumour which produces metastases regularly, spontaneously and consistently to give multiple lung metastases2–4. We have attempted to do this not only because the ability to invade adjacent tissues is riot shared by most normal dividing tissues5, but also because it seems entirely possible that the basic processes of secondary tumour formation—invasion, dissemination and implantation—may have similar biochemical and biophysical characteristics in most malignant tumours.

LYMPHOID cells from a highly inbred parental strain of rat injected into F1hybrids derived from that strain and another inbred strain provoke a reaction, characterized among other manifestations by a hyperplasia of the recipients' spleen and other lymphoid tissues1. A striking splenic enlargement can also be produced in the chick embryo by intravenous injection of adult chicken spleen cells, or peripheral white blood cells2. The splenomegaly in both instances is due to an attack by the inoculated immunologically competent cells directed against a host incapable of reacting against them3–5. The splenomegaly is part of a more generalized graft versus host (GVH) reaction and reduction of the degree of splenomegaly is therefore a measure of the inhibition of the GVH reaction6,7.

Cats and dogs were allocated in veterinary practices located in three regions of Germany and in two regions of France. Fecal samples of 1,292 cats and 1,355 dogs were examined for the presence of nematode eggs. 141 positive cats and 131 positive dogs were treated with the test product or an established positive reference product: for cats a spot on combination of 10.0 mg/kg Imidacloprid and 1.0 mg/kg Moxidectin or 5 mg/kg Praziquantel and 57.5 mg/kg Pyrantelembonat, administered orally; for dogs a spot on combination of 10.0 mg/kg Imidacloprid and 2.5 mg/kg Moxidectin or 5.0 mg/kg Praziquantel, 14.4 mg/kg Pyrantelembonat and 15 mg Febantel, administered orally. Efficacy was assessed by analyzing the reduction in fecal egg counts of a fecal sample taken between days 7 to 1 before treatment in comparison to a fecal sample taken between days 7 to 13 after treatment. In cats, for the test product an efficacy of 99.99 % against Toxocara cati and an efficacy of 99.64 % against Ancylostomatidae was calculated. For the reference product an efficacy of 99.96 % and 100 % respectively was calculated. In dogs, for the test product an efficacy of 98.81 % against Toxocara canis and an efficacy of 99.92 against Ancylostomatidae was calculated. For the reference product an efficacy of 99.96 % and 99.91 respectively were calculated. In no cat or dog treated with the spot on combination of Imidacloprid and Moxidectin any adverse drug reaction was observed.

In a field trial 363 dogs naturally infested with ticks (n ? 1) and/or fleas (n ? 5) were enrolled at 23 centres in Germany, France and Italy. A total of 229 dogs were treated once with the test product, a topical formulation of imidacloprid 10% and permethrin 50%. 134 dogs were treated once with a registered control product, a topical fipronil 10% formulation, according to the label instructions. All dogs and cats living in the same household were treated with the control product. Cats living with the imidacloprid-permethrin treated dogs were treated with a mono imidacloprid formulation. Efficacy and safety of the products were assessed 2 days and 1,2,3 and 4 weeks after treatment by individual parasite counts and clinical examination. Continuous infestation pressure during the trial period was demonstrated by monitoring other dogs presented to the clinics. Efficacy calculations were based on geometric means of the individual parasite counts compared to pre-treatment infestation. The acute efficacy (day 2) of the imidacloprid permethrin combination vs. the control product was 91.1% vs. 89.7% against Ixodes. ricinus, 85.4% vs. 80.9% against Rhipicephalus spp. and 98.3% vs. 97.0% against Ctenocephalides spp. Residual efficacy (day 28) of the two products was 95.2% vs. 69.5% against I. ricinus, 98.5% vs. 89.4% against R.. spp. and 92.5% vs. 93.5% against C. spp. Results of the trial proved the safety of both products in treated dogs and in dogs and cats, living in the same household.

Since 1995 multiple clinical studies on efficacy of different compounds were performed in France and Germany according to the GCP guidelines. Approximately 3000 cat faecal samples of 44 participating practices were examined. Cats tested positive for nematodes were included into the study. Additionally, the faecal samples sent to the routine diagnostic lab of the Institute of Parasitology were analysed and compared with the study samples. Although both sets of data did not derive from epidemiological studies with representative sample calculation, they represent extensive data with following result: 12% of the samples examined contained endoparasites of different stages. 92% of these positive samples were Toxocara cati, 2.8% - 3.9% stages of either hookworms, Toxascaris leonina, Dipylidium spp. or taeniids. Due to the methods used in these multicenter field studies a detection of protozoa was not applicable. In an additional approach a questionnaire was completed for all positive cases from one of the multicenter studies with information to origin, environment, conditions of animal housing and anthelmintic treatment of the endoparasite positive cats. Approximately 60% of the positive cats live in urban, 40% in rural environment, 20% on agricultural farms. About 20% of the positive cats were housed indoors without any access to outdoor environments. Furthermore the study showed that a frequency of anthelmintic treatment 3-4 times per year reduced the prevalence significantly,.80% of the cats were dewormed less than 3 times per year, only 2% of the more frequent dewormed cats (3-4 times per year of more often) belong to the study included population.

FURTHER studies of the cholinesterase present in the sweat glands of the pad of the cat's foot1have shown that the pattern of response of this enzyme is not identical with that of other tissue cholinesterases.

It has recently been shown by Rose et al.(1950) that trimethylol melamine exerts an inhibitory action on certain malignant growths. This compound is, however, like dimethylol urea (D.M.U.) also a well-known intermediate in the acid-catalysed polymerisation process which results eventually in melamine and urea-formaldehyde plastics.Trimethylol melamine, as well as D.M.U., because they are inter aliawater-soluble, relatively non-toxic and may be polymerised in the cold, had been suggested earlier (Hellmann, 1950) as compounds which could perhaps, by the utilisation of the acid conditions elicited in malignant tissue by the administration of considerable quantities of glucose (Voegtlin et al., 1935; and Kahler and Robertson, 1943), effect a selective polymerisation within or around the malignant cells.

BECAUSE the chick embryo is immunologically immature during the first two weeks of its development, heterologous tissues such as human and rat tumours can be grown on the highly vascular chorio-allantoic membrane (CAM) of this organism without the necessity of pre-treating it in order to suppress the immune response. Tumours grown in this way have been used to assess the effects of potential anti-tumour drugs1–6.

IN order to test for functional competence in thin pieces of isolated tissue containing muscular elements, such as the skin of the rat (which contains smooth muscle and a sheet of skeletal muscle known as the panniculus carnosus)', a bath was devised in which the muscles could be excited directly or indirectly by transmural stimulation1. The response of the stimulated muscle provided a measure of functional competence in the surviving tissue. This bath and also our method of recording the pressure changes developed in it are described here.

FURST1has argued that most drugs which retard the growth of human or experimental neoplasms are actual or potential chelating agents. Although the correlation of the two properties is probably often no more than coincidental, the idea of attempting to influence the growth of cells and tumours with chelating agents has been examined2–5. It is an attractive idea because many enzyme systems depend on or contain trace metals.