利福布汀对非结核分枝杆菌抗菌活性的初步探讨

目的观察利福布汀对非结核分枝杆菌的抗菌活性,探讨利福布汀对常见致病性非结核分枝杆菌的实验室耐药临界浓度,为临床合理应用利福布汀治疗非结核分枝杆菌病提供依据。方法采用液体培养基倍比稀释法检测利福布汀和利福平对50株非结核分枝杆菌（NTM）的最低抑菌浓度（MIC）。结果 （1）对34株鸟分枝杆菌复合群的MIC：76.5%（26/34）菌株的利福平MIC≥1μg/ml,而利福布汀MIC有85.3%（29/34）分布在0.125~2μg/ml,其中在0.125~1μg/ml的有25株;（2）6株偶然分枝杆菌的MIC：利福平的MIC多〉8μg/ml,而利福布汀的MIC为1~8μg/ml;（3）5株脓肿分枝杆菌的MIC：利福平的MIC〉64μg/ml,利福布汀的MIC为2~32μg/ml;（4）其他非结核分枝杆菌：利福平和利福布汀对蟾蜍分枝杆菌、堪萨斯分枝杆菌、戈登分枝杆菌、瘰疠分枝杆菌、不产色分枝杆菌的MIC分别为〉64μg/mlvs1μg/ml、2μg/mlvs0.25μg/ml、8μg/mlvs1μg/ml、4μg/mlvs1μg/ml、4μg/mlvs1μg/ml。结论初步得出利福布汀对常见致病性非结核分枝杆菌的实验室耐药临界浓度为4~8μg/ml。利福布汀对鸟分枝杆菌复合群、勘萨斯分枝杆菌的抗菌活性优于利福平;蟾蜍分枝杆菌、戈登分枝杆菌、瘰疠分枝杆菌、不产色分枝杆菌对利福平体外MIC值达到临床耐药浓度时,利福布汀对其仍有体外抗菌活性。     

Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997 2003

BACKGROUND: The prevalence of pulmonary non-tuberculous mycobacteria (NTM) infection is reportedly increasing. A study was undertaken of the "isolation prevalence" of pulmonary NTM in Ontario, Canada between 1997 and 2003 and the frequency of pulmonary NTM "disease". METHODS: In a retrospective cohort, the "isolation prevalence" was studied by reviewing all positive NTM culture results from the Tuberculosis and Mycobacteriology Laboratory, Ministry of Health and Long-Term Care in Toronto from 1997 to 2003. This laboratory identifies at least 90% of NTM isolates in Ontario, Canada. Prevalence was compared between years using a negative binomial model. To study the frequency of "disease" (defined by American Thoracic Society criteria), the records of patients who had an isolate in 2003 and had been assessed at our hospital were reviewed. RESULTS: 22,247 pulmonary isolates were obtained from 10,231 patients. The "isolation prevalence" of all species (excluding Mycobacterium gordonae) was 9.1/100,000 in 1997, rising to 14.1/100,000 by 2003 (p<0.0001) with a mean annual increase of 8.4%. Similar increases were observed for individual species. 200 patients assessed at our institution were studied using American Thoracic Society criteria for "disease". Microbiological criteria were fulfilled by 37%. Of patients with adequate data, 74% fulfilled clinical criteria, 77% fulfilled radiological criteria and 33% fulfilled all criteria. CONCLUSIONS: The "isolation prevalence" of pulmonary NTM has significantly and rapidly increased in Ontario; a sizeable proportion of patients are likely to have "disease".     

Combined cell killing effects of anticancer drugs and hyperthermia in vitro

Using an in vitro colony forming assay system, cytotoxic effects of anticancer drugs, adriamycin (ADM) and peplomycin (PEP), and the combined effect of hyperthermia and anticancer drugs on cultivated KK-47 cells were investigated. From the response curves obtained at 42 and 43 degrees C hyperthermia, 20% growth inhibition time (IT20) at 42 and 43 degrees C hyperthermia and 50% growth inhibition time (IT50) at 43 degrees C were calculated. The IT20 and IT50 hyperthermia were combined with a 2-hour treatment of each of the anticancer drugs. When the hyperthermia was combined with various concentrations of ADM ranging from 0.005 to 0.1 microgram/ml, enhanced cell killing effects were obtained at the concentrations of less than 0.02 microgram/ml of ADM, whereas, there was no increase in cell killing effect at the concentrations of more than 0.05 microgram/ml of ADM. The combination of hyperthermia with PEP considerably enhanced the cell killing effects with an increase of PEP concentration.     

Measurement of the concentration of three antituberculosis drugs in the focus of spinal tuberculosis

This is an experimental study on the distribution of antituberculosis drugs such as rifampin, isoniazid, and pyrazinamide in pathologic vertebrae of spinal tuberculosis in order to provide the regimen of chemotherapy and surgical treatment of spinal tuberculosis. The distribution of antituberculosis drugs in pathologic vertebral tissues matters greatly to the clinical effect of spinal tuberculosis’ treatment. However, few pharmacokinetic studies and clinical reports about the concentrations of antituberculosis drugs in vertebral foci have been published so far. Twenty-four patients with spinal tuberculosis were divided into sclerotic group (n = 15) or non-sclerotic group (n = 9) according to radiographic features of lesion. All patients received chemotherapy with 2HRZ/2·5H₂R₂Z₂ for a duration of 4.5 months. Four weeks after chemotherapy all patients underwent surgery and the specimen of serum, ilium, and pathologic vertebral tissues, including sclerotic wall, subnormal osseous tissue, and foci were obtained during operation in 120–130 and 180–190 min after oral intake in the morning, respectively. The levels of three drugs in the specimen were measured using HPLC method. The concentration levels of isoniazid, rifampin and pyrazinamide varied greatly in different tissues of spinal tuberculosis, of which the bactericidal concentration values of isoniazid and rifampin and fivefold minimal inhibitory concentration (MICs) of pyrazinamide were found in subnormal vertebral bone and self-contrast ilium, the MICs of all drugs were found in sclerotic wall outside foci, and undetected level was found in foci inside the sclerotic wall. To patients without vertebral sclerotic wall around the foci, the isoniazid in foci was of bactericidal level and rifampin and pyrazinamide in foci corresponded to the MICs respectively. The sclerotic bone of affected vertebra plays an important role in blocking the antituberculosis drug’s penetration into tuberculosis focus.     

In vitro sensitivity testing of human kidney tumors to cytostatic drugs with a rapid in vitro test

We present a new modified in vitro culture assay for primary human renal cell carcinoma similar to the 'soft agar clonogenic assay'. However, the carrying out and expense of metrology are more simplified, allowing tumor-specific chemotherapeutic drug sensitivity testing under easier conditions. Twelve different samples of human renal carcinoma and one sample of a transitional cell carcinoma of the renal pelvis were tested for in vitro chemotherapy sensitivity using this modified colony-forming assay. The rate of tumor cells establishing in culture was 100%. Corresponding to clinical experience we observed a nearly complete resistance to the cytotoxic effects of standard chemotherapeutic agents at usual plasma concentrations in man. Only higher concentrated chemotherapeutic drugs showed in vitro therapeutic effects. The assay described here lasts about 7 days, which is beneficial from the clinical point of view. The modification of this in vitro chemotherapeutic drug treatment is unlimited for plasma concentration and duration of standard and experimental chemotherapeutic agents, drug combination and so on. So we have interesting scientific steps which could not have been undertaken under usual clinical-empirical conditions.     

Evaluation of single versus multiple cryogen spray cooling spurts on in vitro model human skin

Many commercially available dermatologic lasers utilize cryogen spray cooling for epidermal protection. A previous tissue culture study demonstrated that single cryogen spurts (SCS) of 80 ms or less were unlikely to cause cryo-injury in light-skinned individuals. More recently, multiple cryogen spurts (MCS) have been incorporated into commercial devices, but the effects of MCS have not been evaluated. The aim was to study an in vitro tissue culture model and the epidermal and dermal effects of SCS vs patterns of shorter MCS with the same preset total cryogen delivery time (t_c) and provide an explanation for noted differences. Four different spurt patterns were evaluated: SCS: one 40-ms cryogen spurt; MCS2: two 20-ms cryogen spurts; MCS4: four 10-ms cryogen spurts; MCS8: eight 5-ms cryogen spurts. Actual t_c and total cooling time (t_Total) were measured for each spurt pattern. RAFT tissue culture specimens were exposed to cryogen spurt patterns and biopsies were taken immediately and at days 3 and 7. Actual t_c was increased while t_Total remained relatively constant as the preset t_c of 40 ms was delivered as shorter MCS. Progressively more epidermal damage was noted with exposure to the MCS patterns. No dermal injury was noted with either SCS or MCS. For a constant preset t_c of 40 ms, delivering cryogen in patterns of shorter MCS increased the actual t_c and consequently the observed epidermal cryo-injury as compared to an SCS.     

Insulin sensitivity of the large human adipocyte in vitro.

Adipose tissue from twelve normal-weight and ten obese subjects on weight-maintaining diets and nine obese subjects on hypocaloric diets was removed at surgery and incubated in vitro. Basal glucose oxidation correlated significantly (r = 0.68, p less than 0.005) with fat-cell diameter in subjects on weight-maintaining diets. This relationship was significantly altered (p less than 0.02) in subjects on calorie-restricted diets. In tissue from subjects on weight-maintaining diets, physiologic concentrations of insulin (25 muU./ml.) significantly increased glucose incorporation into carbon dioxide (p less than 0.005) and glycogen (p less than 0.001). Maximum insulin-stimulated glucose oxidation (increase over basal) was significantly enhanced (p less than 0.05) in tissue from obese subjects, whereas insulin-mediated glucose incorporation into glycogen was similar in controls and obese subjects on weight-maintaining diets. Insulin-stimulated glucose oxidation was imparied in tissue from subjects on hypocaloric diets although fat-cell diameter was similar to those of obese subjects on weight-maintaining diets. The effect of insulin on glucose incorporation into glycogen in isolated adipocytes was also studied. There was no correlation between insulin-stimulated glycogen synthesis and cell diameter. When cells from the same individual were separated into small and large adipocytes by differential flotation, the insulin effect was similar whether expressed as absolute or per cent increase over basal. These results indicate that in vitro glucose oxidation by adipose tissue, in both the absence and the presence of insulin, is largely determined by dietary factors. This may also be true for insulin-stimulated glycogen synthesis. No evidence is provided for the concept that the enlarged human fat cell of obesity is insensitive to insulin in vitro.     

A trial of the in vitro sensitivity test of anti-cancer drugs using primary cultured urogenital cancer cells

Summary An in vitro chemosensitivity test was applied to clinical specimens of urogenital cancer tissues obtained at operation. Incorporation of ³H-leucine into primary cultured cells 24 h after treatment with cytotoxic drugs was used as an index for cell viability. Primary cell culture was performed using specimens obtained from 37 patients including 20 with transitional cell carcinoma, 15 with renal cell carcinoma and 2 with testicular cancer. Primary cell growth was achieved in 27 (73%) out of 37 specimens and 10 were tested for chemosensitivity. Each specimen of the tumor revealed different sensitivity to drugs, and results of quadruplicate tests for each specimen were identical. It was concluded that the present method of measuring incorporation of radioactivity using urogenital cancer cells primarily cultured in microtiter plate is practically applicable to an in vitro chemosensitivity test.     

The controversy of single versus multistaged urethroplasty.

Experience with various 1 stage repairs for urethral strictures (patch graft, and excision and reanastomosis techniques) gained by ourselves and others is compared to reports on multistaged urethroplasties (Johanson, Leadbetter-Johanson and Turner-Warwick). Increased hospitalization, absence from employment and the morbidity of multiple anesthetics and operations are features of the multistaged approaches compared to the 1 stage operations. Furthermore, no advantage was seen when initial or final success rates were compared.     

A simple and rapid in vitro test for determining sensitivity of cancer cells to anticancer drugs

For practical utilization of chemosensitivity tests of malignant cells to anticancer drugs in clinical studies, we developed a new method which is simple, rapid, and applicable to fresh human tumors. The principle of the method is to measure the content of ATP of living cells by chemoluminescence, after drug exposure. A straight linear relationship was observed between the number of viable cells and the light intensity. This method seems to be a good indicator for the selection of anticancer drugs in cancer chemotherapy.     

A simple and rapid in vitro test for determining sensitivity of cancer cells to anticancer drugs

For practical utilization of chemosensitivity tests of malignant cells to anticancer drugs in clinical studies, we developed a new method which is simple, rapid, and applicable to fresh human tumors. The principle of the method is to measure the content of ATP of living cells by chemoluminescence, after drug exposure. A straight linear relationship was observed between the number of viable cells and the light intensity. This method seems to be a good indicator for the selection of anticancer drugs in cancer chemotherapy.     

Practice patterns versus practice guidelines in pediatric otitis media.

OBJECTIVE: To study the practice patterns of physicians and their adherence to an evidence-based practice guideline (PG) on pediatric otitis media with effusion. We hypothesized that overall knowledge of the recommendations from the guidelines would be less than 75%, and that specialist physicians would have better knowledge of the recommendations than generalist physicians. METHODS: We performed a survey study of 1167 otolaryngologists, pediatricians, and pediatric otolaryngologists. Each physician was sent a 6-item survey asking about their practice patterns and treatment preferences for young children with otitis media with effusion. We compared responses between different specialties. RESULTS: The overall response rate was 48%. Only 8 (1.4%) of the 558 responding physicians answered all 6 items congruent with the PG. Overall, pediatricians, otolaryngologists, and pediatric otolaryngologists had similar total scores, but different scores on individual items. CONCLUSIONS: These results indicate that the practice patterns of pediatricians, otolaryngologists, and pediatric otolaryngologists differ from the recommendations of an evidence-based PG. In particular, 2 items covering key treatment recommendations were answered in agreement with the PG by fewer than half of the physicians. It is not clear from this study whether these discrepancies were due to poor dissemination or knowledge concerning the PG, or disagreement with its recommendations.     

Measurement of androgen sensitivity in the human prostate in in vitro three-dimensional histoculture.

We have adopted an in vitro three-dimensional histoculture technique for assay of androgen sensitivity in explants of human benign prostatic tissue. The assay is based on the uptake of 3H-thymidine/micrograms protein in explants of prostate incubated in parallel with dihydrotestosterone (DHT) and hydroxyflutamide (HF) controls. The ratio of 3H-thymidine/micrograms protein in DHT treated samples per 3H-thymidine/micrograms protein in HF treated samples provides an index of androgen sensitivity. The DHT/HF index measured in 24 BPH specimens averaged 3.6. To determine the specificity of the HF effect, we measured the DHT/HF index in a single prostate at different concentrations of HF in the presence of fixed concentrations of DHT (2 x 10(-8) M) and noted a dose-response relationship. In addition we noted no effects of HF on 3H-thymidine incorporation over a range of 2 x 10(-4)M compared to 2 x 10(-7)M, except at the highest concentration. Of surprise was the finding of an average DHT/HF index in 5 different nonprostate tissues, including breast, uterus, colon, kidney, and thyroid, that was similar to the index found in prostates. We plan to adapt this androgen sensitivity assay to measure the DHT/HF index in biopsy-size samples of prostate, since such an assay could then be utilized to determine androgen sensitivity in individual patients with prostate cancer.     

A neuropharmacological investigation on hallucinogenic drugs. Laboratory results versus clinical trials

Summary This paper deals with a presentation of some data obtained in biochemical, electrophysiological and animal behavioural studies with LSD and parent compounds, with the purpose of relating them to clinical observations.Biochemical studies were based first on the sympathomimetic properties (Rothlin, Cerletti) and then on the antiserotoninic effect of the drug (Gaddum, Woolley, Brodie). The electrophysiological investigations have put in evidence striking modifications of the EEG of LSD treated animals, which were described as desynchronization and as flattening (Bradley, Delay, Longo). In the field of animal behavioural investigations, the results obtained in avoidance conditioned reflexes in rats were rather deceiving, and only a facilitation of the response was observed after high doses (0.5 mg./kg.) (Taeschler, Cook, Maffii). In rabbits an instrumental conditional reward response is also facilitated and prolonged by LSD (Sadowski andLongo), Of particular interest seems to be a new technique developed in the rabbit (McGaugh and coll.), in which the animals are taught an instrumental reward discrimination. LSD exerts a disrupting influence on this response in very low doses (0.01–0,02 mg./kg.). Based on these data, a recent investigation performed in our laboratory dealt with the influence of several lysergic acid derivatives on the performance of an instrumental reward discrimination (IRD) as well as on the cerebral electrical activity (EEG) of freely moving rabbits. To establish the IRD, rabbits bearing chronically implanted cortical and subcortical electrodes were first trained to pull a ring at the sound of a buzzer for a food reward. The animals were then taught to discriminate between a continuous buzzer (which was followed by a reward) and an intermittent buzzer (which was not followed by a reward).The effects of the following compounds upon the different components of the IRD and upon the EEG were investigated: Lysergic acid ethylamide (LAE), propanolamide (ergometrine), butanolamide (methyl-ergometrine), 1methyl-butanolamide (UML) and pyrrolidide (LPD), lysergic acid diethylamide (LSD), isolysergic acid diethylamide (I-LSD), bromlysergic acid diethylamide (BOL). The most active compounds were found to be LSD, LPD, and LAE which disrupted the performance of the exercise and flattened the EEG at a dose of 0.025 mg./kg. Ergometrine and methyl-ergometrine had an effect only at higher doses (0.5–1.0 mg./kg.). BOL, I-LSD and UML did not exhibit any effect.Comparison of pharmacological and clinical data shows a poor correlation with biochemical results, while exhibiting good correlation with the electroencephalographic and behavioural results. In fact, the EEG changes and the blocking of the instrumental reward discrimination are present only after administration of drugs which provoke hallucinations and mental disturbances in man.

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Zusammenfassung Diese Arbeit gibt eine Darstellung einiger Ergebnisse biochemischer, elektrophysiologischer und Tierverhaltens-Untersuchungen mit LSD und Mutterkornverbindungen, um sie mit klinischen Beobachtungen zu korrellieren.Die biochemischen Untersuchungen stützten sich einmal auf die sympathicomimetischen Eigenschaften (Rothlin, Cerletti) und weiterhin auf den Antiserotonin-Effekt der Droge (Gaddum, Woolley, Brodie). Die elektrophysiologischen Untersuchungen haben deutliche Veränderungen im EEG der mit LSD behandelten Tiere ergeben, die man als Desynchronisation und als Abflachung bezeichnet (Bradley, Delay, Longo). Auf dem Gebiet der Tierverhaltens-Untersuchungen waren unter Vermeidung bedingter Reflexe die Ergebnisse bei Ratten recht enttäuschend, und es konnte nur eine Erleichterung in der Beantwortung nach hohen Dosen (0,5 mg/kg) beobachtet werden (Taeschler, Cook, Maffii). Bei Kaninchen wird eine instrumentelle bedingte Belohnungsbeantwortung (instrumental reward response) ebenfalls mit LSD erleichtert und verlängert (Sadowski undLongo). Von besonderem Interesse scheint eine neue, für Kaninchen entwickelte Methode zu sein (McGaugh und Mitarbeiter), bei der den Tieren eine instrumentelle Belohnungsunterscheidung (instrumental reward discrimination) gelehrt wird. Die LSD bewirkt eine Unterbrechung dieser Beantwortung in sehr kleinen Dosen (0,01 bis 0,02 mg/kg). Auf Grund dieser Ergebnisse untersuchten wir kürzlich den Einfluß verschiedener lysergsauren Derivate auf die Ausführung einer instrumentellen Belohnungsunterscheidung (IRD — instrumental reward discrimination) und auf das Hirnstrombild (EEG) bei sich frei bewegenden Kaninchen. Um die instrumentelle Belohnungsunterscheidung festzusetzen, wurden Kaninchen, die chronisch implantierte corticale und subcorticale Elektroden trugen, zuerst daraufhin trainiert, für eine Nahrungsbelohnung einen Ring beim Ertönen eines Summers zu ziehen. Den Tieren wurde dann gelehrt, zwischen einem Dauersummen (dem eine Belohnung folgte) und einem unterbrochenen Summen (dem keine Belohnung folgte) zu unterscheiden.Es wurde der Einfluß folgender Verbindungen auf die verschiedenen Teile der IRD und auf das EEG untersucht. Lysergsäure-Äthylamid (LAE), Propanolamid (Ergometrin), Butanolamid (Methyl-Ergometrin), 1-Methyl-Butanolamid (UML) und Pyrrolidid (LPD), Lysergsäure-Diäthylamid (LSD), Isolysergsäure-Diäthylamid (I-LSD), Bromlysergsäure-Diäthylamid (BOL). Es konnte festgestellt werden, daß die aktivsten Substanzen die LSD, LPD und LAE waren, die die Durchführung der Übungen unterbrachen und eine Abflachung im EEG bei einer Dosis von 0,025 mg/kg bewirkten. Ergometrin und Methyl-Ergometrin waren nur in höherer Dosierung (0,5 bis 1,0 mg/kg) wirksam. BOL, I-LSD und UML zeigten keine Wirkung.Vergleiche der pharmakologischen und klinischen Daten zeigten eine schlechte Übereinstimmung mit den biochemischen Ergebnissen, während eine gute Übereinstimmung mit den elektroencephalographischen und Verhaltensergebnissen bestand. Überhaupt sind EEG-Veränderungen und Blockierung der instrumentellen Belohnungsunterscheidung (instrumental reward discrimination) nur feststellbar, wenn Drogen verabreicht werden, die Halluzinationen und Verwirrtheitszustände beim Menschen hervorrufen.

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Resumen En este trabajo se presentan algunos datos obtenidos con estudios bioquímicos, electrofisiológicos y de comportamiento de los animales con LSD y compuestos similares. El propósito del trabajo es relacionar estos hallazgos con observaciones clínicas.Los estudios bioquímicos se basan en primer lugar en las propiedades simpáticomiméticas de la droga (Rothlin, Cerletti) y en segundo lugar en su efecto antiserotonínico (Gaddum, Wooley, Brodie). Las investigaciones electrofisiológicas han evidenciado una modificación evidente del trazado electroencefalográfico de los animales tratados con LSD, modificaciones que se han descrito como «desincronización» y como «aplanamiento» (Bradley, Delay, Longo). En lo que se refiere al comportamiento de los animales los resultados obtenidos estudiando la inhibición de los reflejos condicionados en ratoas fueron más bien decepcionantes y únicamente se obtuvo una facilitation de la respuesta después de la administración de dosis altas (1,5 mg/kg) (Taeschler, Cook, Maffii). En conejos una respuesta condicionada también se facilita y prolonga por la administración de LSD (Sadowski,Longo). Parece tener un interés particular una nueva técnica desarrollada en el conejo (McGaugh y coll.), en la cual se enseña a los animales una discriminación condicionada. En dosis muy bajas (0,01 a 0,02 mg/kg) el LSD tiene una influencia interruptora de esta respuesta. Una investigación reciente basada en estos datos y realizada en nuestro laboratorio estudió la influencia de diversos derivados del ácido lisérgico sobre la realization de pruebas de discriminación instrumental (IRD) y sobre la actividad eléctrica cerebral en conejos despiertos y moviendose libremente. Para establecer el IRD se enseñó primero a conejos con electrodos crónicos implantados a tirar de una anilla cuando sonaba un zumbador para obtener alimento. Después se enseñó a los animales a distinguir entre un zumbido continuo (que se seguía de premio) y un zumbido intermitente (que no se seguia de premio).Se investigó el efecto de los siguientes compuestos sobre los diferentes componentes del IRD y del EEG: Acido lisérgico etilamida (LAE), propanolamida (ergometrina), butanolamida (metilergometrina), l-metil-butanolamida (UML) y pirroladida (LPD), ácido lisérgido dietilamida (LSD), ácido isolisérgico dietilamida (I-LSD), ácido bromolisérgico dietilamida (BOL). Los compuestos más activos fueron el LSD, LPD y LAE que interrumpieron la realización del ejercicio y aplanaron el EEG a dosis de 0,025 mg/kg. La ergometrina y la metilergometrina solo daban lugar a este efecto en dosis mas altas (0,5 y 1,0 mg/kg). BOL, I-LSD y UML no dieron lugar a ningún efecto.La comparación entre los datos clínicos y farmacológicos muestra una correlación escasa con los resultados bioquímicos y una buena correlación con los resultados electroencefalográficos y de comportamiento. De hecho, las alteraciones EEG y el bloqueo del IRD solo aparecen cuando se administran drogas que dan lugar a alucinaciones y trastornos mentales en el hombre.

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Résumé Ce travail présente quelques données obtenues dans des études sur le comportement animal, électrophysiologiques et biochimiques avec LSD et des composés proches, dans le dessein de les rapporter à des observations cliniques.Les études biochimiques étaient d'abord basées sur les propriétés sympathicomimétiques (Rothlin, Cerletti) et puis sur l'effet antisérotonique de la drogue (Gaddum, Woolley, Brodie). Les recherches électrophysiologiques ont mis en évidence des modifications frappantes des animaux traités EEG de LSD que l'on décrivait comme «une désynchronisation» et comme «un aplatissement (-flattening)» (Bradley-Delay-Longo).Dans les champ des recherches sur le comportement animal, les résultats obtenus pour éviter les réflexes conditionnés chez des rats furent plutôt décevants et on observa seulement une réponse plus facile après des doses élevées (45 mg/kg) (Taeschler-Cook-Maffie). Chez les lapins une réponse utile conditionnée à une récompense est aussi facilitée et prolongée par LSD (Sadowski-Longo). D'un intérêt particulier semble être une nouvelle technique développée sur le lapin (McGaugh et coll.), dans laquelle on enseigne aux animaux une distinction de récompense utile. LSD exerce une influence sur cette réponse à très basses doses (0,01 –0,02 mg/kg). Basée sur ces données, une recherche récente effectuée dans notre laboratoire a traité de l'influence de plusieurs dérivés de l'acide lysergique sur la réalisation d'une distinction de récompense (IRD) aussi bien que sur l'activité cérébrale (EEG) des lapins agissant librement. Pour établir le IRD, des lapins supportant des électrodes corticales et subcorticales chroniquement implantées furent d'abord entraînés à tirer un anneau au son d'un bourdonnement pour avoir de la nourriture. On enseigna alors aux animaux à distinguer entre un bourdonnement continu (qui était suivi d'une récompense) et un bourdonnement intermittent (qui n'était pas suivi d'une récompense).On a recherché les effets des composés suivants sur les constituants différents de I'IRD et sur I'EEG: Ethylamide d'acide lysergique (LAE), propanolamide (ergométrine) butanolamide (méthylergométrine), l-méthyl-butanolamide (UML) et pyrrolidide (LPD) diéthylamide acide lysergique (LSD) diéthylamide acide isolysergique (I-LSD) diéthylamide acide bromlysergique (BOL). On trouva que les plus actifs composés étaient LSD-LPD et LAE qui interrompaient l'exécution de l'exercice et «aplanissaient» (flattened) l'EEG avec une dose de 0,025 mg/kg.L'ergométrine et la méthyl-ergométrine avaient seulement un effet avec des doses plus élevées (0,5–1,0 mg/kg). BOL, I-LSD et UNL ne produisent aucun effet.La comparaison des données pharmacologiques et cliniques montre une faible corrélation avec les résultats biochimiques tandis qu'il se produit une forte corrélation avec les résultats électroencéphalographiques et sur le comportement.En fait les changements d'EEG et le blocage de la distinction instrumentale de récompense ne se présentent qu'après l'administration de drogues qui provoquent des hallucinations et troubles mentaux chez l'homme.

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Riassunto Nel presente lavoro sono presentati e discussi i dati della lelteratura riguardanti gli effetti farmacologici della dietilamide dell'acido lisergico (LSD), allo scopo di mettere in evidenza quale delle varie proprietà descritte nelle indagini sperimentali sia la più specificatamente rispondente alle qualitá allucinogene e psicomimetiche di questo farmaco.I lavori riguardanti gli effetti farmacologici dell'LSD hanno seguito tre direttive di ricerca: la biochimica, l'elettrofisiologica e quella dello studio del comportamento. Gli studi biochimici hanno messo in evidenza un effetto antagonista del farmaco nei riguardi della 5-idrossitriptamina. Dal punto di vista elettroencefalografico, particolare importanza è stata data all'appiattimento del tracciato come caratteristico effetto dell'LSD sull'attività elettrica cerebrale. I risultati ottenuti studiando gli effetti dell'LSD sulle risposte condizionate di avoidance o di reward, indicano che questo farmaco ha un'azione facilitante piuttosto che inibente. Un test di risposta discriminata strumentale messo a punto nel nostro Laboratorio sul coniglio si è invece rivelato particolarmente sensibile all'LSD, che inibisce la risposta a dosi di 0,01–0,02 mg/kg. L'animale è condizionato a tirare, durante il suono continuo del campanello, una leva con i denti per ottenere la comparsa di cibo nella mangiatoia. Quando invece il campanello suona ad intermittenze l'animale si deve astenere dal tirare 1'anello.I seguenti farmaci sono stati studiati: monoetilamide (LAE), propanolamide (ergometrina), butanolamide (metilergometrina), 1-metil propanolamide (UML) e pirrolidide (LPD) dell'acido lisergico; dietilamide dell'acido lisergico (LSD), dietilamide dell'acido isolisergico (I-LSD) e dietilamide dell'acido bromolisergico (BOL). I composti più attivi nel bloccare l'esercizio condizionato si sono rivelati, nell'ordine, LSD, LPD e LAE, che agivano a dosi di 0,01–0,025 mg/kg. L'ergometrina e la metilergometrina erano efficaci solo a dosi molto più elevate (0,5–1 mg/kg). BOL, UML e I-LSD non avevano nessun effetto.Un paragone tra gli effetti farmacologici e le proprietà allucinogene accertate in clinica per questi prodotti ha messo in evidenza che solo i derivati ad azione allucinogena e psicomimetica provocavano nell'animale le alterazioni elettroencefalografiche e il blocco dell'esercizio di discriminazione.

     

The effect of cytostatic drugs on the synthesis of DNA in adenocarcinomas of the stomach. An in vitro study.

The sensitivity of adenocarcinomas of the stomach to various cytostatic drugs has been tested in short-term incubations. A suspension of single cells and small tissue fragments was prepared. It was used for incubation with the following drugs: melphalan, vinblastine sulphate, amethopterin, and 5-fluoro-uracil. The effect of the cytostatic drugs was measured as the difference in incorporation of labelled precursors in treated tubes and untreated control tubes. The different tumours were found to vary significantly in the their sensitivity. Moreover, a correlation of the effects between melphalan and vinblastine sulphate, and between amethopterin and vinblastine sulphate was observed.