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PubMed1982

Phospholipid metabolism changes in rat tissues in vitro after injections of propranolol.

When added to incubations in vitro. (+/-)-propranolol, a cationic amphiphilic drug, causes profound alterations in incorporation of [32P] orthosphosphate into rat cerebral cortex phospholipids. These include increases in the labeling of phosphatidic acid and polyphosphoinositides abd a decrease in the labeling of phosphatidylcholine. Similar changes occurred in a dose-dependent manner in incubations of cerebral cortex mince, prepared from animals injected i.p. 30 min before death with doses of propranolol ranging from 7.5 to 45 mg/kg. All changes in total incorporation and in labeling pattern had disappeared 3 hr after injection, indicating the reversibility of the effect. Repeated injections of low doses of propranolol (7.5 mg/kg) brought about significant changes in the labeling of brain cortex mince phospholipids, and especially a reduction in total incorporation. Addition of propranolol to kidney and liver minces caused reductions in the labeling of phosphatidylcholine and phosphatidylethanolamine and selective increases in the labeling of acidic lipids, restricted to phosphatidic acid in liver and phosphatidylinositol in kidney. After injection of 45 mg of propranolol per kg, but not at 15 mg/kg, some alterations in the labeling pattern were observed in liver and kidney minces. The differential response of tissues to propranolol injections can be explained on the basis of the pharmacokinetics of drug distribution and clearance and metabolic capacities of the tissues. Changes in phospholipid metabolism may be in part responsible for deleterious side effects that can occur during therapy with high doses of propranolol.

Animals↗

PubMed1982

Defleecing effect of betamethasone and other long-acting corticosteroids, their influence on wool growth and some physiological processes in sheep.

The defleecing effects of the long-acting derivatives of prednisolone, triamcinolone and dexamethasone were compared with those of betamethasone alcohol when these steroids were administered at the rate of 3.3 mg/kg liveweight in three equal intramuscular injections of 1.1 mg to Merino wethers. Prednisolone showed no defleecing activity whereas the other steroids produced positive but variable responses. Prolonged depression of wool growth was evident following treatment with dexamethasone esters. Betamethasone alcohol injected intramuscularly at 1.1 mg/kg daily for 3 days produced a similar defleecing response to intravenous infusion of 3.3 mg/kg betamethasone phosphate over 8 days. A range of dose rates (0.3-3.3 mg/kg) of betamethasone as multiple and single intramuscular injections indicated that the minimum effective defleecing dose was approximately 2.1 mg/kg. The response to simultaneous administration of betamethasone and insulin or chlorpropamide (to increase glucose utilization) and glucose or xylazine (to increase hyperglycaemia) suggested that the gluconeogenic role of this steroid had little effect on fibre shedding. Thyroxine (300 micrograms per sheep) administered on the first day with an injection of betamethasone (0.9 mg/kg), and alone daily for 20 days thereafter, did not influence the changes in wool production resulting from betamethasone treatment. These results are discussed in relation to the molecular structure and physiological characteristics of a potentially specific defleecing steroid.

Adrenal Cortex Hormones↗

PubMed1980

Disposition of oxytetracycline in the bovine genital tract: systemic vs intrauterine administration.

The distribution of oxytetracycline (OTC) in genital tissues, uterine secretions, milk, and plasma was examined after systemic (IM) and intrauterine (IU) administration at various intervals after administration in normal-cycling diestrous cows and in cows with chronic endometritis. The IM route resulted in OTC concentrations in endometrium and uterine secretions that were higher than were concentrations in plasma and milk over 72 hours. Twenty-four hours after IM administration, OTC concentrations in tissues of the genital tract (ovaries, oviducts, myometrium, serosa, cervix, and vagina), muscles, and udder were 100% higher than were concentrations in plasma. The IU administration resulted in a high concentration in the endometrium and uterine cavity over the 72-hour posttreatment period. The plasma concentrations were considerably lower than after the IM injection, indicating a lesser absorption from the uterus than from the IM injection site. This was more pronounced in cows with endometritis. Elimination from plasma and milk occurred in 24 hours. Contrary to results of the IM route, the IU route did not result in detectable concentrations in genital tissues apart from the endometrium 24 hours after administration.

Animals↗

PubMed1981

[Epidural application of opiates in chronic pain due to malignoma (author's transl)].

In 75 patients epidural opiates were applied for relief of chronic cancer pain. In order to avoid local infection during long-term therapy part of the catheter was placed subcutaneously. Different opiates were used separately or in combination with local anaesthetics to define the degree and duration of pain relief after epidural opiate application. Haemodynamic and respiratory parameters, changes in lower extremity blood supply and other side-effects were recorded during epidural pain therapy. Epidural opiate application cause a long-lasting reduction of pain, which may become restricted during long-term or repeated use, especially after a period of systemic opiate therapy. Side-effects, for example slight respiratory depression in the first hour after injection, indicate an initial phase of resorption beeing followed by a long-lasting reduction of pain without attendant symptoms. Keeping in mind certain precautions epidural opiate therapy is superior to systemic opiate application.

Adult↗

PubMed1978

Muscle irritation caused by different products containing oxytetracycline.

Muscle irritation studies were done in rabbits using 9 different commercial products. Eight products had propylene glycol and 1 had polyvinylpyrrolidone as a vehicle. Macroscopical examination 3,6 and 10 days after intramuscular injection indicated that the irritation caused by the 8 products with propylene glycol as a vehicle were very similar. The product with polyvinylpyrrolidone caused much less damage and healing took place more quickly. Saline used as a control caused no tissue damage.

Animals↗

PubMed1981

Induction of canine in vitro reactivity to alloantigen following intralymphatic immunization.

An experimental model has been developed using the dog to study the induction of systemic cell-mediated immunity following intralymphatic immunization (ILI) with allogenic cells. As detected in one-way mixed lymphocyte cultures, blastogenically-reactive immune peripheral blood lymphocytes were observed after the third ILI with 10(7) cells. The in vitro reactivity was augmented by a fourth ILI to a node not previously injected indicating that a response in one node was followed by the trafficing of memory cells to other nodes. No immune PBL were detected after four ILI with lower doses of 10(3) cells. However, these dogs subsequently responded to a single injection of 10(7) cells with high levels of immune lymphocytes which were detectable for up to 24 days. Apparently, ILI with 10(3) or 10(5) cells, while insufficient to produce detectable levels of alloreactive lymphocytes were sufficient for lymphocyte priming. Results obtained with this model will aid in ongoing human trials of intralymphatic immunotherapy of malignant disease.

Animals↗

PubMed1981

Half-life of 13,14-dihydro-15-keto prostaglandin f2 alpha in peripheral plasma of the pig.

The metabolite of prostaglandin F2 alpha (PGF2 alpha ) namely 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM), was administered as an intravenous bolus injection into five adult pigs. Concentrations of PGFM in blood collected periodically after injection indicated a biexponential decline suggesting a rapid distribution to the extracellular fluid and a slower elimination by metabolism. A mean half-life value of 14.97 +/- 1.33 (SD) minutes was calculated for the second component of the decline in PGFM concentration.

Animals↗

PubMed1976

Practical considerations for the use of a pulmonary artery thermistor catheter.

The use of a pulmonary artery thermistor catheter for pressure measurement and thermodilution cardiac output determination was evaluated in 11 dogs. Pulmonary artery wedge pressure was a reliable index of left atrial pressure at end-expiratory pressures less than 10 cm. H2O. Fluctuations in pulmonary artery temperature occurred at a frequency equal to the respiratory rate and an amplitude of 0.010 to 0.086 degrees C. Changes in amplitude were associated with changes in ventilatory waveform, respiratory rate, and level of anesthesia. Intermittent and continuous positive-pressure ventilation generally dampened and reversed the pulmonary artery temperature pattern exhibited during spontaneous breathing. This suggested that when end expiration is used to time indicator injection, cardiac output will be underestimated during spontaneous breathing and overestimated during continuous or intermittent positive-pressure ventilation. When indicator was injected at the same point in the ventilatory cycle, successive values of cardiac output deviated from one another by 0.0 to 6.7 percent. Deviations as large as 14 percent resulted if sequential injections were out of phase by half a respiratory cycle. These deviations can be minimized by injecting indicator at the same point in the respiratory cycle, if it is not feasible to measure cardiac output during apnea. The clinical utility of a pulmonary artery thermistor catheter can be optimized through appreciation of its specific strengths and limitations.

Animals↗

PubMed1994

Intracellular doxorubicin kinetics in lymphoma cells and lymphocytes infiltrating the tumor area in vivo: a flow cytometric study.

Recently we have reported the development of a safe and effective chemoimmunotherapy protocol involving doxorubicin (Dox) in combination with interleukin 2 which, in C57BL/6 mice, boosts local T cell responses, and, in 50 to 80% of the cases, this resulted in the complete eradication of established syngeneic EL4 lymphoma or its Dox-resistant variant, EL4/A. Accumulation of host-derived leukocytes in the peritoneal cavity was increased up to 8-fold after tumor inoculation, but, in absolute numbers, did not increase further following Dox administration. The cellular pharmacokinetic studies undertaken to clarify the role of Dox following a single IV injection indicate that 4 h later, lymphocytes found in the peritoneal cavity have detectable levels of Dox; but the lymphoma cells (both EL4 and EL4/A) have, in proportion to their larger size, taken up more drug as judged by flow cytometry. The estimated drug "concentration" (i.e., intracellular amount divided by estimated cell size) at the 4-h time point, however, was found to be essentially equivalent in both the lymphoma cells and the lymphocytes. Thereafter, the drug content and intracellular "concentration" in the EL4/A cells rapidly declined while their numbers progressively increased. In contrast, the EL4 lymphoma cells and the lymphocytes found in the peritoneal cavity in the presence of either lymphoma consistently exhibited higher levels of drug 24-48 h than at 4 h. Splenic and tumor-infiltrating mature T (CD3+) cells were completely insensitive to Dox cytotoxicity and actually showed increased CTL activity when examined ex vivo. Although EL4 cells had identical Dox uptake patterns to those of CD3+ cells, they were sensitive to the drug and their numbers decreased, resulting in increased host/tumor cell ratios in these mice. The pharmacokinetic parameters of the drug and the insensitivity of the mature T cells to the drug determined in this study can explain, in part, the efficacy of a chemoimmunotherapy protocol boosting local T-cell responses.

Animals↗

PubMed1994

Systemic release and protective role of IL-10 in staphylococcal enterotoxin B-induced shock in mice.

Staphylococcal enterotoxin B (SEB) is a bacterial superantigen that induces the production of several pro-inflammatory cytokines, leading to a self-limited shock. In the present study, we show that SEB also triggers the systemic release of IL-10, an anti-inflammatory and immunosuppressive cytokine. Serum IL-10 was undetectable (< 1000 pg/ml) in control BALB/c mice and rose to 8500 +/- 2850 pg/ml (mean +/- SEM) 4 h after injection of 100 micrograms SEB. Cell depletion experiments and analysis of IL-10 mRNA expression indicated that CD4+ cells played a major role in SEB-induced IL-10 production. Pretreatment of mice with neutralizing anti-IL-10 mAb before SEB challenge did not modify the release of TNF but led to increased and sustained IL-2 and IFN-gamma serum levels. Furthermore, although no lethality occurred in mice injected with SEB and control mAb, injection of anti-IL-10 mAb before SEB resulted in a 30% lethality (p < 0.05). This lethality was completely prevented by anti-IFN-gamma mAb injection, indicating that IFN-gamma plays a crucial role in the increased toxicity of SEB in anti-IL-10 mAb-injected mice. We conclude that SEB induces the production of IL-10 by CD4+ cells in vivo and that endogenous IL-10 plays an important immunoregulatory role in this model by down-regulating IL-2 and IFN-gamma production.

Animals↗

PubMed1994

[Experience of fluconazole granules and injection in pediatric patients].

Fluconazole (FLCZ) is an antifungal agent of triazole class and has been proven to be effective against deep-seated mycosis caused by Candida spp., Aspergillus spp. and Cryptococcus spp. This time, as we had an opportunity to use fluconazole granules, a new dosage form of the agent, we investigated its efficacy and safety in children with deep-seated mycosis together with the efficacy of the injectable form of the agent. FLCZ was administered to 6 patients with fungal infections for treatment and 5 compromised hosts with a high risk of fungal infections for evaluation of its prophylactic effect. The patients enrolled in the study were 11 in total, of whom 6 patients were evaluated for efficacy: fungal phlegmon in 2, esophageal candidiasis in 2, fungal bronchitis in 1 and oral mycosis in 1. Causative fungi for those infections were Candida albicans in 4 patients, Aspergillus, fumigatus in 1 and Aspergillus flavus in 1. The clinical efficacies were excellent in 3 patients and good in 3. The mycological efficacies were rated as eradicated in 5 patients and reduced in 1. In 5 patients to whom FLCZ was given prophylactically, development of neither fungal infection nor unknown fever was noted. No side effects nor clinical laboratory abnormalities were observed during treatment with either granules or injection, indicative of its safety in children.

Administration, Oral↗

PubMed1993

Biotinylated iodo-polylysine for pretargeted radiation delivery.

Efforts to achieve rapid specific targeting of radioisotopes to disease processes using antibodies conjugated with avidin or streptavidin for pretargeting and radiobiotin derivatives for isotope delivery are attracting substantial interest. At present, these approaches appear to be limited by low delivery of radiotracer to the target. As an alternate radiobiotin tracer, biotinylated/iodinated polylysine (BIP) was prepared by conjugating poly-L-lysine (MW approximately 10,200) with biotin succinimide esters and the Bolton-Hunter reagent. This reagent was then radioiodinated with 125I via the lodogen method. BIP was characterized by radio-HPLC and its in vitro binding to streptavidin. The in vivo localization of BIP was evaluated in a rat model in which streptavidin agarose beads were physically localized to precapillary arterioles in the lungs. Biodistribution and blocking studies performed at 4 and 24 hr after BIP injection indicated specific binding and localization of the radiolabeled peptide to the lungs (lung-to-blood ratio approximately 8 at 4 hr postinjection). Comparative studies of BIP and 111In chelated to biotin showed BIP to have two-fold higher lung targeting and lower splenic and hepatic uptake than the 111In biotin derivative. Our study demonstrates: (1) the feasibility of using a small peptide as a biotin carrier for pretargeting (and for solubilizing organic tracers which may otherwise be difficult to administer in vivo) and (2) that BIP and BIP-like compounds may be suitable and simple alternatives to radiometal-labeled biotin for pretargeting and may offer improved targeting to prelocalized streptavidin.

Animals↗

PubMed1993

Detection of doxorubicin cardiotoxicity in patients with sarcomas by indium-111-antimyosin monoclonal antibody studies.

To assess myocardial cell damage due to doxorubicin cardiotoxicity, we prospectively studied 30 patients with sarcomas who were receiving chemotherapy, including doxorubicin. Sixteen patients were treated by continuous infusion over 72 hr and 14 patients were treated by bolus injection. Antimyosin studies and left ventricular ejection fraction (LVEF) measurements were performed before chemotherapy and at intermediate and maximal cumulative doses. Myocardial antimyosin uptake was quantified by a heart-to-lung ratio (HLR). Myocardial antimyosin uptake was observed in all patients at 240-300 mg/m2 when ejection fraction was still maintained. Seven patients presented with a decrease of > or = 10% in absolute ejection fraction units at 420-600 mg/m2. Five of these patients had mild congestive heart failure. All patients who presented with a decrease in LVEF > or = 10% at 420-600 mg/m2 had increased antimyosin uptake with HLR > or = 1.90 at a cumulative dose of 240-300 mg/m2. Patients who were treated with continuous infusion had less antimyosin uptake than those who were treated with bolus administration (mean HLR of 1.70 +/- 0.09 versus HLR of 2.01 +/- 0.16 at a cumulative dose of 240-300 mg/m2, p < 0.01; HLR of 1.86 +/- 0.12 versus HLR of 2.32 +/- 0.34 at a cumulative dose of 420-600 mg/m2, p < 0.01). Two of 16 patients treated by continuous infusion and 5 of 14 patients treated by bolus injection presented with a decrease in ejection fraction > or = 10%. LVEF after chemotherapy in the infusion group was 56% +/- 5% and 48% +/- 8% (p < 0.05) in the bolus group. Antimyosin studies are helpful in the assessment of doxorubicin cardiotoxicity. Intense antimyosin uptake at intermediate cumulative doses identifies patients at risk of cardiotoxicity before ejection fraction deteriorates. Patients with sarcomas treated by continuous infusion present with less antimyosin uptake than those treated with bolus injection, indicating less severe cardiotoxicity.

Antibodies, Monoclonal↗

PubMed1993

[3H]1-(cyclopropylmethyl)-4-(2-(4-fluorophenyl)-2-oxoethyl) piperidine HBr (DuP 734). A selective ligand for sigma receptors in mouse brain in vivo.

1-(Cyclopropylmethyl)-4-(2-(4-fluorophenyl)-2-oxoethyl) piperidine HBr (DuP 734) is a novel sigma receptor ligand which exhibits promise in preclinical animal models as an antipsychotic agent without motor side effects. In vitro and in vivo receptor binding profiles of DuP 734 in mouse brain using [3H]DuP 734 and [3H]N-allylnormetazocine ((+)-SKF 10,047) were studied. The pharmacology and stereospecificity of [3H]DuP 734-labeled sites in mouse brain, both in vitro and in vivo, was consistent with sigma receptor pharmacology. Specific in vivo binding of [3H]DuP 734 in brain peaked 1 hr after i.v. injection and this level of binding was maintained up to 4 hr. On the other hand, plasma concentration of [3H]DuP 734 decreased rapidly within 20 min after injection, indicating different pharmacokinetics between brain and plasma levels. Nonspecific binding, defined using 1 mg/kg (2.66 mumol/kg) of haloperidol, was approximately 30% of total binding 1 hr after injection of radiotracer. Administration of DuP 734 potently antagonized the binding of [3H]DuP 734 and [3H](+)-SKF 10,047 to brain sigma receptors in vivo with ID50 values of 0.02 and 0.07 mg/kg (0.07 and 0.25 mumol/kg), respectively. However, (+)-SKF 10,047, which possess a high affinity (IC50 = 22.5 nM) for [3H]DuP 734 binding in vitro, failed to displace [3H]DuP 734 binding in vivo. Thus in vitro receptor binding data may not predict in vivo receptor occupancy. Overall, the data suggest [3H] DuP 734 is a good ligand for in vivo imaging of sigma receptors.

Animals↗

PubMed1996

[A case of dilated cardiomyopathy with early back-diffusion of 123I-BMIPP].

A 28-year-old woman was pointed out cardiomegaly and diffuse hypokinesis of left ventricle by ultrasonography in community hospital. Coronary angiography showed normal coronary artery and, left ventriculography revealed diffuse hypokinesis (LVEF 40%). She was diagnosed idiopathic dilated cardiomyopathy by myocardial biopsy and other clinical information. Myocardial scintigraphy with 201Tl. revealed dilatation of left ventricle and diffuse inhomogeneous accumulation of 201 Tl. Dynamic 123I-BMIPP SPECT image 2 minutes after injection showed BMIPP accumulation in all segment, though, static image 15 minutes after injection indicated reduced BMIPP accumulation. These findings suggested existence of the early back-diffusion in inferior segment. Early back-diffusion of BMIPP may become a marker of abnormal fatty acid metabolism in patient with dilated cardiomyopathy.

Adult↗

PubMed1977

Suppression of the primary immune response by chemical sympathectomy.

The effects of general sympathectomy with 6-hydroxydopamine (6-OHDA) on antibody production to sheep red cells (SRBC) were studied in mice. Intraperitoneal administration of 6-OHDA in a dose of 1 to 300mg/kg resulted in a significant decrease in hemagglutinin titer and number of direct plaque-forming cells which were observed only in the early period of the primary immune response. Following treatment with 6-OHDA 10mg/kg i.p., the noradrenaline content in murine spleen was significantly reduced from 63 to 42% of control value between 2 and 10 days after injection indicating that chemical sympathectomy suppresses the primary immune response.

Animals↗

PubMed1977

Blood-tissue exchange in liver and heart: the influence of heterogeneity of capillary transit times.

The single-injection multiple indicator-dilution technique has been used to explore blood-tissue exchange in the heart and the liver. Analysis of the classical description of exchange at the level of the single capillary following an impulse injection indicates that the loss of the material from the impulse in each capillary depends on the transit time of that capillary. Thus, in a multiple indicator-dilution experiment, early in time, for barrier-limited substances, the relation between the reference and diffusible substances as a function of time will reflect the manner in which the underlying capillary transit times have varied. In the heart, labeled sucrose exchange was used to quantitate the underlying pattern of capillary heterogeneity. With maximal coronary vasodilation, the capillary transit times appeared uniform (and there was a corresponding maximal heterogeneity of large vessel transit times). With more normal coronary tone, both the underlying capillary and large vessel transit times were found to increase along the outflow curve with the outflow arrival time. In the liver, in contrast, the transit times through the exchange area were found to show a maximal heterogeneity (and there was, in the large vessels, a corresponding uniform transit time).

Blood Flow Velocity↗

PubMed1979

Delayed hypersensitivity to Staphylococcus aureus in mice: in vivo responses to isolated Staphylococcal antigens.

The development of delayed hypersensitivity (DH) to Staphylococcus aureus in Swiss mice was evaluated by the footpad (FP) assay. In order to determine which component of the bacteria was responsible for the in vivo immune reactivity, purified Staphylococcal cell wall, cell membrane, protein A, lipoteichoic acid, teichoic acid, as well as lipid-free membrane proteins were isolated. The immune responses of mice receiving one to eight S. aureus injections indicated that the first DH peak, following three injections, was primarily dependent upon protein antigens associated with the bacterial membrane. Increased bacterial injections gave rise to a second DH peak following seven injections which was dependent upon multiple bacterial components including cell wall, protein A, and membrane proteins.

Animals↗