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The location of nuclei of different labelling intensities in autoradiographs of the anterior forebrain of postnatial mice injected with [3H]thymidine on the eleventh and twelfth days post-conception.

The location of neuron nuclei of different labelling intensities in autoradiographs of the anterior forebrain of two 22 day old mice which had been injected with [3H]thymidine at 11 and 12 days post-conception respectively was charted on photocollages of sections enlarges 175 times. The pattern of distribution of the heavily labelled nuclei, i.e. those nuclei belonging to cells most likely to have been born shortly after the time of [3H]thymidine injection, indicated that the inner two thirds of the neocortex is laid down along a ventro-dorsal gradient, i.e. the lateral neocortex starts to form before the dorsal; and that cells born at a particular time lie in cortical layer VI at the dorsal edge of the gradient is traced ventrally. Progressively more weakly labelled cells formed intermediate steps in this migration. A model or cortical growth fitting these findings is presented. Some inferences are also made about the possible role of the ganglionic eminences in providing cortical cells, at least during the initial stages of cortical histogenesis.

Animals↗

Drug monitoring at an Australia depot phenothiazine clinic.

Three aspects of treatment with injectable neuroleptics, are presented. An individualized approach to the dosage of Fluphenazine decanoate must be practiced in conjunction with, and taking into account the time spent in treatment and the sex and age variables reported. Our flexible approach to the interval between injections, indicated a large group could be maintained at intervals of 5 to 8 weeks. Complex and challenging problems can be found with antiparkinsonian drugs; 30% of nearly 400 outpatients still require these drugs.

Adult↗

Cytotoxic activity, tumor accumulation, and tissue distribution of ruthenium-103-labeled bleomycin.

Bleomycin (BLM) was labeled with gamma-emitting 103Ru. Yields of 103Ru-labeled BLM as high as 50.6% were attained. 103Ru-labeled BLM was stable in vitro and the 103ru label was not displaced by large excesses of Cu (II) and Co (II) or Fe (III). Chromatography of the urine following 103Ru-labeled BLM injection indicated no in vivo decomposition. Pharmacokinetic studies in healthy inbred SD and tumor-bearing inbred BUF rats demonstrated tumor accumulations, tissue distributions, and clearance nearly identical with those reported for 3H-labeled BLM. Cytotoxicity studies on a WI-L2 human B-cell line showed that BLM labeled with nonradioactive Ru retained 100% of the activity demonstrated by native BLM. Thus BLM may be labeled with isotopes of Ru to form stable complexes by a simple, rapid reaction without loss of its chemotherapeutic properties or variations in its in vivo distribution. BLM labeled with the proper Ru isotope should prove useful as a gamma-emitting tracer for BLM or a beta-emitting compound capable of providing combination chemotherapy and radiotherapy of tumors.

Animals↗

Biokinetics of bone tracers by means of deconvolution analysis--comparison of 99mTc MDP, 99mTc DPD and 99mTc EHDP.

Transfer functions of 99mTc methylene diphosphonate (MDP), 99mTc 2,3-dicarboxypropane-1,1-diphosphonate (DPD) and 99mTc ethane-1-hydroxy-1,1-diphosphonate (EHDP) into bone and extravascular fluid of soft tissues were determined in 5 dogs by deconvolution analysis of the time-course of plasma, soft tissue and bone radioactivity. The transfer rates 5 min after injection--indicating the rapid exchange of the tracer between plasma and the extravascular fluid--decrease in the order MDP greater than EHDP greater than DPD (P less than 0.05). The transfer rates into bone--determined from transfer rates between 30 and 60 min--decreased in a different order, i.e. MDP greater than DPD greater than EHDP (P less than 0.05). The fractional bone uptake of diphosphonates estimated from the ratio of early to late transfer rates was slightly greater for DPD than for MDP and EHDP respectively. The difference between DPD and MDP was not significant (P greater than 0.05). The average bone and soft tissue concentrations of DPD 60 min after injection were greater than that of MDP and EHDP due to different plasma concentrations (DPD greater than EHDP greater than MDP), whereas the bone-to-soft tissue ratios decreased in the sequence MDP greater than DPD greater than EHDP (P less than 0.05).--Our results reveal different biokinetics of MDP, DPD and EHDP explaining variations in osseous and soft tissue uptake suggesting that deconvolution analysis could play an important role in bone scan interpretation.

Animals↗

Energy metabolism of the peritoneal membrane in silica-induced peritonitis. A biochemical and enzyme histochemical study.

Oxygen and glucose consumption and lactate production of the peritoneal membrane and intra-abdominal adhesions were measured in rats after a single intra-peritoneal colloidal silica injection. Enzyme histochemical studies were made of lactate dehydrogenase, succinate dehydrogenase, NADH2-diaphorase, NADPH2-diaphorase, glucose-6-phosphate dehydrogenase, glutamate dehydrogenase, acid phosphatase, leucylaminopeptidase and alkaline phosphatase in the peritoneal membrane. Anaerobic glycolysis comprises 47% of the total glucose consumption in the the normal peritoneum. Glucose consumption and lactate production of the peritoneal membrane increased sharply in the early phase of silica-induced peritonitis and stayed at a high level for a week indicating an enhanced anerobic metabolism. Oxygen and aerobic glucose consumption increased more slowly than anaerobic glucose consumption and reached their maxima 1 week after silica injection, indicating that the rate of aerobic metabolism is also higher in chemical peritonitis than in the controls. On the other hand, glucose consumption and lactate production increased in a parallel fashion in adhesions and in the peritoneum in the early phase of peritonitis. However, the maximum and later levels were less in adhesions than in the peritoneum. In the enzyme histochemical study high activities of enzymes indicating anaerobic energy metabolism and metabolism via the pentose phosphate shunt were seen in cells of the peritoneal membrane during the early phase of peritonitis. No activity was identified in enzymes indicating aerobic energy metabolism and increased catabolism before the end of the first week.

Animals↗

[Effect of intracellular injection of cyclic adenosine monophosphate on the calcium current in identified snail neurons].

The effect of intracellular cyclic adenosine monophosphate (cAMP) injection and extracellular theophylline application on calcium current were investigated in Helix RPa3 and LPa3 neurons. It was found that iontophoretic cAMP injection (current 10-35 nA, duration about 1 min) caused a decrease in the amplitude of calcium current which restored to the initial level following the cessation of injection. Its current-voltage characteristic was not displaced along the potential axis in the presence of cAMP injection indicating that the calcium current decrease was due to the fall of maximum calcium conductance. Extracellular theophylline application in concentration of 1 mM/1 caused a decrease in the calcium current amplitude by 50-75% from the initial level. The hypothesis is discussed about the participation of cytoplasmic factors in regulation of calcium current in mollusc neurons.

Animals↗

[Interferon in skin diseases].

In the dermatological field, interferon is used in clinical trials for viral skin diseases and for malignant skin tumors such as malignant melanoma. In regard to viral diseases, clinical trials have shown promising results in viral warts, herpes simplex and herpes zoster. In the double-blind trial, patients with bilateral common warts of the extremities were treated at weekly intervals with intralesional injections of either human fibroblast interferon or placebo. More than 81% of the interferon-treated extremities were either cured by or responded effectively to the therapy, while only 17% of the placebo responded. Although our data has confirmed that interferon is effective in the treatment of common warts diseases, the method of application and repeated injections indicate that this therapy may not be helpful in routine cases but only in selected patients in whom other therapy has failed. However, development of new delivery systems or modification of dosages may increase the value of interferon therapy for warts disease. Interferon seems also effective for herpes zoster. But herpes zoster usually regresses spontaneously within three weeks, therefore, it is not easy to define efficacy of interferon in this disease. Therefore, we need to examine the effect of interferon on herpes zoster both in placebo controlled and double-blind trials involving patients with immunocompromised diseases.

Adult↗

Clearance rate of gonadotrophin releasing hormone in peripheral plasma of the pig.

Gonadotrophin releasing hormone was administered as an intravenous bolus injection into four boars and four ovariectomized sows. Radioimmunoassay of concentrations of gonadotrophin releasing hormone 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 2.12 +/- 0.95 (SD) minutes was calculated for the first component and of 13.15 +/- 2.55 minutes was calculated for the second component of the decline in gonadotrophin releasing hormone concentrations. No significant difference was detected between boars and sows for half-life value of either component. In the four boars, luteinizing hormone values reached a peak in plasma 20 minutes after injection and that of testosterone at 90 minutes after gonadotrophin releasing hormone treatment.

Animals↗

Arthritis inflammation monitored by subcutaneous millimeter wave thermography.

A new technique for remote, noninvasive mapping of temperature elevations of the human joints is described; it uses the mm wave radiation emitted by the human body. A solid state switched scanner for 68 GHz is described which overcomes the depth limitations of conventional, infrared thermographs and can measure to subcutaneous depths of several mm with a temperature resolution of 0.25 degrees C. Measurements on rheumatoid arthritic knee joints are presented which show little correlation with simultaneously measured skin temperatures. Significant longterm thermographic changes induced by steroid injection indicate a potential for objective patient monitoring and development of new treatment methods.

Adult↗

Studies on intestinal absorption by single-injection technique and continuous measurement of portal vein blood electrolyte concentration and hematocrit in the alert rat.

Whole blood and ultrafiltrate conductivity in the portal vein (as a measure of hematocrit and total electrolyte concentration, Cel, respectively) and arterial pressure of alert rats were measured continuously. Single intraduodenal injections of solutions iso- and hyperosmotic to blood (0.5 or 1 per cent of body weight) produced characteristic changes which were compared with those after the application of water. Whereas H2O and isosmotic passively absorbed substances (sorbose and urea) caused a very variable Cel drop, isosmotic actively absorbed nutrients elicited individually constant but interindividually different (glucose greater than alanine++ greater than arginine) changes due to solute coupled electrolyte free water transport. This was taken as evidence of variable paracellular shunt permeability playing a role in passive, but not in active absorption. The magnitude of Cel changes was related to absorption rate, which was confirmed by behaviour with hypertonic solutions, where osmotic activity in the gut was lost the sooner, the more rapid absorption rate was. Shunt permeability was temporarily blocked by arginine. Hct changes immediately after injections indicated fluid loss from portal vein blood, which could be evaluated in the case of mannitol. The thickness of the absorptive layer, obtained from latency of Cel change after urea, delivered values not exceeding 0,51 mm for the unstirred layer. The latencies after glucose and alanine were usually not much greater than after urea. Cel rise after hypertonic solutions had the same latency as Cel drop after water. Small arterial pressure changes after nutrient solutions, mostly absent after injections of water and NaCl, indicated circulatory effects originating in the gut in association with the former.

Alanine↗

Removal of Pu and am from beagles and mice by 3,4,3-LICAM(C) or 3,4,3-LICAM(S).

Decorporation of Pu and Am by tetrameric catechoylamide (CAM) ligands has been investigated in beagles and mice. Eight dogs were injected intravenously (iv) with 237 + 239Pu(IV) + 241Am(III) citrate, and 30 min later, pairs of dogs were injected iv with 30 mumole/kg of 3,4,3-LICAM(C) [N1,N5,N10,N14-tetrakis(2,3-dihydroxy-5-sulfobenzoyl)tetr aazatetradecane, tetrasodium salt], 3,4,3-LICAM(S) [N1,N5,N10,N14-tetrakis(2,3-dihydroxy-4-carboxybenzoyl)te traazatetradecane, tetrasodium salt], CaNa3-DTPA, or each of the latter two ligands. Blood was sampled, and excreta were collected for 7 days, at which time the dogs were sacrificed and nuclide retention in liver and nonliver tissue was measured. Groups of five mice were each given 238Pu(IV) or 241Am(III) citrate iv; 3 min later 30 mumole/kg of a CAM ligand was injected intraperitoneally, mice were killed at 24 hr, and separated excreta and tissues were analyzed. In the dogs, average retention at 7 days of the injected Pu and Am, respectively, was as follows: 12 and 70% after treatment with a CAM ligand alone; 30 and 20% after DTPA; 12 and 20% after LICAM(S) plus DTPA; 90 and 89% without a ligand. In the mice, mean retention of the injected Pu and Am, respectively, was as follows: 14 and 66% after treatment with LICAM(C); 21 and 54% after LICAM(S); 91 and 87% without a ligand. In both species, about 99% of net Pu excretion (excretion with ligand - excretion without ligand) promoted in 24 hr by DTPA or LICAM(S) was in the urine, whereas about 10% of net Pu excretion promoted by the less hydrophilic LICAM(C) was in feces. Delayed excretion of both Am and Pu was significant in all ligand-treated dogs. Comparison of the nuclide content of tissues of ligand-treated mice with those of mice killed 3 min after nuclide injection indicated that the CAM ligands chelated circulating Pu and Am and prevented further deposition. In addition, the CAM ligands removed much of the presumably loosely bound Pu present in liver and skeleton at the time of ligand injection. LICAM(C) was more effective in removing Pu from liver and LICAM(S) was more effective in the skeleton. Moderate to severe uremia and histological evidence of cell killing in the distal tubules of the kidney were observed in the four dogs injected once with 30 mumole/kg of LICAM(S).(ABSTRACT TRUNCATED AT 400 WORDS)

Americium↗

D-penicillamine-induced angiopathy in rats. The effect of high dose D-penicillamine treatment on aortic permeability to albumin and on the ultrastructure of the vessel.

Male Sprague-Dawley rats were treated with D-penicillamine (D-pen) 500 mg/kg/day for 10 or 42 days. Pair fed rats served as controls. Changes in aortic morphology were examined by light- and transmission-electron microscopy (TEM). In addition, the endothelial permeability and the penetration through the aortic wall of albumin were studied 10 minutes, 24 and 48 hours after i. v. injection of human serum 131I-albumin (131I-HSA). TEM revealed extensive elastolysis in the arterial wall of D-pen-treated rats, consistent with an inhibitory effect on crosslink formation. In experimental animals excess deposition of collagen and glycoaminoglycans was observed in the subendothelial and medial layer of the aortic wall, together with prominent basal membrane substance around aortic smooth muscle cells. The aorta/serum-ratio and the radioactive build-up 24 and 48 hours after injection of 131I-HSA was reduced in animals treated with D-pen for 42 days, indicating an impeded transmural transport of tracer which may be caused by a steric exclusion effect of abundant hyaluronate. The endothelial ultrastructure was unaffected by D-pen, and no differences in aortic 131I-HSA radioactivity or aorta/serum-ratio were recorded between experimental and control groups 10 minutes after tracer injection, indicating that the permeability of the endothelial barrier to albumin remained unaffected by D-pen treatment. These observations support the hypothesis that treatment with high doses of D-pen may induce a fibroproliferative response in rat aorta, possibly by an inhibitory effect on the cross-linking of collagen and elastin.

Animals↗

Effects of scopolamine and methylscopolamine on classical conditioning of the rabbit nictitating membrane response.

Classical conditioning of the rabbit nictitating membrane response was accomplished by presenting tone- and light-conditioned stimuli for 800 msec before delivery of a 100-msec shock as the unconditioned stimulus. Scopolamine significantly retarded the rate of acquisition and final asymptotic performance of conditioned responses to the tone- and light-conditioned stimuli. Methylscopolamine was approximately 20 times less potent than scopolamine in retarding the rate of acquisition, and had no effect on the final asymptotic performance of conditioned responses. The retardation in acquisition of conditioned responses produced by scopolamine could still be detected 5 days after cessation of drug injections, indicating that the effects of scopolamine were on acquisition and not performance. In contrast, scopolamine and methylscopolamine had no affect on the development of long-term habituation produced by the unpaired presentations of tone, light and shock stimuli. Control experiments indicated that the acquisition of conditioned responses by animals injected with saline, scopolamine or methylscopolamine was not contaminated by the presence of changes in base-line responding, sensitization or pseudoconditioning. In addition, scopolamine and methylscopolamine did not affect the unconditioned nictitating membrane reflex. In previously trained animals, scopolamine produced a significant, approximately 25-db elevation in the intensity threshold of a tone-conditioned stimulus for elicitation of conditioned responses. It was concluded that scopolamine blocks the excitatory properties of tone stimuli and this accounts for its ability to retard the rate of acquisition of conditioned responses.

Acoustic Stimulation↗

Concurrent inductions of avian hepatic lipogenesis, plasma lipids, and plasma apolipoprotein B by estrogen.

The inductions of hepatic fatty acid synthesis, estrogen-specific plasma proteins, plasma lipids, and apolipoproteins by a single subcutaneous injection of diethylstilbestrol (40 mg/kg body weight) have been examined in immature male turkeys. Estrogen induced the appearance of phosvitin, lipovitellin, and apoVLDL-II in the blood plasma. The highest concentrations of these estrogen-specific plasma proteins were observed 48 hr following hormone administration. Estrogen increased the concentration of triglyceride in the liver, predominantly those molecular species containing 16 carbon fatty acids (triglycerides with 53 and 55 carbon atoms). Liver cholesterol was present predominantly as free cholesterol. Although estrogen did not affect the concentrations of free or esterified cholesterol in the liver, the hormone increased the amount of cholesterol esterified with 20-carbon fatty acids and caused a corresponding decrease in cholesterol esterified with 18 carbon fatty acids. Estrogen treatment elevated the plasma triglycerides 55-fold, tripled the plasma phospholipid, and approximately doubled the plasma cholesterol. The de novo synthesis of fatty acids in the liver in vivo was stimulated by estrogen administration, as exhibited by increased 3H2O incorporation into the phospholipids and triglycerides of both liver and plasma. In contrast, hepatic cholesterol synthesis was unaffected. The amounts of newly synthesized triglyceride in the liver and plasma and the specific radioactivities of the plasma triglyceride following 1-hr in vivo labeling periods, 0, 24, 48, and 72 hr after estrogen injection indicate that increased hepatic fatty acid synthesis is a primary and major casuative factor in the development of estrogen-induced hyperglyceridemia in this avian species. The concentration of apolipoprotein B in the plasma increased in parallel with hepatic fatty acid synthesis and the appearance of newly synthesized triglyceride in the plasma, whereas the plasma apolipoprotein A-I level decreased. These observations indicate that in the avian liver estrogen causes a coordination of inductions in the conversion of carbohydrate to triglyceride and in the production of proteins (apolipoprotein B and apoVLDL-II) involved in the assembly of triglyceride-rich lipoprotein particles, leading to hypersecretion of these lipoproteins into the circulation.

Animals↗

High dose netilmicin therapy of severe or chronic infections.

Sixteen patients with chronic or recurrent urinary tract infections, 14 with septicaemia, 2 with salmonellosis, 2 with pneumonia and 1 with acute mastitis were treated with 200 mg (2.2-3.6 mg/kg) netilmicin intramuscularly every 8 hours for 7-10 days (mean 8.8 days). 28 patients were cured, 5 showed marked improvement and 2 patients with septicaemia and severe underlying diseases failed to respond to treatment. The bacterial isolates were inhibited by 4.0 mg netilmicin/l or less. Antibiotic serum level determinations were performed in 32 patients. Mean serum concentrations of netilmicin 1 and 8 hours after injection were 12.6 and 2.0 mg/l respectively in 27 patients with normal serum creatinine levels. In 5 patients with elevated serum creatinine, mean peak and trough values were 21.5 and 5.8 mg/l, respectively. Mean netilmicin concentrations in serum and skin blister fluid obtained from 4 patients were equal 2-3 hours after injection, indicating appropriate tissue penetration. Nephrotoxicity occurred in 2 patients. Ototoxicity was not demonstrated. Netilmicin appears to be an effective and safe drug in the treatment of a variety of bacterial infections.

Adult↗

Effects of gastrin on emptying and composition of digesta of the omasum of sheep.

Three adult sheep were prepared with a denervated pouch of fundus of the abomasum and a reentrant fistula system that connected the remaining proximal and distal portions of the abomasum. The proximal cannula of the reentrant system was close to the omasoabomasal orifice, allowing for easy collection of fluid leaving the omasum. Intravenous injection of 0.5, 1.0, or 2.0 microgram/kg/hr of synthetic human gastrin I caused a marked decrease in flow rate of fluid from the omasum. The concentration of particulate matter in the digesta was inversely related to rate of omasal outflow. An increase in acid output from the denervated abomasal pouch during gastrin injection indicated that the hormone was given at pharmacologically effective doses. Results indicate that gastrin has a modulating effect on the flow of ingesta through the ruminant forestomachs. Actual sites of action were not identified.

Animals↗

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↗