Iodine-123-Rose bengal: An improved hepatobiliary imaging agent.

A practical method for preparing )23-I-rose bengal that allows for its rapid and efficient incorporation into the molecule is reported. Administration of 123-I-rose bengal to normal healthy patients showing the normal uptake and excretory pattern visualized with this radio pharmaceutical is also presented. The overall reduction in imaging time and radiation exposure together with the improved images possible should greatly improve our diagnostic capabilities in evaluating the jaundiced patient.


Organ distribution of 99m-Tc-and 51-Cr-labelled thymocytes.

We have employed 99mTc as a radioisotopic label to study the organ distribution of murine thymocytes. The compartmentalization of 99mTc-labeled cells that had not been reduced by treatment with stannous chloride was similar to that of 51Cr-labeled cells and was characterized initially by 48-50% uptake of the injected radioactivity by the lungs. Increased hepatic and splenic and decreased pulmonary localization were noted at 1 hr and these shifts were more pronounced by 4 hr. Technetium-99m-labeled cells reduced by stannous chloride had significantly different patterns of hepatic, pulmonary, and splenic localization and at 4 hr the lungs still retained 24% of the injected radioactivity compared with only 3% in the spleen. Size distribution studies revealed that unlabeled as well as unreduced and reduced 99mTc-labeled thymocytes were almost identical to one another so that differences in compartmentalization could not be attributed to this factor. Since reduction with stannous chloride did not alter the distribution of 51Cr-labeled cells, this suggested some type of complex interaction between stannous ions and the labeling species of 99mTc. The in vivo localization of intravenously administered Na99mTcO4 and Na2CrO4 was markedly different from the corresponding radiolabeled cells thereby indicating that the distribution patterns that we observed truly represented cell-associated radioactivity. Although it may not necessarily be the proper reference point, the similarity in organ distribution of 99mTc- and 51Cr-labeled cells should allow direct comparison of previously reported data employing this radionuclide and that obtained in future studies with 99mTc.


Generator-produced 99m TcO4-: carrier free.

A solution of 99m-TCO4-minus, as eluted from a 99Mo-99mTc radionuclide generator contains a greater chemical quantity of technetium than that attributable to the metastable isomer alone. The isomeric transition of the radionuclide of interest, 99mTc, gives rise to a determinable and chemically significant quantity of technetium carrier, 99Tc. A method is presented for calculating the total chemical quantity of technetium in a generator eluate.


Estimation of radiation dosage and transmutation effect of 14-C involved in measuring rate of albumin synthesis with 14-C-carbonate.

For direct measurement of the rate of albumin synthesis Na2 14CO3 was used intravenously. The assessment of the radiation hazard involved in the study was based on the knowledge of the minimum dose of Na214CO3 necessary for a sufficient incorporation of 14C in the guanidine-C of arginine in albumin to obtain measurable radioactivity. By measurement of expired 14CO2 and excreted 14C-urea in the urine during a 5-hr period following intravenous administration of Na214CO3 in five subjects, some quantitative data  on 14C retention and radiation dosage were obtained. In comparison with animal studies, the rate of expiration of 14CO2 in man is slower. About 50% of the total radioactivity injected was lost through the respiratory route in the first hour. The total amount of expired 14C during the 5 hr of investigation was about 75% of the injected dose for the five subjects. The amount of 14C excreted as urinary 14C-urea during the 5 hr of investigation is very small in comparison with the expired 14C; it was only about 0.5% of the dose injected. The total absorbed radiation dose after complete elimination of 14C from the body was calculated with various assumptions. The extra risk of genetic damage due to disintegration of retained 14C in comparison with that of natural 14C in the body during 30 living years is about 50%.


Effect of positron range on spatial resolution.

The effect of beta+ range on spatial resolution of imaging systems employing the detection of 511-keV annihilation radiation was determined by measuring the variation in the line-spread functions (LSFs) of positron-emitting radionuclides of 64Cu, 11C, and 15O as compared with the 514-keV gamma-ray emitter 85Sr. These radionuclides have maximum beta+ energies of 0.656, 0.960, and 1.72 MeV, respectively. The LSFs were measured in a tissue-equivalent phantom with high-resolution (approximately 2.4 mm FWHM) and low-resolution (approximately 8.8 mm FWHM) straightbore collimators coupled to a NaI(Tl) detector. Theoretical LSFs for the beta+ ranges were also calculated and convolved with the 85Sr LSF to yield the predicted LSFs for 11C and 15O. The high-resolution study showed a 0% and 2.3% increase in the full-width half-maximum (FWHM) and full-width tenth-maximum (FWO.1M) for the low-energy beta+ of 64Cu and a 37% (FWHM) and 52% (FWO.1M) increase for the high energy beta+ of 15O as compared with 85Sr. However, when the system resolution was decreased to 8.8 mm FWHM, the 64Cu showed no change at FWHM or FWO.1M and the 15O showed a 2.3% (FWHM) and 7.8% (FWO.1M) relative to 85Sr. The predicted LSFs were in good agreement with the experimental. These data indicate that the effect of beta+ range on spatial resolution is minimal unless the beta+ energy is larger than or equal to 1.5 MeV and the system resolution is on the order of a few millimeters.


Positron camera with extended counting rate capability.

Positron emitters may be imaged using two opposing scintillation cameras without collimators. The counting rate limitation of this approach can be largely largely overcome by using graded absorbers to reduce scattered radiation from the patient and using not only photopeak events but Compton events in the scintillator as well. This increases the useful counting rate by more than a factor of 5. By combing this technique with the use of fast electronics, useful images have been obtained in the presence of scattering material at counting rates above 7,500 cps.


Coincidence and noncoincidence counting (81Rb and 43K): a comparative study.

This paper compares the accuracy of imaging and resolution obtained with 81Rb and 43K using coincidence and noncoincidence counting. Phantoms and isolated infarcted dog hearts were used. The results clearly show the superiority of coincidence counting with a resolution of 0.5 cm. Noncoincidence counting failed to reveal even sizable defects in the radioactive source.


New adrenal-scanning agent.

A new adrenal-specific compound, 6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol(NCL-3-I), which is derived from 19-iodocholesterol (CL-19-I), has been found. Tissue distribution studies have revealed that the rat adrenal gland accumulates ten times more NCL-6-131-I than CL-19-131-I. The advantage of NCL-6-131-I as a possible adrenal-scanning agent is discussed.


Scintigraphic elvaluation of liver metastases from thyroid carcinoma.

Thirty-one patients with carcinoma of the thyroid were evaluated using 131-I scan of the torso including the area of the liver. Focal areas of 131I uptake were found in the liver in two patients with follicular thyroid carcinoma. Both patients showed associated abnormalities on 99m-Tc-sulfur colloid liver scans. The remaining 29 patients showed either no uptake or a normal diffuse pattern of 131-I uptake in liver. Careful evaluation of the liver is recommended on the radioiodine body scan for metastases in patients with thyroid carcinoma.


Preliminary observations on excretion of 37Ar from man following whole-body neutron activation--an indicator of total-body calcium.

Measurements of exhaled 37-Ar produced by total-body neutron irradiation of 40-Ca were used to determine total-body calcium in 16 human subjects. There was a good correlation between body calcium using the 30-min postirradiation breath sample of 37-Ar and body calcium determined by measurement of 49-Ca.


Abnormal brain scans: Contribution of blood radioactivity to image.

Images obtained with 99m-Tc-labeled red blood cells were compared with 99m-Tc-pertechnetate scans in 26 patients with primary and secondary brain tumors, intracerebral infcts, and hemorrhage. The results indicated that the contribution of blood pool radioactivity to a positive brain scan was minor.


Elimination of scalp blood flow by headband during dynamic brain scintigraphy.

The effect of the application of a headband during brain scintigraphy was investigated in 11 healthy volunteers. In each person, extracranial recording of a bolus of 99mTc-pertechnetate injected intravenously was done on two occasions during  a scintillation camera. On one occasion a narrow sphygmomanometer cuff encircling the head from brow to occiput and inflated to 300 mmHg was applied during measurements; another time, the procedure was identical except for the headband. A comparison between counting rates under the derived time-activity curves showed significantly lower values on headband application (p less than 0.01). Static scintigrams consisting of the first 300,000 counts recorded after bolus release with and without headband application show a clear delineation of the headband position with prevention of "halo" appearance about the cranial cavity. It has thus been possible by simple means to reduce the irrelevant radionuclide distribution which, especially during dynamic investigations of cerebral circulation, constitutes a source of error.


Erythrocyte survival in the Mongolian gerbil.

Erythrocyte survival studies using 51-Cr- and DF-32-P-labeling procedures were performed on the Mongolian gerbil, a "recently discovered" rodent used for medical research. Various isotopic techniques were performed and evaluated.


The intracellular localization and stability of the dihydrofolate synthetase in pea seedlings.

The amount of folate compounds rapidly increased during germination of the pea. An especially high increase was observed 2 days after sowing, with a continouously increasing content during germination. Dihydrofolate synthetase [EC 6.3.2.12] activity also increased with the increase in the amount of folate compounds, and the maximum activity was observed at 6 days after sowing in the dark and at 8 days after sowing in the light. The dihydrofolate synthetase was localized mostly in the mitochondrial fraction and it was easily extracted from the cell particles by osmotic shock. A similar localization was also observed in spinach leaves. The enzyme which was extracted from the isolated mitochondria was relatively stable im comparison with that extracted from whole cells.


The effects of maltitol on rat intestinal disaccharidases.

1. The highese disaccharidase activity for sucrose maltose and maltitol was found in the jejunum, followed by the ileum and duodenum. However, the disaccharidase activity for maltitol was extremely low compared with that for sucrose and maltose. 2. For maltitol, the Km value was very large and the Vmax value was very low compared compared with the values for sucrose and maltose. 3. The initial velocity (v) in the presence of the sucrose and maltitol, was equal to the sum of the rates for individual substrates sucrose ann maltitol (v1, v2) respectively (v=v1+v2). Thus, no competition between these substrates was observed. In the case of maltose and maltitol, the initial velocity (v) in the presence of both substrates was less than the sum of the individual rates for maltose and maltitol (v1, v2) in the absence of the other substrate (v is less than v1 + v2). This finding demonstrates that there is competition between these two substrates for the same enzyme. Furthermore, the apparent Michaelis constant (Km) and the apparent maximal velocity (Vmax) for pure and mixed substrates, i.e., maltose and maltitol, at various mole fractions of maltose showed dependence on the mole fraction of maltose. The obtained kinetic data provide strong evidence that both maltose and maltitol react at the single active center of maltase.


Effect of exogenous polyunsaturated fatty acids on lipogenic enzyme activity in rat liver under fixed carbohydrate consumption.

Studies were conducted to evaluate specific dampening of hyperlipogenesis (i.e. enhanced lipogenic enzyme activity of the liver in rats refed a high carbohydrate, fat-free diet: F-diet) by exogenous polyunsaturated fatty acids under fixed carbohydrate consumption. In force-feeding of rats with a linoleate-rich diet (F-diet containing 4.5% safflower oil), the lipogenic enzyme activities; fatty acid synthetase (FAS) and malic enzyme (ME) in the liver supernatant were found to be significantly lower than those in rats force-fed only an F-diet (p is less than 0.02), under conditions of identical consumption of carbohydrate. Among the various methylestery of unsaturated fatty acids administered by gastric intubation at a dose of 0.3 g per 100 g body weight, arachidonate was most potent in bringing about a significant reduction of hyperlipogenesis without seriously affecting food intakes. During the same three-day experimental period, fatty acid GLC spectra in both the liver and plasma lipids reflected the exogenous input of PUFA. Plasma total fatty acid concentration (mainly triglyceride) signigicantly decreased in the arachidonate group (p less than 0.01).


Semi-automated system for analysis of vitamin B6 complex by ion-exchange column chromatography.

A simple system for semi-automatic analysis of pyridoxal, pyridoxine and pyridoxamine has been developed using diazide of 5-chloroaniline 2,4-disulfonyl chloride as a color-producing reagent in combination with desoxypyridoxine as an internal standard. It employs Aminex A-5 column, 10x0.6ø cm, as an adsorbent. Adsorbates were eluted successively with 3 discrete phosphate buffers (0.4 N Na+). The effluent is mixed continuously with capillary streams of the diazide reagent and of sodium acetate. The mixture, maintained at 65 degrees C in a heating bath, then passes through a spiral of Teflon tubing with a residence time of 2 min. Characteristic orange colored products formed by a diazo coupling reaction are continuously monitored at 440 nm in a flow photometer. The individual peaks on the recorded chromatogram are manually integrated by a conventional HW method. The elution position and recovery of desoxypyridoxine permits correction for sensitivity changes or mechanical losses which might occur during a series of analyses. The analyzer system described allow quantitation from 2 to 25 mug of pyridoxal, pyridoxine and pyridoxamine in a single sample within 2 hr and with a precision of 100 +/- 4%. It is also found suitable as a routine procedure for the analysis of varied biological samples.


The content of free and bound inositol in human and cow's milk.

The gaschromatographic method was used for the quantitative analyses of inositol in milk. The content of inositol in human and cow's milk at the different lactation periods was determined. The content of total myoinositol in human milk was 32.7 plus or minus 15.2 mg/100 ml in colostrum, 17.8 plus or minus 1.9 mg/100 ml in transitional milk, and 14.9 plus or minus 3.1 mg/100 ml in mature milk. In cow's milk, it was 10.6 plus or minus 1.0, 7.0 plus or minus 1.1, and 4.1 plus or minus 1.0 mg/100 ml, respectively. These values were very similar to those obtained by the microbiological method. The presence of lipid-bound myoinositol in both kinds of milk was confirmed and the content was 0.22 plus or minus 0.09 mg/100 ml in human milk and 0.36 plus or minus 0.10 mg/100 ml in cow's milk. A small amount of scylloinositol was found in both human and cow's milk, while dextroinositol was not found in either.


Fatty acid composition of glycerides and stereospecific analysis of triglyceride in pea seeds.

Pea seeds were shown to contain ten kinds of neutral lipids, among which triglyceride, free sterol and sterolester are the main components and diglyceride, monoglyceride, free fatty acid, wax and some pigments are the minor ones. The major component fatty acids in the glycerides and the free fatty acid are C18:2, C18:1 and C16:0. The positional distribution of fatty acids in triglyceride is such that, position 1 and 3, especially the former, abound in saturated fatty acids, and position 2 is filled almost entirely with unsaturated fatty acids.


Exacerbating effect of dietary 12-keto oleic acid on vitamin E deficiency in the rat.

12-Keto oleic acid, possibly one of the oxidation products of long-chain, unsaturated fatty acids, was added to the feed of weanling male rats at the 1% level. Their growth curves, tissue weights, plasma alkaline phosphatase, GOT, and GPT activities, and plasma and liver lipid (cholesterol, triglyceride and phospholipid) levels were investigated and compared with those of weanlings fed a vitamin E deficient diet. Both the diet containing 12-keto oleic acid and the diet deficient in vitamin E decreased the growth rate of body weight and tissue weight, and increased the liver triglyceride and cholesterol levels. Parallel with these, increased hemolysis and stimulation of lipid peroxidation and fluorescent production in the liver homogenate were observed. Elevated plasma alkaline phosphatase and GOT activities which may be considered to be due to a functional disorder of the liver were also observed.


Accelerating effect of 12-keto oleic acid on lipid peroxide and fluorescent productions in mouse liver homogenate.

12-Keto oleic acid is generally considered to be a secondary degradation product of peroxides produced by lipid peroxidation. The acid was added to a mouse liver homogenate or to a bovine serum albumin and its influences on lipid peroxidation and fluorescent production were investigated and compared with other acids. Just as with vitamin E deficiency, 12-keto oleic acid was shown to increase lipid peroxide formation and fluorescence productiod directly and indirectly. The increase of lipid peroxide formation was caused directly through the increase of the free radical production, and indirectly through change of the biomembrane structure. The fluorescence production increase was caused directly by reaction of the 12-keto oleic acid itself, and indirectly by acceleration of the lipid peroxidation.


Genetic determinants of morphological differentiation in a lymphoma-sarcoma hybrid.

Hybrid cells, YACIR/MSWBS were produced by fusion of the cells of a methylcholanthrene induced murine sarcoma MSWBS and a virus induced murine lymphoma YACIR. The hybrid cells were maintained in vitro and syngenic mice challenged at various periods after fusion. Karyological analysis has been performed on the cell line, and on the tumours which arose in vivo. The tumours were also examined histologically. Over the 2 yr following fusion there was a progressive loss of chromosomes but biarmed MSWBS derived chromosomes were selectively retained. Tumours could be divided into those whith a chromosome complement similar to that of the early line in vitro, those in which chromosome loss had occurred and those in which karyology showed a mixture of the two foregoing types. Histology showed a minority of sarcoma-like tumours reminiscent of MSWBS and the majority of these showed little chromsome loss. Most tumours showed an intermediate morphology and the great majority of these had lost moderate numbers of chromosomes. There was a very small number of lymphomatoid tumours in which chromosome loss was marked.


Effects of simple lipids on macrophages in vitro.

Tricaprin increase the rate of spreading of macrophages on glass. The treated cells showed increased pinocytosis and are avidly phagocytic. Cholesterol oleate delays the onset of phagocytosis which however proceeds efficiently once it has begun. Ethyl palmitate induces abnormal movement and the formation of unusual club shaped pseudopodia; ethyl palmitate prevents the ingestion of antibody coated erythrocytes and it is postulated that this substance interferes with the syntheses of IgG receptors.


An ultrastructural and biochemical study of hexachlorophane-induced fatty liver in sheep.

The administration of single or multiple oral doses of hexachlorophane to yearling sheep resulted in a periportal fatty liver. The accumulation of fat is accompanied by ultrastructural changes in the hepatocyte organelles, particularly the endoplasmic reticulum and Golgi apparatus, and by decreased serum lipid and triglyceride levels. It is suggested that an impairment in the triglyceride secretory mechanism of the liver cell may be the patho-physiological basis for fatty liver. However, the changes in the liver were not accompanied by an evidence of significant impairment of liver cell function.


The ultrastructure of the abnormal reticulum cells in Hodgkin's disease.

The ultrastructure of tissues from 23 cases of Hodgkin's disease is described. The atypical neoplastic reticulum cell or Hodgkin cell has several features that suggest that it is of macrophage lineage. Rings of small lymphocytes are found round the neoplastic reticulum cell; less often macrophage processes are found closely related to it. The features may be those of a lymphoreticular reaction to the neoplastic reticulum cells. The fibrosis may also represent a host reaction.


Haemorrhagic nasal polyps of the horse.

A series of 10 haemorrhagic polyps of the equine nasal cavity is described. The lesions show haematoma formation, abundant haemosiderin in macrophages and giant cells, and organising fibrous tissue. In one case, angiomatoid lesions were observed in the mucous membrane of the paranasal sinuses and it is suggested that some haemorrhagic nasal polyps may originate from pre-existing haemangiomatous areas in the respiratory mucosa.


Brown patches in the epididymis.

Brown patches were found in the head of the epididymis in 66 out of 100 consecutive male necropsies. They appear to be lesions due to local obstruction of ductuli efferentes by dehydrated semen. These common lesions are probably similar to origin to sperm granulomas, and might be significant in the origin of sperm auto-antibodies; their further study might help to elucidate some of the outstanding problems of male fertility.


Histological effects of lipids on the liver and spleen of mice.

Lipids administered by the intravenous route produced ultrastructural changes in the liver and spleen of mice. Treatment with tricaprin resulted in prominent and enlarged Kupffer cells possibly with increase numbers of dense bodies. Cholesterol oleate was found within Kupffer cells and splenic macrophages. The Kupffer cells were distended by lipid and obtruded on the sinusoidal lumen; similar changes were seen in the macrophages of the red pulp and marginal zone of the spleen. Cholesterol oleate delayed but did not prevent eventual phagocytosis or colloidal carbon; the spleen contained much more carbon than usual after treatment with this substance. Treatment with ethyl palmitate resulted in diminished retention of carbon in both liver and spleen; this lipid, unlike tricaprin or cholesterol oleate, was cytotoxic to both macrophages and lymphocytes.


Experimental bacterial endocarditis. IV. Structure and evolution of very early lesions.

The vegetations of experimental sterile and bacterial endocarditis in rabbits were studied using light, immunofluorescent and electron microscopy. At an early stage, both lesions were composed chiefly of masses of platelets supported in a scaffolding of fibrin strands. In previous studies, this structure has often been described merely as "fibrin". After i.v. injection of Thorotrast, sterile vegetations showed remarkable accumulations of mononuclear phagocytes containing this substance, on surfaces projecting into the bloodstream. Sections fixed 30 min. after i.v. injection of streptococci also showed these phagocytes, which contained large numbers of bacteria. The possibility that BE is initiated by phagocytosis of circulating bacteria has been raised. Smaller numbers of circulating streptococci reached the vegetation by direct adhesion to exposed surfaces. In contrast, a majority of Proteus and Staphylococcus albus adhered directly to vegetations, without phagocytosis. Subsequently, these first settlers multiplied rapidly to form rounded colonies surrounded by capsules of fibrin, which apparently provided protection from phagocytosis. The vegetations grew by accretion of layers of fibrin and platelets, with colonies sandwiched between them. This suggested that a cycle of thrombosis and reseeding by circulating bacteria was a factor in their growth. Colonies showed morphological changes consistent with ageing after two days. Healing occurred by endothelialisation and organisation, and was greatly accelerated by penicillin treatment.


An eosinophilotactic factor derived from rat mast cells.

Rat eosinophils have been showed to respond chemotactically to the supernatant from mast cells which have been disrupted by freezing and thawing and from mast cells which have been specifically degranulated by Compound 48/80 or by antigen challenge or sensitised cells. The fact that the chemotactic response is not dependent on allergic degranulation suggests that the chemotactic factor is present pre-formed in the mast cells rather than being generated in response to an antigen-antibody reaction.


An ultrastructural study of initial changes in epithelium damaged by surface freezing.

The changes seen in frozen thawed epithelium have been compared with pathological changes occurring under other circumstances. The intact cell membranes, invaginated cells, and varying densities of cell cytoplasm are all compatible with osmotic changes occurring after alteration in cell membrane permeability as is the development of bullae under these conditions. It is suggested, therefore, that this constitutes the major mechanism of cryosurgical attack at these temperatures. The finding that ultrastructural damage was evident very shortly after thawing, implicates changes directly due to freezing and thawing but does not necessarily rule out later additional cell damage occurring in an ischaemic situation.


Ultrastructural changes in muscle following freezing in situ by a surface applied cold probe.

Freezing of tissues under the conditions of cryosurgery resulted in changes in the muscles shortly after thawing occurred. The changes were progressive and included dilatation of mitochondria and sarcoplasmic reticulum, loss of glycogen, disruption of myofilaments and pyknotic changes in the nuclei. The progression of events is similar to other diseases of muscle but is structurally and chronologically unique. It does not appear to be typical of the early stages of ischaemia of muscle. It is suggested that the rapid onset of fibre damage following thawing is consistent with progressive alterations caused by ice-crystals at the time of freezing.


Light and electron microscopy studies on homograft and heterograft heart valves.

Light and electron microscopical changes were studied in 23 valvular homografts and six pig aortic heterografts, which had been inserted into patients for lengths of time varying from three days to 54 months. Prior to insertion, eleven of the homografts had been sterilised by beta-propriolactone and freeze-dried, the other twelve had been sterilised by gamma-radiation. The morphological changes in the freeze-dried group were characterised by moderate to severe structural changes including gross vacuolation, fibrinoid degeneration and calcification in the absence of any significant cellular events. It is concluded that the structural changes were due to physico-chemical degradation of the collagen due to improper preservation of the graft, prior to insertion. The morphological changes in the homografts treated with gamma-radiation were fewer and less severe in that there was less vacuolation of the matrix, less fibrinoid degeneration and no examples of calcification. Clear-cut examples of graft regeneration were never observed in either group, but the significance of minor cellular infiltrates in two of the gamma-irradiated grafts is discussed in terms of abortive regeneration. The heterografts showed moderate to intense cellularity, predominantly of macrophages. It is postulated that graft rejection phenomena are responsible for the graft failure in this group.


Diet-induced aortic atherosclerosis in Malaysian long-tailed monkeys (Macaca irus).

Moderate hypercholesterolaemia has been produced in eight adult male M. irus monkeys by feeding an egg-toast preparation containing butter and 0.14 per cent. total cholesterol. At autopsy, after two to four years of persistent hypercholesterolaemia, there was massive fatty streaking of the aorta involving 21 to 78 per cent. of the intimal surface. The distribution and morphology of the fatty streaks was similar to that in man. In addition, there were fibrous plaques including "soft" lipid-rich atherosclerotic plaques identical to their human counterpart. There was no grossly detectable thromobosis, haemorrhage or ulceration. Atherosclerotic lesions were also present in the coronary, carotid, subclavian, iliac and femoral arteries. In a control group of monkeys fed a low-fat, cholesterol-free diet, arterial lesions were identical in type and extent to those in freshly captured wild monkeys.


Rhabdomyoma of the vagina.

A case of rhabdomyoma of the vagina in a 47-year-old woman is reported. This newly recognised entity is distinct from sarcoma botryoides and the socalled "benign vaginal polyp".


Amprolium poisoning of preruminant lambs: an investigation of the encephalopathy and the haemorrhagic and diarrhoeic syndromes.

An experiment was conducted to investigate the mechanisms responsible for the brain lesions, diarrhoea and haemorrhages produced by amprolium poisoning of preruminant lambs. The encephalopathy was preceded by a reduction of cerebrocortical transketolase activity. Diarrhoea was not associated with histological evidence of pathological change in the small intestine, and in lambs with severe diarrhoea the small intestinal levels of alkaline phosphatase and lactase were unaffected. Haemorrhages were associated with a thrombocytopenia which was attributed to degeneration of bone marrow megakaryocytes. The bone marrow of the majority of the lambs which had received amprolium for 3 wk or more was severely depopulated, erythrocyte precursors being the most severely affected. The marrow depopulation was atrributed to decreased cell production, as the majority of the remaining cells showed little evidence of degeneration and the number of mitotic figures in the marrow of amprolium-treated lambs was considerably reduced as compared with the controls.


Transfusional iron overload: the relationship between tissue iron concentration and hepatic fibrosis in thalassaemia.

The interrelationships between liver iron concentration, the duration of iron-loading, and hepatic fibrosis, assessed morphometrically, have been studied in 32 specimens of liver obtained from 19 heavily transfused patients with thalassaemia major whose age ranged from 4 to 19 yr. Similar observations were made in a matched group of thalassaemic patients treated with long-term chelation therapy. The degree of liver damage ranged from very slight increase in fibrous tissue to severe fibrosis and cirrhosis. The severity of the fibrosis was closely correlated both with liver iron concentration and with age. While the relationship between fibrosis and age was linear, both the severity and the rate of fibrosis were exponentially related to liver iron concentration, damage accelerating as liver iron concentration exceeded 3 per cent, dry weight. By producing a modest but significant reduction in liver iron concentration chelation therapy resulted in a disproportionate but predictable retardation in the progression of the fibrosis. The factors affecting the distribution of iron between parenchymal and reticuloendothelial cells were also examined. In general stainable iron was uniformly distributed between parenchymal and reticuloendothelial cells from the early stages of iron-loading. Parenchymal siderosis was relatively heavier in splenectomised patients and in patients with liver iron concentrations above 3 per cent, dry weight than in non-splenectomised patients or patients with liver iron levels of less than 3 per cent, dry weight, but this did not affect the severity of the fibrosis. The relevance of these findings to the traditional concepts of the pathology of transfusional siderosis is discussed.


Extramedullary plasmacytoma of the breast.

The clinical and histopathological features of a case of solitary extramedullary plasmacytoma of the breast are described. After 46 mth of follow-up, there has been no recurrence of the tumour, and no evidence of further extramedullary plasmacytomas, multiple myeloma or diffuse myelomatosis either clinically, radiologically or on biochemical and haematological investigations. She has developed diabetes mellitus. Distinction is made between the true extramedullary plasmacytoma and those which are a manifestation of multiple myeloma. The unpredictable behaviour and prognosis of extramedullary plasmacytomas is indicated.


An investigation of recurrent pine oil poisoning in an infant by the use of gas chromatographic-mass spectrometric methods.

An 18-month-old infant required six hospital admissions in a period of six months for episodes consisting of coughing, respiratory depression, hematemesis, coma, dehydration, and lesions about the mouth. A negative history of ingestion of toxins was repeatedly obtained from the family and two home inspection by the local Health Department failed to identify potential toxins. Metabolic work-up was entirely negative. Utilizing methods of GC-MS, metabolites of a-terpineol were isolated from infant urine on two admissions to the hospital. These metabolites were confirmed by mass spectrometry to be the same metabolites excreted by Sprague-Dawley rats injected with a-terpineol or pine oil. The child had no additional episodes after physical separation from the home environment.


Fenfluramine poisoning.

Fenfluramine is a substituted phenylethylamine structurally related to amphetamine. Within three hours following the ingestion of 1,600 mg of fenfluramine, a 17-year-old girl, who was initially agitated and had tachycardia, developed convulsions, cardiac arrhythmia, and cardiorespiratory arrest. In previously reported cases, flushing, sweating, mydriasis, tachycardia, and agitation commonly occur, as well as convulsions and abrupt cardiorespiratory arrest. The rapid onset and progression of symptoms, the short interval between ingestion and death, and the lack of responsiveness to resuscitative measures are common findings in fatal cases.


Melioidosis in childhood.

Two cases of childhood melioidosis in conjunction with five from the literature are presented. Although most reported cases come from Southeast Asia, importation into the United States by travelers and military personnel has occurred. The course of the disease may be acute or chronic; the onset is generally with fever and pneumonia. Melioidosis should be considered in any patient with pneumonia who has returned recently from an endemic area.


U-shaped palatal defect in the Robin anomalad: developmental and clinical relevance.

The palatal defect in patients with the Robin anomalad was found to be U shaped. This finding is compatible with the hypothesis that the underlying dysmorphic event is usually early mandibular hypoplasia with secondary extrinsic obstruction of palatal closure by a posteriorly displaced tongue. The more common V-shaped defects of palate closure arise by a different mechanism. Unfortunately, available recurrence risk data for cleft palate do not allow for this distinction. Furthermore, physicians should be alert for instances in which the Robin anomalad is but one feature of a broader pattern of malformation. In the current study, 25% of the 28 patients ascertained as having the Robin anomalad had a recognizable syndrome for which specific, but varying, genetic counsel was indicated.


Rennes-like variant of galactosemia: clinical and biochemical studies.

The first recognized case of a Rennes-like variant form of galactosemia in a Caucasian individual is described. Galactose-1-phosphate uridyl transferase activity was approximately 10% of the normal in both erythrocytes and cultured skin fibroblasts. Electrophoretic mobility of the variant enzyme in erythrocytes was slower than that of normal individuals and identical to that of the two cases originally reported from Rennes, France. In normal cultured skin fibroblasts, four transferase bands were found. In this tissue, the patient again had a slower moving transferase. It is proposed that in transferase variants an altered subunit results in a specifically altered enzyme mobility analogous for each tissue.


Slow tremor and macrocephaly: expanded version of the bobble-head doll syndrome.

The clinical features of three children in whom a slow tremor involving the head, trunk, or limbs was associated with macrocephaly are presented. The findings were similar but not identical to those previously reported in four children with the bobble-head doll syndrome. These seven children have many of the signs and symptoms found in patients with surgically or spontaneously arrested hydrocephalus, including motor incoordination, behavior and psychologic deviations, and endocrine dysfunction. The tremor which can be voluntarily inhibited and which disappears following shunt surgery, is unique. The theoretical basis for the tremor is briefly discussed.


Ionized calcium: serum levels during symptomatic hypocalcemia.

The concentration (activity) of ionized calcium in serum [Ca-++] was measured in nine patients with symptomatic hypocalcemia of diverse etiology. In all nine patients the [Ca-++] was smaller than or equal to 2.50 mg/dl. No significant correlation was found between the [Ca-++] and serum levels of either total calcium or phosphate. Use of the McLean-Hastings nomogram failed to reveal any significant statistical correlation between the predicted [Ca-++] values and those actually measured. These data indicate that: (1) symptomatic hypocalcemia occurs when levels of ionized calcium in serum fall near or below a critical threshold concentration of 2.50 mg/dl and (2) the [Ca-++] must be measured directly to confirm the clinical impression of hypocalcemia.


Hiatal hernia in infants and young children: a 2- to 3-year follow-up study.

Nine children were evaluated two to three years after institution of either medical or surgical management of their hiatal herniae. Four children treated medically ranged from 6 to 16 months of age. There were clinically cured of symptoms and one clinically improved, indicating the efficacy of medical management in some young children. The fifth medically treated child, age 10 years, was also clinically improved. Four children initially had surgical hiatal hernia repair: one (16 days old) because of pulmonary aspiration with associated cardiorespiratory arrest, two (ages 3 and 6 years) because medical management failed, and one (age 7 years) who presented with an esophageal stricture. Surgery for hiatal herniae in children should be reserved for patients in whom medical management has failed or for patients with serious complications.


Effects of starvation in infancy (pyloric stenosis) on subsequent learning abilities.

The model of starvation in this study was the medical condition of congenital hypertrophic pyloric stenosis. Pyloric stenosis involves a period of brief starvation in early infancy, is unrelated to socioeconomic conditions, and is easily correctable. A number of specific learning abilities together with the general adjustment of 50 subjects, 5 to 14 years old, who had PS were studied and compared to those of 44 siblings and 50 matched controls. Learning ability was negatively correlated with the degree of severity of the starvation. Starvation resulting in reduction of more than 10% of the expected body weight in infancy was associated with poorer learning abilities, especially those involving short-term memory and attention.


Histiocytosis x--an analysis of prognostic factors.

A retrospective analysis of data garnered from the study of 83 patients with histiocytosis X suggests that evaluation of the function of certain organs and the histologic appearance of the lesions may be quite valuable in determining the prognosis and treatment of affected patients.


Nephrosonography in the evaluation of renal failure and masses in infants.

The diagnostic accuracy of nephrosonography is compared with conventional radiologic techniques and surgical findings in 13 infants aged 1 day to 14 months, who were in renal failure or had abdominal masses. Ten of the 13 infants presented with marked renal failure and in half of them neither kidneys nor collecting systems were visualized on the first intravenous pyelogram. Normal renal architecture was demonstrated by nephrosonography in three, hypoplastic kidneys in three, hydronephrosis in three, and a combination of hydronephrosis and contralateral multicystic kidney in one. In the three infants without renal failure, only one kidney was demonstrated by IVP; The cystic contralateral kidney in each of them was demonstrated by nephrosonography. In all cases the diagnosis was confirmed by conventional radiologic techniques when renal function had improved or by surgical exploration. This technique appears to be a useful adjunct to conventional radiography in the differential diagnosis of the infant with abnormalities of the urinary tract. Nephrosonography is of especial value when a kidney is not visualized by IVP, and it may appropriately aid in therapeutic decisions regarding the use of invasive procedures in small critically ill infants.


The renal lesion of the Laurence-Moon-Biedl syndrome.

In nine children with the Laurence-Moon-Biedl syndrome a high incidence of nephropathy was documented. Renal involvement was noted in seven patients before or simultaneously with the diagnosis of LMBS. Five have uremia and two have died. All patients had an abnormal urogrum. The spectrum of renal lesions ranged from mesangial tissue proliferation to glomerular clerosis, interstitial scarring, and medullary and cortical cyst formation. A relationship between the lesions seen in the LMBS and those of other hereditary retinal-renal conditions is suggested.


Glomerular filtration rate in the first three weeks of life.

Clearances of inulin and para-aminohippuric acid were performed in 22 newborn infants without renal disease. Ages varied from 12 hours to 25 days. The mean values of inulin and PAH clearances during the first four days of life were 10.8 +/- 1.0 ml/min/m2 and 30.8 +/- ml/min/m2, respectively. A twofold increase in glomerular filtration rate was observed during the first 14 days of life. A similar increase in PAH clearance occurred during this period. No correlation was found between gestational age (range: 32 to 39 weeks) and GFR in ten neonates studied during the first four days after birth.


Percutaneous catheterization of the radial artery in the critically ill neonate.

Percutaneous catheterization of the radial artery appears to be a simple and safe alternative to catheterization of the umbilical artery for monitoring critically ill neonates. This avoids the serious and potentially fatal complications associated with use of the umbilical arterial catheter, and it is also applicable to monitoring of neonates in whom the umbilical artery is no longer patent. We observed no serious sequelae in cannulation of the radial artery and think that the technique should be used more widely.


A short-term intensive training program for pediatric nurse practitioners.

A pediatric nurse practitioner course has been described in which 30 nurse trainees spent six seeks in an intensive training program followed by six months of preceptorship with a pediatrician in their own agency. This short but intensive program had advantages of permitting the PNP student to retain her health care agency position during the intensive part of the program and of assuring her a position as a PNP once the course was completed. Evaluation of the students by written and practical examinations indicated that they had made significant gains in their knowledge and understanding of pediatrics and in their ability to evaluate and refer patients and to provide well-child care and maternal counseling.


Sex differences in the eyes of expert personality assessors: unwarranted conclusions.

In a recent paper, Haan and Livson reported sex differences between male and female psychologists in their evaluations of adult men and adult women. Their conclusions have implication for the validity of clinical assessments and were interpreted in terms of stereotypic sex role perceptions. However, their statistical analysis was in fundamental error. When the data they employed were reanalyzed, no reliable sex differences between men and women psychologists were found, a finding in accord with a number of previous investigations of this problem.


An effect on Rorschach M responses of a boy's relationship with his mother.

This paper is concerned with testing the hypothesis that children who have good relationships with their parents will more often give M responses to the Rorschach than will children whose relationships with their parents are not good. The sample consisted of 20 boys who were divided into two groups according to the number of their M responses. Their relations with their parents were tested by the Family Relations Test. The results supported only the hypothesis with regard to the boys' relationships with their mothers. This seems to indicate that the ability to make M responses develops at an early age when the relationship with mother is overwhelming importance.


Further studies of a measure of adience-abience: reliability.

Previous studies have suggested adequate reliability for a measure of perceptual adience-abience based on the HABGT in view of significant evidence concerning its construct and predictive validity. The present study explored the test-retest reliability of this scale with 40 process schizophrenics over a two-week interval. Reliability was found to be adequate for both males and females (rho equals .84) for the total scale. The four components of the scale were similarly found to be reliable. No subject changed on retest with respect to adient or abient orientation. Interjudge reliability was very high (rho = .912).


Psychopathology scale of the Hutt adaptation of the Bender-Gestalt Test: reliability.

The test-retest reliability of the Hutt Adaptation of the Bender-Gestalt test was explored with a population of 40 process schizophrenics over a two-week interval. The total Psychopathology Scale Score was found to have high retest reliability for both male and female patients (rho = .87 for males and .83 for females). Moreover the three major components for the Scale were found to have high reliability, and fairly high reliabilities were obtained for patients scoring high as well as low on the Scale. Interjudge reliability was also found to be very high (rho = .895), confirming previous studies in this respect. On these grounds, the Scale offers promise both for clinical and research purposes.


Race and the differential "power" of the MMPI.

The interpretation that blacks' tendency to score higher on MMPI clinical scales is due to educational deprivation has been challenged by research in which, when educatation was held constant, race-related differences remained. Racial differences in type of psychopathology have seldom been controlled in part research. After establishing that a grester proportion of black psychiatric patients may receive a schizophrenic diagnosis (Study 1), MMPI protocols of black and white schizophrenic and nonschizophrenic psychiatric patients were obtained. All patients had received 12 or more years of education. Schizophrenics scored significantly higher on the MMPI F and Sc scales and nonschizophrenics tended to score higher on Pd. No race-related differences were observed on any of the 11 MMPI scales considered.


Utility of the Mini-Mult with parents of emotionally disturbed children.

In order to determine the potential usefulness of the Mini-Mult as a screening instrument with parents of emotionally disturbed children, two studies were conducted. In the first study 128 MMPI profiles were rescored for the Mini-Mult and comparisons with MMPI were made. In the second study 50 parents were administered both the MMPI and the Mini-Mult. Results of both studies indicate that the Mini-Mult is not a good screening instrument with parents of emotionally disturbed children.


Birth order and a two-dimensional assessment of personality.

Higher order personality dimensions of extraversion-introversion and neuroticism were studied as functions of birth order in two-sib families, using 141 female subjects, with control over sex of sibling and sib age separation. No significant personality dimension variance was attributable to birth order in females. The results were considered briefly in terms of the importance of birth order, heritability questions, and the possible contribution of birth order to lower order traits.


Schizophrenic performance on form E of Cattell's 16PF test.

Form E of Cattell's 16PF test was administered to 515 hospitalized schizophrenics. This sample was compared to Cattell's standardization population for both raw scores and sten scores. Comparisons were made between males and females, acute patients and chronic patients, and amongst three categories of schizophrenia (paranoid, undifferentiated, schizo-affectives). The results indicate that the "schizophrenic profile," reported in previous research with Form A, did not obtain expected differentiations among schizophrenic categories. The question of the usefulness of Form E in diagnosing schizophrenia was raised.


Leader esteem for the least preferred co-worker score, training, and effectiveness: an experimental examination.

A laboratory experiment supported Fiedler's Contingency Model analysis of leadership training. The effect of leadership training on group performance was contingent on leadership style, that is, the leader's relation to his least preferred co-worker (LPC). Training improved the performance of high LPC leaders, but was detrimental to the performance of groups with low LPC leaders. High intelligence leaders profited more from training than low intelligence leaders, but low intelligence leaders were more productive overall. Leader LPC times Intelligence interactions indicated that follower satisfaction and interpersonal affect were highest for groups with high LPC-low intelligence leaders or low LPC-high intelligence leaders. Implications for contingency theories of leadership are discussed.


Attribution versus persuasion as a means for modifying behavior.

The present research compared the relative effectiveness of an attribution strategy with a persuasion strategy in changing behavior. Study 1 attempted to teach fifth graders not to litter and to clean up after others. An attribution group was repeatedly told that they were neat and tidy people, a persuasion group was repeatedly told that they should be neat and tidy, and a control group received no treatment. Attribution proved considerably more effective in modifying behavior. Study 2 tried to discover whether similar effects would hold for a more central aspect of school performance, math achievement and self-esteem, and whether an attribution of ability would be as effective as an attribution of motivation. Repeatedly attributing to second graders either the ability or the motivation to do well in math proved more effective than comparable persuasion or no-treatment control groups, although a group receiving straight reinforcement for math problem-solving behavior also did well. It is suggested that persuasion often suffers because it involves a negative attribution (a person should be what he is not), while attribution generally gains because it disguises persuasive intent.


Defensive externality and its relation to academic performance.

This study examined the relationship between locus of control and academic performance by evaluating the academic achievement of defensive externals, which has been considered a confounding factor in previous research. A further objective was an examination of the effect of two mediating variables in their relation to locus of control and academic performance. One hundred sixty college students were administered the Internal, Powerful Others, and Chance scales, the Fear of Negative Evaluation scale, and the Achievement via Independence/via Conformance scales. Obtained results demonstrated that internals were academically superior to both defensive and congruent externals. Defensive externals were shown to have higher grade point averages than congruent externals, and female defensive externals achieved greater academic success than their male counterparts. Further results suggested that the relationship between locus of control and academic performance may not be a direct one but may be modified by specific mediating variables.


. . . And some men have leadership thrust upon them.

Viewing leadership behavior as a joint function of situational factors, individual predispositions, and followers' responsive behavior, this study used 64 subjects, half of them high and half of them low in measured leadership self-concept. Half had a high and half a low stake in a group task. Each subject was twice appointed leader of a three-man group, once exposed to "followers" (experimenter's condederates,) altercasting him to lead, once to followers alter-casting him to follow. Multivariate analyses of variance showed effects of followers' behavior on profiles of a subject's behavior (when subjects were pushed to lead they led, when pushed to follow they increased socioemotional activity) and perceptions of followers. These effects were specified by leadership self-concept (little difference between groups when confronting pushy followers, more when confronting passive ones), prompting an interpretation in terms of role incongruity.


Witnessed aggression: influence of an observer's sex and values on aggressive responding.

Two experiments investigated the effects of the presence of an observer on aggressive responding. In one experiment, male subjects observed by a male aggressed more than those observed by a female. When the male observer was removed from the situation, subjects' level of aggressiveness more closely matched the level manifested by the opponent. The removal of the female observer had little effect on the subjects' behavior. In the second experiment, the male or female observer of the subject's behavior was disguised as a member of an organization with explicit values (aggressive or pacifistic) regarding the use of aggression. In this case, significant differences in aggression were associated with the observer's values but not the observer's sex. Following the departure of the observer, the shock settings of subjects in the two aggressive-value observer groups showed a signifcant decrease. The average shock setting of subjects in the two pacifistic-value observer groups remained at about the same level. In sum, the results indicated that the subjects' aggressive behavior was apparently a function of their expectations of approval for such behavior, based on the inferred or explicit values of the observer. The results were further discussed in terms of social learning theory.


Involvement in everyday imaginative activities, attitudes toward hypnosis, and hypnotic suggestibility.

One hundred male and 83 female subjects were assessed on absorption (i.e., involvement in everyday imaginative activities), attitudes toward hypnosis, and hypnotic suggestibility. Significant positive correlations were obtained for both sexes between absorption and attitudes and between each of these variables and hypnotic suggestibility. Multiple regression analyses indicated that most of the predicted variance in hypnotic suggestibility scores was accounted for in both sexes by the absorption variable.


Elimination rate of N-acetylprocainamide after a single intravenous dose of procainamide hydrochloride in man.

Equations were derived which made it possible to determine the elimination rate of N-acetylprocainamide from urinary data after intravenous administration of procainamide hydrochloride. A single dose of 500 mg of the drug was infused intravenously in four healthy subjects. On the basis of theose equations, the formation rate of the metabolite could be calculated presuming that all rate processes were occurring by first-order processes. However, close examination of the excretion rate data appears to support the contention that the formation or excretion of N-acetylprocainamide may be occurring by a saturable process


Rational development of a soluble prodrug of a cytotoxic nucleoside: preparation and properties of arabinosyladenine 5'-formate.

The 5'-O-formate ester of arabinosyladenine was synthesized and shown to be suitable as a water-soluble prodrug, being at least 60 times more soluble than the parent cytotoxic nucleoside. This increased solubility was ascribed to a decrease in intermolecular interaction in the crystalline state, as evidenced by an similar 90 degrees lower melting point for the ester relative to the parent compound. The prodrug reverted to the parent compound in aqueous solution, its pH-rate profile being V-shaped with maximum stability at a pH similar 4.2, corresponding to a half-life of about 10 days. The rate of hydrolysis of the prodrug at 37degrees in 91% human serum and 91% whole blood was studied. At an initial concentration of 0.4 mg of prodrug/ml of 91% whole blood, reversion to arabinosyladenine appeared to be essentially complete in about 15 min. The prodrug did not appear to be subject to enzymatic deamination. This feature, together with the good solubility of the prodrug, makes possible the effective formulation of arabinosyladenine for intravenous purposes. The rationale involved in the general design of a prodrug and the specific considerations necessitated in the case of adenine arabinoside are discussed.


Assay for acetazolamide in plasma.

A method for the analysis of acetazolamide, 5-acetamido-1,3,4-thiadiazole-2-sulfonamide, sensitive to 25 ng/ml in plasma, was developed. After extraction of acetazolamide and its propionyl analog, 5-propionamido-1,3,4-thiadiazole-2-sulfonamide, the internal standard, from plasma with ethyl acetate and removal of lipids from the residue of the ethyl acetate extract with methylene chloride, the sulfonamides were chromatographed on an octadecyl trichlorosilane bonded phase using high-pressure liquid chromatography. The method was developed to study plasma level profiles of different dosage forms of acetazolamide.


Absorption of metrizamide from cereb rospinal fluid to blood: pharmacokinetics in humans.

The rate of transfer of contrast agents from cerebrospinal fluid to blood is of clinical importance in radiological examinations of the subarachnoid space. Metrizamide, a potential contrast medium, was injected intrathecally to humans and serum levels at different times after injection were measured. A one-compartment open model was found to apply to the data. Considerable individual variations were found, but the mean absorption rate constant indicated that more than 50% of the absorbed dose had disappeared from the cerebrospinal fluid 0.75 hr after injection. TLC of the fraction excreted in the urine showed that metrizamide was not metabolized in the body.


Nature of anionic or alpha-site of cholinesterase.

The nature of the so-called anionic binding site of acetylcholinesterase was investigated using a technique called receptor mapping using model interaction calculations. The results support the suggestion that coulombic forces play only a minor role in the binding event at this enzyme site.


Microbiological determination of drug partitioning. IV. Drug-protein interactions.

The protein binding characteristics of chloramphenicol, furazolium chloride, benzalkonium chloride, and phenylmercuric nitrate were described from their partitioning behavior in gelatin-acacia complex coacervate systems. Although the partitioning was determined by two different methods (microbiological and chemical), the microbiological method was more reliable for this type of investigation. Drug-protein parameters were calculated for the four antimicrobials. The advantages of the coacervate systems over other models for protein binding studies of drugs are discussed.


Quantitation of propoxyphene and its major metabolites in heroin addict plasma after large dose administration of propoxyphene napsylate.

A sensitive and specific GLC assay method was developed for the determination of propoxyphene, its major metabolite norpropoxyphene, and lesser known metabolites cyclic dinorpropoxyphene and/or dinorpropoxyphene in plasma of heroin addicts administered up to 800 mg of propoxyphene napsylate. The assay used a mass internal standard of pyrroliphene. The compounds were extracted from pH 9.8 carbonate-buffered plasma with butyl chloride, back-extracted into acidified water which was then washed with hexane, and reextracted with chloroform from the aqueous phase made basic. Quantitation of the drug and its metabolites was accomplished by temperature-programmed GLC. Absolute identification of the compounds chromatographed was completed by GLC-mass spectrometry.


Intersubject variation in absorption of digoxin in normal volunteers.

The absorption of oral digoxin preparations was evaluated following single-dose administration of 0.5 mg of digoxin to 16 normal volunteers in a randomized crossover design. Absorption was estimated using the cumulative excretion of digoxin in urine for 7 days and the area under the 24-hr serum digoxin concentration curve (AUC). Significant intersubject variability was observed with both parameters, but this variability was greater for the AUC. After intravenous administration, the 7-day digoxin excretion was 68% of the dose. The elixir and a rapid dissolution tablet were significantly better absorbed (84.5 and 77.8%, respectively) than was a slow dissolution tablet (66.7%), as reflected by the fraction of the amount excreted in the urine following intravenous administration of the same dose. There was a highly significant correlation between the cumulative digoxin excretion in urine during the first 2 days compared to 7 days (r = +0.972,p less than 0.001). Bioavailability of oral digoxin preparations can be reliably determined by comparison of the cumulative 2-day excretion of digoxin following a single dose.


Alcoholysis of medicinally active 5-aminodibenzo(a,d)cycloheptenes.

The rate constants for alcoholic solvolysis of the hydrochloride salts of diethylaminodibenzo(a,d)cycloheptene and related amino congeners were determined. The objective was a study of the comparative ease of cleavage of the C-N amino linkage by various aliphatic alcohols. The interaction of protonated amines of this series with alcoholic hydroxyls presumably leads to formation of the corresponding ethers in a manner somewhat analogous to alkoxide reaction with alkyl bromides. The methyl ether produced from solvolysis of diethylaminodibenzocycloheptene hydrochloride was isolated and identified. Methanol appears to react somewhat more rapidly with the amine hydrochlorides than other aliphatic alcohols. The latter produce almost invariant velocity constants with a given amine hydrochloride. The exception was tertbutanol, which resulted in Kobs values about one-third of those given by the other alcohols. Some velocity constants in formic and acetic acids were evaluated. Generation of carbonium ions of appreciable lifetime was indicated in formic acid by the formation of a highly colored (red-violet) solution. This color may be a manifestation of the dibenzotropylium ion.


Combined assay, identification, and foreign related steroids test for methandrostenolone by high-speed liquid chromatography.

A high-speed liquid chromatographic system is described, which can be used for the simultaneous identification of the anabolic steroid methandrostenolone and its impurities and the quantitation of each of these compounds. Separation is effected by adsorption chromatography on a slurry-packed microparticulate silica gel column.


Effect of compaction on particle size.

Compressed tablets were prepared on a hydraulic press at several different compaction pressures by a standardized technique, using aspirin, dicalcium phosphate dihydrate, calcium phosphato-carbonate, alumina, and microcrystalline cellulose. All tablets except microcrystalline cellulose contained a cation-exchange resin as disintegrant. The particle-size spectra of the disintegrating compacts were evaluated using a particle-size counter or an air jet sieve. It is shown that compacts made from different materials but of the same initial particle-size spectra disintegrate to give particles of a considerably different size. Determination of the change in particle size produced by the compaction process provides useful insight into the nature of the compaction process.


Water-sorption properties of tablet disintegrants.

The water-sorption properties of four tablet disintegrants, starch, sodium carboxymethylcellulose, sodium starch glycolate, and a cation-exchange resin, were examined in the form of powders and in compressed tablets prepared from calcium phosphate dibasic dihydrate. Dissolution properties of the tablets compare well to the water-sorption properties. The effect of storage in the presence of water vapor upon tablets containing the various disintegrants was evaluated in terms of tablet hardness and disintegration time. Differences in the effects produced in the various tablet formulations can be related to the differing mechanisms whereby the disintegrants effect tablet rupture. Photomicrographic data support the conclusions drawn from the water-sorption, disintegration, and dissolution studies. Sodium starch glycolate and the cation-exchange resin merit careful consideration by formulators using calcium phosphate dibasic dihydrate or similar direct compression matrixes.


Effects of cyproterone acetate on uterine motility in rats.

The effect of cyproterone acetate, an antiandrogen, on uterine contractility when the compound is administered to rats during midpregnancy was investigated. Pregnant Wistar rats were given cyproterone acetate subcutaneously on Days 8-11 of gestation. The results indicate that cyproterone acetate, either directly or indirectly, inhibits uterine contractility, an effect that may explain the prolongation of the gestational period observed in all treated animals.


Anticonvulsant activity of N,N'-bis[3-(3-substituted urea)propyl]piperazines.

Several N,N'-bis[3-(3-substituted urea)propyl]piperazines were synthesized and characterized by their sharp melting points, elemental analyses, and IR spectra. All substituted piperazines were found to possess anticonvulsant activity, which was reflected by 20-70% protection observed against pentylenetetrazol-induced seizures in mice. Some of these compounds inhibited oxidation of pyruvic acid by rat brain homogenate. No correlation could be observed between the anticonvulsant activity possessed by these substituted piperazines and their ability to inhibit the oxidation of pyruvic acid.


Drug-biomolecule interactions: mechanisms and kinetics of interactions of biomolecules at interfaces.

At the air-water interface, the area occupied by the molecules of each component of mixed monomolecular layers of cholesterol with hexadecyl alcohol, hexadecylic acid, or hexadecylamine was independent of the presence of the other component. The values of the free energy of mixing of these lipids were within the range of the entropic factor of the free energy even at high surface pressures. Mixed monolayers of cholesterol and bovine serum albumin showed a similar independence of the area per molecule and of the free energy of mixing values when the concentration of the protein was expressed in terms of amino acid residues per molecule of protein forming the mixed monolayer. Higher values of the free energy of mixing were obtained for mixed monolayers of cholesterol with dipalmitoyl lecithin and dipalmitoyl phosphatidylethanolamine than were expected from an entropic factor. The interaction between monomolecular layers of lipidic biomolecules with bulk subphase components, the energy of activation, interaction kinetics, and effects of added electrolytes were also studied. The implications of these data to a mechanism of action are discussed.


Drugs-biomolecule interactions: binding study of substrate and inhibitors to acetylcholinesterase using NMR.

NMR was used to study the binding of acetylcholine, atropine, and physostigmine to acetylcholinesterase. Changes in the linewidth of the N-methyl resonance of acetylcholine, resulting from association with the enzyme during hydrolysis, were utilized to study the enzyme-substrate interaction. Physostigmine inhibited the binding of the substrate while atropine accelerated substrate hydrolysis without interfering with its binding. The dissociation constant, KD and the linewidth of the acetylcholinesterase-inhibitor complex, increment v bound, for atropine and physostigmine can be estimated from the linewidth changes of the N-methyl and phenyl group resonances of atropine and from the N-methyl and C-methyl group resonances of physostigmine resulting from association with the enzyme. The results indicate that there is at least one binding site on the enzyme surface for atropine and one for physostigmine. Further evidence that the two sites are distinct is indicated by the fact that gallamine displaces atropine from its site without competing with physostigmine.


Release of corticoids from oleaginous ointment bases containing drug in suspension.

Simplified methods for studying the release of drugs suspended in oleaginous ointment bases were developed. These procedures were used in studying the release rates of two corticoids, fluocinonide and flucloronide, from white petrolatum and petrolatum containing various adjuvants. A practical method for measuring drug solubilities was developed and used in determining solubilities of these corticoids in ointment bases. When using physical data obtained from model ointments, the release rates of drugs from modified ointment bases were predicted. Comparisons of the observed and predicted rates from ointments containing hydrophobic adjuvants indicated the usefulness of the physical model approach in predicting the release rates. For ointments containing emulsifying agents, the simple model used did not provide useful predictions.


Comparison of analgesic effects of isosteric variations of salicylic acid and aspirin (acetylasalicylic acid).

A reliable and sensitive method was used to compare the analgesic activities of salicylic acid and aspirin (acetylsalicylic acid) and several phenoxy substituted isosteric pairs. Those isosteric compounds studied did not show analgesic activity. The analgesic activity of aspirin was more than twofold greater than that of salicylic acid.


Fluorocarbon aerosol propellants IV: pharmacokinetics of trichloromonofluoromethane following single and multiple dosing in dogs.

An intravenous dosage form of trichloromonofluoromethane, a common aerosol propellant, was formulated in polyethylene glycol 400 for single and multiple dosing to unanesthetized dogs. A three-compartment open model was proposed for disposition of this compound in dogs with average half-lives of 3.2, 16, and 93 min for three disposition phases. This finding is contrary to several reports where blood levels were monitored for shorter periods. A computer analysis of tissue compartment distribution following a single dose showed that about 2 hr was required to achieve pseudodistribution equilibration, following which more than 90% of the dose remaining in the body was retained in tissue compartments. Pulmonary clearance and volumes of distribution were calculated considering first-pass effect through the lung. The volume of distribution was approximately six times the body weight in terms of blood concentrations, and about 30% of the propellant was cleared from blood passing through the lung in each cycle. Disposition of propellant followed dose-independent kinetics after multiple dosing, and accumulation in tissues continued for a much longer period, resulting in high tissue compartment levels.


Theoretical considerations on mononuclear aggregations of mixed nucleosides in dilute aqueous solutions based upon osmometric measurements.

A theory is presented based on experimental work reporting shifts in the critical micelle-like concentrations of nucleosides and caffeine. An increase in these concentrations by multiple integers (called complexing capacity numbers) of the concentration of the vehicle compound, whose concentration was fixed, was observed for substances that tend to form complexes with each other and with some other compounds and to self-associate as well when their concentrations are varied. The physical model presented assumes the significance of the potential hydrogen bonding sites in determining the mode of aggregation as well as the magnitude of these complexing capacity numbers. This assumption was verified experimentally when reducing the hydrogen bonding by using 1,3-dimethyluracil. The mathematical model hypothesized has provided a means for calculating equilibrium constants for various consecutive processes as well as other quantities of theoretical interest.


Ketonitrophenols from mestranol and related compounds.

Mestranol (17alpha-ethynylestradiol 3-methyl ether), when placed on a carrier such as powdered silica gel and exposed to the atmosphere, is converted to a yellow product. The compound formed was shown to be 1alpha-ethynyltetrahydro-1beta-hydroxy4 - (2 - hydroxy - 5 - methoxy - 3 - nitrophenethyl) - 7a - methyl-5(4H)-indanone. The 3-methyl ethers of three other steroids having aromatic A rings yielded products of a similar type. Identical compounds were prepared from the respective steroids by treatment with nitrating agents in acetic acid. This reaction in acetic acid is light catalyzed. An independent synthesis of a model compound, 6-(2-hydroxy-5-methoxy-3-nitrophenyl)-3-hexanone, established the position of the constituents on the aromatic ring as well as the location of the carbonyl. The mechanism proposed for the formation of these products is an initial oxidation of the 1-substituted tetralin to form a hydroperoxide, which is ionically decomposed to form a ketophenol. The phenol is then nitrated in the ortho-position.


Bioavailability of micronized griseofulvin from corn oil-in-water emulsion, aqueous suspension, and commercial tablet dosage forms in humans.

The purposes of this investigation were to determine and to compare the oral absorption characteristics of micronized griseofulvin (500 mg) after its administration to humans in the form of a corn oil-in-water emulsion containing dispersed drug, an aqueous suspension, and two different commercial tablets (A and B). The four dosage forms were administered in a random crossover fashion to five fasting subjects, and drug absorption was assessed from urinary excretion data for the major metabolite of the antibiotic (6-desmethylgriseofulvin). The drug was most rapidly, uniformly, and completely absorbed from the corn oil-in-water emulsion. As compared to either the aqueous suspension, Tablet A, or Tablet B, three- to fourfold increases in the maximum body levels and a twofold enhancement in the bioavailability of the antibiotic were observed after administration of the emulsion dosage form. A mechanism based on the ability of the linoleic and oleic acids liberated during the digestion of corn oil to inhibit GI motility and stimulate gallbladder evacuation may explain the marked enhancing effect of emulsified corn oil on griseofulvin absorption in humans. This new lipid-in-water emulsion dosage form of micronized griseofulvin appears to offer several clinical advantages in the treatment of fungal infections.


GLC determination of ibuprofen [dl-2-(p-isobutylphenyl) propionic acid] enantiomers in biological specimens.

To study the behavior of the d- and l-isomers of ibuprofen in humans, a method for the determination of the individual enantiomers in plasma and urine was required. A specific procedure was developed based on (a) benzene extraction of the acidified specimens, (b) TLC of the benzene extract residue, (c) formation of the l-alpha-methylbenzylamides of the materials eluted from the chromatograms, and (d) quantification of the resulting diastereoisomeric amides by GLC in conjunction with flame-ionization detection. When using a 1-ml aliquot of the specimen, the method is sensitive to 1 mug of each enantiomer/ml of plasma or urine. As compared to simple aqueous solutions, the average recoveries of the enantiomers from plasma and urine ranged from 94 to96%. Mass spectrometric analyses, in conjunction with GLC, confirmed the specificity of the method for the intact enantiomers. The procedure was applied successfully to drug absorption studies in humans. After oral administration of the racemic mixture, the predominant enantiomer in peripheral circulation and excreted in urine was of the d-configuration.


Viscosities of acacia and sodium alginate after sterilization by cobalt-60.

Acacia and sodium alginate powders were sterilized by cobalt-60 irradiation to a total dose of 2.5 Mrad with no increase in residual radioactivity of the gums as a result of the treatment. Viscosity measurements showed an 11% reduction in the viscosity of acacia in water and a 16% decrease in the intrinsic viscosity in barium chloride solution due to the irradiation. Viscosities of sodium alginate solutions in 0.1 N sodium chloride showed a 70% decrease in intrinsic viscosity, indicating changes in the molecular structure corresponding to degradation to 30% of the original degree of polymerization. This dose of gamma-radiation from cobalt-60 is not an appropriate method of sterilization for these gums.


Development and evaluation of method for simultaneous determination of phenobarbital and diphenylhydantoin in plasma by high-pressure liquid chromatography.

A procedure for the simultaneous analysis of diphenylhydantoin and phenobarbital in plasma by high-pressure liquid chromatography was developed and evaluated. Separation is effected on a porous particle silicic acid column with chloroform dioxane-isopropanol-acetic acid (310:9.7:1.0:0.1 by volume) and is monitored at 254 nm. Results of the procedure were compared with results of a GLC assay.


Constituents of Cannabis sativa L. VIII: Possible biological application of a new method to separate cannabidiol and cannabichromene.

Synthetic and naturally occurring cannabidiol and cannabichromene were distinctly separated without derivation by GLC using a 6% OV-1 column; an artifact of cannabichromene, cannabicyclol, was separated from (minus)-delta9-trans-tetrahydrocanna-bivarin. This procedure is versatile and applicable for the quantitation of Cannabis containing both cannabidiol and cannabichromene. Biological interaction among (minus)-delta9-trans-tetrhydrocanabinol, cannabichromene, and other cannabinoids in natural Cannabis preparations can now be studied. In the phenyl methyl silicone polymer series, cannabidiol precedes ca-nabichromene on columns containing below a 50% phenyl-to-methyl ratio. Columns containing below a 50% phenyl-to-methyl ratio. Columns containing a 50:50 or greater ratio of phenyl to methyl reverse the separation order with cannabichromene preceding cannabidiol.


Electron-capture GLC determination of a new antiarrhythmic agent, alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl) benzylamine, in biological fluids.

A highly specific and sensitive GLC method was developed for the analysis of alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl) benzylamine, a new orally active antiarrhythmic drug, in biological fluids. The procedure involves the addition of an internal standard, 4-(alpha,alpha,beta,beta-tetrafluorophenethyl)benzylamine, to the plasma or urine samples followed by extraction of the drugs into benzene at pH 8. The extracted amines are converted to the trifluoroacetyl derivatives (characterized by GLG-mass spectrometry), chromatographed, and detected with a 63Ni electron-capture detector. The sensitivity of the method is such that 10 ng of alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)benzylamine/ml of plasma can be analyzed. These levels are suitable for the analysis of samples obtained following a therapeutic dose.


Effect of aspirin on fate of 14C-acetaminophen in guinea pigs.

The interaction of 14C-acetaminophen, 150 mg/kg (20 muCi/kg), and orally administered aspirin, 200 mg/kg, was studied in male guinea pigs. Aspirin-pretreated animals possessed higher 14C blood levels than controls. Paper chromatography of 0-6 hr urines demonstrated that pretreated animals excreted significantly greater amounts of mercapturate than controls; however, it was only a minor metabolite, accounting for 1-3% of the counts in the urine. The major metabolite, the glucuronide, accounted for 90% of the counts, with free acetaminophen and its sulfate responsible for the remaining counts. Tissue distribution studies indicated that blood plasma and kidneys from aspirin-pretreated animals possessed statistically higher 14C levels than did control tissues. Bile duct and ureter cannulation experiments indicated that aspirin inhibited the concentrating processes into the urine and bile.


Partition of an organophosphorus compound, dichlorvos, between liquid and liquid crystalline phases.

The partition coefficients for an organophosphorus compound, dichlorvos (2,2-dichlorovinyl dimethyl phosphate), between pure liquids, micellar solutions, and liquid crystalline phases were determined by spectrometric analysis of the dichlorvos content after equilibration and separation of the phases. The results demonstrated the pronounced importance of associated colloid structures on the partition coefficient and showed that the partition coefficient did not display a simple concentration dependence.


Synthesis of sparsomycin analogs as potential antitumor agents.

No information is available on the structural requirements for the antitumor activity of sparsomycin, an antibiotic obtained from the fermentation broth of Streptomyces sparsogenes. Its high in vivo and in vitro activity, novel structure, and uncommon mode of action have, therefore, suggested the synthesis of analogs. This report describes the preparation and screening of a series of N-substituted 3-aryl acrylamides which are closely related to sparsomycin. Three compounds exhibited some tumor inhibition but insufficient to warrant further testing.


Structure determination of the anorexic agent mazindol.

The anorexic agent mazindol was shown to exist as the carbinolamine tautomer 5-p-chlorophenyl-2,3-dihydro-5H-imidazol[2,1-a]isoindol-5-ol in solution and in the solid state. The latter was established by diffuse UV reflectance spectroscopy.


Composite membrane estradiol implant.

The diffusion and permeability of large organic molecules through polymeric films were investigated, specifically the passage of estrogen through films of polyethylene, silicone, or a composite of these two films. Such systems are of interest because of the possibility of constructing a biocompatible implant that releases a hormone at a controlled and desired rate. Diffusion and permeability coefficients through implants of a desirable size-successfully tested in rats-were measured by the "time lag" method of diffusion, and solubility coefficients were determined by the method of sorption kinetics. Independently derived values were in good agreement. An interesting observation was made with implications for the controlled release from membrane-based drug delivery systems. Permeability coefficients of estrogen are orders of magnitude higher when estrogen is present as a solid rather than in a dilute solution, while diffusion coefficients are equal. This finding is explained by the considerably higher partial vapor pressure of estrogen in the former case. In fact, control of the partial vapor pressure of the encapsulated drug is a powerful method for controlling its release rate.


Hypothermic response following administration of 2-amino-4-pentenoic acid (allylglycine).

Intraperitoneal administration of allylglycine resulted in a hypothermic response in rats. At a dosage of 90 mg/kg, a significant decrease in temperature was noted at 4 and 8 hr after administration, but no significant difference was noted at 12 hr. The same dose administered intraperitoneally to decapitated rats did not result in a hypothermic response, and intraventricular administration resulted in a rapid onset of hypothermia after 1 hr. These findings are indicative of a central site of action for the allylglycine-induced hypothermia. Quantitative assay of hypothalamic monoamines (norepinephrine, serotonin, and dopamine) did not show any significant changes at 4, 8, and 12 hr postadministration when compared to controls. A significant decrease in hypothalamic gamma-aminobutyric acid was noted at each of these time points when compared to controls. These data suggest an important role for gamma-aminobutyric acid in mammalian thermoregulatory control.


Fluorescence reactions of fluorescamine with levodopa and its derivatives: fluorescence assay of 3-methoxy-4-hydroxyphenylalanine in levodopa dosage forms.

A simple fluorometric method for the quantitation of 3-methoxy-4-hydroxyphenylalanine, either alone or in the presence of levodopa, is presented. Fluorescence is developed by reaction with fluorescamine. The interactions of this reagent with levodopa and a number of its derivatives under various experimental conditions were studied. Negligible fluorescence was obtained with levodopa, dopamine, levodopa benzyl ester, and 6-hydroxydopamine.


Soft gelatin capsules II: Oxygen permeability study of capsule shells.

A method is reported for studying the effects of several factors at room temperature on the oxygen permeability of soft gelatin capsule shell films. The method involves the use of a permeability cell assembly and the spectrophotometric determïnation of oxygen with an alkaline pyrogallic acid solution. Factors investigated were relative humidity, plasticizers, equilibrium water, an insoluble additive, and film thickness. Results from the effects of film thickness and oxygen partial pressure correlated well with the permeability equation. For greatest stability of encapsulated oxygen-labile materials, it is recommended that the soft gelatin capsule shells be prepared with a low plasticizer concentration and that the finished capsules be stored at low relative humidity.


Quantitative analysis of triclocarban in blood.

A method is presented for quantitatively determining triclocarban in blood. Triclocarban is extracted from blood with ether, isolated by TLC, and measured through its UV absorption at 265 nm in methanol. This method is sensitive to 250 ng (50 ppb in 5 ml of blood) of free triclocarban with a relative standard deviation of 5.2%, correlated with a radiotracer analysis of 14C-labeled triclocarban. It has been applied successfully to the analysis of triclocarban in human and rabbit blood.


Clindamycin phosphate: neuromuscular and blood pressure effects in cats.

Three doses (10, 20, and 40 mg/kg) of clindamycin phosphate were tested in each of three feline neuromuscular preparations in a Latin-square sequence, and the muscular responses and blood pressures were compared. No statistically significant dose-related neuromuscular or blood pressure effects were observed.


Unexpected sulfuration reaction of 1-substituted azulenes.

Azulenes reacted unexpectedly and readily with thionyl chloride to give sulfonic acid chlorides and bisthioethers. The sulfonic acids but not the thioethers have antibacterial activity.


Determination of sigma and pi constants of quinolinium acid derivatives.

The apparent partition coefficients of 10 quinoline monocarboxylic acid derivatives in a chloroform-water system were determined. From these data, Hammett's sigma and Hansch's pi values were calculated.


Influence of particle size on rectal absorption of aspirin.

The rectal absorption of aspirin from theobroma oil suppositories was studied in seven human subjects using urinary excretion measurements. The effect of particle size on the excretion rate and cumulative amount of total salicylate excreted was demonstrated by the administration of a 600-mg dose as powdered aspirin and as aspirin disks having 0.023 as much surface as powdered aspirin. In vitro dissolution profiles of aspirin from the suppositories were studied. By the NF XIII Method II, the time required for 50% of the aspirin to dissolve from the suppository was 50 and 100 min for the powdered aspirin and the aspirin disks, respectively. In the bioavailability study, the diffusion equilibrium was attained at approximately 4-5 and 9-10 hr after the rectal administration of powdered aspirin and aspirin disks, respectively. No correlation was found between bioavailability and the dissolution profiles as determined by the USP XVIII dissolution method.


Antiviral, antibacterial, and antifungal activities of isatin N-Mannich bases.

Preliminary antiviral, antibacterial, and antifungal screening results of a series of isatin N-Mannich bases are provided.


Synthesis and CMC determination of a series of aliphatic diamines.

Fifteen aliphatic diamines substituted with one long alkyl chain (C10-C18), a varying number of methylene groups separating the nitrogens (two to six), and various aliphatic substituents were synthesized and their CMC's were determined. While the length of the long alkyl chain plays a dominant role in influencing the CMC, the other N-alkyl substituents as well as the length of the methylene chain separating the two nitrogens of the diamine are significant factors.


Correlations between physical and drug release characteristics of polyethylene glycol suppositories.

The mechanical strength and elastic moduli of blocks of polyethylene glycol with a range of molecular weights were determined. A rotating-basket dissolution test was used to measure the release characteristics of prednisolone from similar blocks. The effects of blending bases of different molecular weight and of the addition of water also were determined. Linear relationships were found for the mechanical strength, molecular weight, and release rate, but no simple relationship could be observed for the elastic moduli.


Comparison of IR spectroscopic analysis and X-ray diffraction of aluminum hydroxide gel.

Data are presented which demonstrate the IR spectrophotometry is more sensitive than X-ray diffraction to structural changes occurring in aluminum hydroxide gel during aging. By examining changes in peak shape and position in the IR spectrum, evidence is seen for an increasing degree of order as the gel ages. The increased order may be responsible for the loss of acid reactivity observed during aging. IR analysis is also recommended for routine monitoring of aluminum hydroxide gels.


Potential fibrinolytic agents: versatile synthetic route to novel 4-(branched alkyl)benzoic acids via beta-monosubstituted or beta,beta-disubstituted styrene-4-carboxylic acids.

A versatile and unambiguous synthetic route to some novel 4-(branched alkyl)benzoic acids via their beta-monosubstituted or beta,beta-disubstituted styrene-4-carboxylic acid precursors is described. The procedure starts with readily available aldehydes or ketones and the common intermediate p-bromobenzyltriphenyl-phosphonium bromide in a Wittig reaction and proceeds in good yield through p-bromostyrene and p-cyanostyrene intermediates. Several benzoic acid derivatives were of potential biological interest as fibrinolytic agents.


Technique for assessment of local effects of substances found in bile upon opening pressure of choledochoduodenal junction.

An assessment of the localized influences of various chemicals found in bile was made by applying them to the interior of the canine choledochoduodenal junction. Test agents were isolated by air bubbles and introduced into the terminal lumen of the intramural portion of the common bile duct via the pressure measurement catheter; they remained in the duct for approximately 1.5 min. The system was flushed and opening pressures were then measured. Responses were measured in terms of alterations in ductal opening pressures generated by a linear pressure ramp. Histamine, serotonin, and bethanechol markedly increased ductal opening pressures, whereas epinephrine and norepinephrine decreased opening pressures. None of the agents affected either cardiovascular or small intestinal motor activity in the vicinity of the sphincter when administered in the manner. The results suggest that the presence in bile of certain neurohumoral transmitters and neurohumoral-like agents may directly affect the canine choledochoduodenal sphincter function.


Effect of uridine diphospho-N-acetylglucosamine and sodium salicylate on L-glutamine-D-fructose-6-phosphate aminotransferase activity from rat gastric mucosa.

Mechanisms of inhibitory action of sodium salicylate on L-glutamine-D-fructose-6-phosphate aminotransferase, prepared from rat gastric mucosa, were studied. Sodium salicylate at lower concentrations (10-20 mM) inhibited reversibly aminotransferase activity by competing with fructose-6-phosphate. At higher concentrations, sodium salicylate inactivated the enzyme irreversibly, with an inactivation rate following first-order kinetics with respect to the enzyme concentration. Uridine-5'-diphospho-N-acetylglucosamine is an endogenous feedback inhibitor. It inhibited the aminotransferase-catalyzed reaction also by competing with fructose-6-phosphate but with an inhibiting activity 1000 times that of sodium salicylate. Uridine-5'-diphospho-N-acetylglucosamine reduced the salicylate inhibition of the enzymic reaction and protected the enzyme from salicylate-induced irreversible inactivation. At a fixed concentration of uridine-5'-diphospho-N-acetylglucosamine (7x10(-6)M), an increase of salicylate concentration produced an increase in enzyme activity as compared with the control.


Formulation of de novo substituent constants in correlation analysis: inhibition of dihydrofolate reductase by 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines.

A correlation equation based solely on de novo constants was formulated for 105 2,4-diamino-5-(3,4-dichlorophenyl)-6-substituted pyrimidines acting as inhibitors of dihydrofolate reductase. An equation with seven indicator variables gives a correlation with a correlation coefficient of 0.903 and a standard deviation of 0.229. The technique used is a modification of the Free-Wilson approach. The results indicate that correlation equations with fewer parameters than the theoretical required to account for all molecular changes may often be encountered. It is also shown that cross-product terms can be used to establish the significance of cooperative substituent effects.


Dissolution profile in relation to initial particle distribution.

A general equation was derived describing the complete and exact dissolution profile of powders under sink conditions. It is applicable to powders having any initial particle-size distribution, with particles dissolving according to any explicit equation. It was applied to develop an equation for the dissolution of log-normal powders that is more generally applicable than previous approaches. The effect of change in initial particle-size distribution parameters on the dissolution profile is illustrated.


Quantitative determination of phenol in phenolated calamine lotion USP.

A method for the quantitative analysis of phenol in phenolated calamine lotion USP is described. The method is based on spectrophotometrically measuring the color produced by reacting phenol with either ferric chloride or ferric nitrate. Beer's law is followed. The effect of ferric-ion concentration on the sensitivity of the assay method is reported.


Identification and quantitation of impurities in dapsone preparations.

Chromatographic and fluorometric procedures were developed to isolate and quantitate small amounts of 2,4'-diamino-diphenyl sulfone and 4-aminodiphenyl sulfone in pharmaceutical preparations of the antileprosy drug 4,4'-diaminodiphenyl sulfone (dapsone). Identification was accomplished by comparison with authentic compounds employing UV absorption, fluorometry, and mass spectrometry in addition to TLC and high-pressure liquid chromatography.


GLC determination of 17 alpha-ethynylestriol 3-cyclopentyl ether.

A rapid, sensitive, and accurate GLC method of analysis of a new estrogenic drug, 17 alpha-ethynylestriol 3-cyclopentyl ether, was developed. The drug and the internal standard, tetratriacontane, are dissolved in chloroform, and an aliquot is heated with N-trimethylsilylimidazole at 80 degrees for 30 min. The silylated sample is chromatographed using a column packed with 1% methyl vinyl silicone gum on Gas Chrom Q. Quantitation is achieved by computer calculation of the peak area ratios. The observed peak is the 16alpha,17beta-bistrimethylsilyl derivative of the new drug substance. The GLC method was applied to the quantitative determination of the estrogenic compound in a tablet formulation containing 25 mug/tablet.


Effect of physical properties on compression characteristics.

The tranmission of force to the die wall was measured by a piezoelectric sensor, and the compression cycles of lactose granules of different shapes were compared. In addition, a nearly spherical fraction of spray-dried lactose was similarly compared with a crystalline sample. Better tablets were formed when the conversion of axial to radial pressure was high and the residual pressure on the die wall remained after removal of the top punch. With acetaminophen and phenacetin, the pressure on the die wall was low, as was the residual pressure, and capping occurred in both cases. With direct compression acetaminophen, higher die wall pressure was produced and capping did not occur. It is considered that these results can be explained by the ease with which the more nearly isodiametric particle can rearrange under pressure and by the elastic properties of the solid.