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Biomedical subjects

L Gu

Publications and source records attributed to L Gu.

At least 145 records · Page 8Linked to original sources
PubMed1990

Drug-excipient incompatibility studies of the dipeptide angiotensin-converting enzyme inhibitor, moexipril hydrochloride: dry powder vs wet granulation.

The drug-excipient incompatibility screen for moexipril hydrochloride (1) using various isothermal stress methods is reported herein. It was found that most of the commonly used filters, disintegrants, lubricants, glidants, and coating agents were incompatible with 1 in dry powder mixtures; moisture and basic (or alkalizing) agents were determined to be the dominant destabilizing factors. In wet granulations, basic agents, however, were found to suppress drug degradation even in the presence of moisture. Supported by the product distribution studies, the stabilization is proposed to involve the neutralization of the acidic drug by the basic excipients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Development and characterization of a lyophilized dosage form of IL-1 beta.

The development and characterization of a lyophilized dosage form for recombinant Interleukin-1 beta is described. Included in the evaluation of the drug product are accelerated and long-term stability studies utilizing a number of biophysical techniques (reverse-phase HPLC, SDS-PAGE, isoelectric focusing and ELISA). Data collected with these methods were examined for correlations with biological activity assessments provided by an in-vitro cell culture system (mouse thymocyte proliferation). Results of these studies demonstrate that a lyophilized dosage form of Interleukin-1 beta can be prepared which retains its potency for at least 1 year when stored at ambient temperature. The analytical methodology used to assess the physicochemical integrity of the protein provided a sensitive and reproducible means of predicting changes in biological activity.

Animals↗
PubMed1989

An unexpected pH effect on the stability of moexipril lyophilized powder.

Because of the limited stability of moexipril (RS-10085; 1) in aqueous solution, lyophilized parenteral formulations were evaluated as a function of pH in this study. In general, the lyophilized powder of 1 showed about two orders of magnitude less reactivity at 50 degree C than in aqueous solution at pH values below 3 or above 6. At pH 5.1, however, the lyophilized powder had maximum reactivity, with the rate actually comparable to that observed in aqueous solution. When the distribution of the two major products, diketopiperazine (DKP) 2 and ester hydrolysis analogue 3, was compared to the observed kinetics as a function of pH, it was clear that removal of water via lyophilization suppressed the spontaneous k1 cyclization process, the spontaneous k3 hydrolysis process, and the specific base-catalyzed k4 hydrolysis process. The overall spontaneous k2 cyclization process, however, was not affected by lyophilization. The latter result is accounted for by the increased equilibrium constant for the formation of the tetrahedral intermediate, To, as a result of lyophilization. This study demonstrates that stability data in solution can not be used for predicting the stability of moexipril in lyophilized powder form.

Chromatography, High Pressure Liquid↗
PubMed1989

Studies of safe maximal daily dietary selenium intake in a seleniferous area in China. I. Selenium intake and tissue selenium levels of the inhabitants.

Studies of marginal safe Se-intake have been carried out in a seleniferous section of China since 1985. Three areas with low, medium and high Se levels were selected for this study. The respective average daily Se-intake (mean +/- SE) was 70.5 +/- 4.8 micrograms, 194.7 +/- 22.9 micrograms and 1438.2 +/- 76.3 micrograms for males, and 62.0 +/- 3.6 micrograms, 198.1 +/- 23.8 micrograms and 1238.5 +/- 64.6 micrograms for females (average body weight: male 55 Kg, female 53 Kg). When the increasing rate of Se-intake was compared with the corresponding tissue-Se levels it was found that the whole blood Se-level reflected more closely the physiological range of Se-intake, while at higher Se-intakes it became less sensitive than the levels in hair, finger-nail and toe-nail, which were comparable to the sensitivity of urine. It is suggested that hair, finger- and toe-nail may all act as excretory organs when excess amounts of Se are ingested. Hair- and blood-Cd are somewhat higher in residents of the high Se area, but whether they have influenced human Se-metabolism at the high level of Se-intake is not yet known. Significant correlations on log-log plots were obtained between levels of daily Se-intake and whole blood r = 0.878), breast milk (r = 0.899) and 24-h-urine (r = 0.859). Highly significant correlations on log-log plots between levels of tissue were also obtained: urine Se--plasma Se (r = 0.968), whole blood Se--hair Se (r = 0.952), fingernail Se--toenail Se (r = 0.919), hair Se--fingernail Se (r = 0.914), hair Se--toenail Se (r = 0.891), whole blood Se--toenail Se (r = 0.849) and whole blood Se--fingernail Se (r = 0.836). The highly significant correlations found between the Se-intake and the tissue-Se level, and also between the Se levels of various tissues, could possibly conveniently be used to convert the known tissue-Se level to the corresponding Se-intake. Taken together with the wide range of Se-intakes and corresponding tissue-Se levels this would provide the necessary conditions for studying the marginal and maximal safe Se-intakes in humans.

Arsenic↗
PubMed1989

Studies of safe maximal daily dietary Se-intake in a seleniferous area in China. Part II: Relation between Se-intake and the manifestation of clinical signs and certain biochemical alterations in blood and urine.

Selenosis occurs in areas of Enshi county because of the high Se content of the food. Morphological changes in finger-nails were used as the main criterion for clinical diagnosis of selenosis. Pathological nails were observed to occur almost only in adults, not at all in young children and very seldom in teenagers. Symptoms of selenosis in susceptible patients were found at or above an Se-intake of 910 micrograms/d, corresponding to a blood Se level of 1.05 mg/L. There was no evidence for an increased susceptibility to dental caries due to high Se consumption, and an increase in Se-intake seems unlikely to reduce the beneficial effects of fluoride on caries. No abnormalities of liver or heart were seen by supersonic B or electrocardiographic examinations. The biochemical investigations showed that with increasing whole blood Se the ratio of plasma Se to erythrocyte Se tended to decrease. As Se-intake increases to over 750 micrograms daily, the ratio decreases to near a minimal level. Reduced glutathione in whole blood decreases within a blood Se range of 1.01 to 2.28 micrograms in the high Se area. The amount of trimethylselenonium ion excreted in urine increased with the increase of urinary Se. Cases with prolonged prothrombin time occurred as blood Se increased to a level above 1 mg/L. The white blood cell count also increased significantly. Quantitative values were obtained only for ratio of plasma-Se to erythrocyte-Se for prothrombin time and for maintenance of nail Symptoms of susceptible patients. The overall results indicated that a daily Se-intake of 750-850 micrograms [corrected] might be the marginal level of safe intake. When other variable factors are also taken into consideration a daily Se-intake of 400 micrograms [corrected] is suggested as the maximum daily safe intake. At this level of Se-intake the corresponding approximate tissue Se levels are: whole blood 0.559 mg/L, plasma 0.327 mg/L, urine excretion 173 micrograms/d, hair 3.60 mg/kg, toe-nails 4.25 mg/kg, and finger-nails 4.70 mg/kg.

Anemia↗
PubMed1988

Transient opacification of the urinary pathways by amorphous debris in children with leukemia.

Our index patient, a 14-year-old male on chemotherapy for acute lymphatic leukemia had extensive opacification of the urinary tract on the preliminary film for an intravenous urogram. Sonography and computed tomography also demonstrated dense material in the calyces, renal pelves and ureters. Since then, we have found another patient, a 9-year-old female with acute lymphatic leukemia who was not receiving chemotherapy, with a similar pattern on sonography and computed tomography. These densities unlike those in our first patient were not visible on a plain film of the abdomen. All of the material disappeared spontaneously in both patients.

Adolescent↗
PubMed1988

Inhibitors of cyclic AMP phosphodiesterase. 4. Synthesis and evaluation of potential prodrugs of lixazinone (N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro-2- oxoimidazo[2,1-b]quinazolin-7-yl)-oxy]butyramide, RS-82856).

The cyclic AMP phosphodiesterase (cAMP PDE) inhibitor and cardiotonic agent lixazinone (N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro-2- oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide, RS-82856, 1) and its acid and base addition salts were found to be insufficiently soluble in formulations suitable for intravenous administration. These results prompted an investigation into potential prodrugs with enhanced aqueous solubility designed to deliver 1 by three distinct mechanisms: (1) decarboxylation of alpha-carboxamides; (2) hydrolytic loss of a solubilizing N-1-(acyloxy)methyl or (N,N-dialkylamino)methyl moiety; or (3) intramolecular closure of a guanidino ester or amide. The target compounds were evaluated as delivery systems for 1 by three criteria: (1) chemical conversion rate to 1 under physiological conditions; (2) inhibition of type IV cAMP PDE at a fixed time point; and (3) in vivo inotropic activity in anesthetized dogs by both intravenous and oral administration. Release of 1 from 4a (series 1) was found to be too slow to be of value as a prodrug of 1, since decarboxylation could be induced only by strong acid, conditions under which hydrolytic ring opening was found to severely compete. Conversely, 1 was released too readily on exposure of (N,N-dialkylamino)methyl derivatives such as 8d (series 2) to physiological conditions, although no large increase in aqueous solubility was realized. Finally, both the physicochemical and in vitro studies indicated that ring closure of the guanidinium esters and amides 17a-k (series 3) to 1 was quantitative and pH- and time-dependent, suggesting the possibility of delivery of the open, water-soluble prodrug form, followed by closure to 1 in plasma. Detailed examination of these agents in vivo, however, demonstrated that only those compounds that rapidly cyclized to 1, as measured by plasma levels of 1, exhibited inotropic activity, indicating that the open prodrug form was not efficiently absorbed upon oral administration.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1988

Preformulation stability studies of the new dipeptide angiotensin-converting enzyme inhibitor RS-10029.

The degradation kinetics, products, and mechanisms of RS-10029 (2), 2-[2-[(1-carboxylic acid)-3-phenylpropyl]amino-1-oxopropyl] 6,7-dimethoxy- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (S,S,S), in aqueous solutions from pH 1 to pH 13 were studied at 50, 60, and 80 degrees C. Pseudo-first-order kinetics were obtained throughout the entire pH range studied, and the log(rate)-pH profile reflected four kinetic processes (ko, k'o, k"o, and kOH) as well as the three pka's of 2. Excellent mass balance (greater than 96%) was obtained for the four major products 3-6 throughout the entire pH range studied even though four other minor products can be detected by high-performance liquid chromatography (HPLC). At pH 8.0 and below, intramolecular aminolysis leading to diketopiperazine (DKP) 5 accounted for greater than 65% of the neutral or water-catalyzed (ko and k'o) processes. Amide hydrolysis leading to products 3 and 4 and epimerization of DKP 5 to the (R,S,S) diastereomer 6 accounted for the remaining 35% of the neutral or water catalyzed processes. At pH values above 8.0, DKP 5 formation begins to decrease as the amide hydrolysis increases so that both mechanisms account for the neutral or water-catalyzed k"o process. Above pH 11.0 amide hydrolysis dominates and is responsible for the specific base-catalyzed (kOH) process. The four minor products detected by HPLC are two diastereomers (7 and 8) of 2 and the two diastereomers (9 and 10) of the DKP 5. The stability results between 2 and its ester prodrug (1) are compared.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

John Caffey Award. Intussusception reduction in children by rectal insufflation of air.

Air was used as the contrast medium for colonic studies in 282 patients with suspected intussusception. Intussusception was documented in 118 of these patients (42%), and reduction was achieved in 89 (75%) of those 118. Twenty-nine patients, in whom the intussusception could not be reduced with air, underwent surgery. Seven of these patients required surgical resection of devitalized bowel. In seven others, the intussusception was reduced by the surgeon with difficulty; in 12, surgical reduction was achieved easily. Three perforations occurred with the use of air. These patients were treated surgically without sequelae. This pilot study of 282 patients suggests that air is a safe substitute for hydrostatic reduction of intussusception.

Administration, Rectal↗
PubMed1987

Diketopiperazine formation, hydrolysis, and epimerization of the new dipeptide angiotensin-converting enzyme inhibitor RS-10085.

The degradation kinetics, products, and mechanisms of RS-10085(1), 2-[2-(1-ethoxycarbonyl)-3-phenylpropyl]amino-1-oxopropyl]-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid(S,S,S), in aqueous solution were investigated at 40, 60, and 80 degrees C from pH 1 to pH 13. Pseudo-first-order kinetics were observed throughout the pH range studied and the log(rate)-pH profiles reflected four kinetic processes (ko, k'o, k'o, and kOH) as well as the two pKa's of 1. Excellent (greater than 98%) mass balance was obtained through products 2-5. At pH 4 or below, intramolecular cyclization leading to diketopiperazine 5 accounted for greater than 93% of the observed neutral- or water-catalyzed processes (ko and k'o). At pH levels greater than 5, hydrolysis giving 2 predominated and was responsible for the observed neutral- or water-catalyzed (k''o) and specific base-catalyzed (kOH) kinetic processes. Some epimerization leading to the S,S,R drug isomer (4) was also observed at pH levels greater than 7. The relative acidity of the protons at the three chiral centers of 1 was qualitatively compared and was used to explain the observed specificity in epimerization.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Characterisation of soy isoflavones and screening for novel malonyl glycosides using high-performance liquid chromatography-electrospray ionisation-mass spectrometry.

HPLC combined with electrospray ionisation (ESI)-MS and photodiode array detection has been employed to study the isoflavone components of soy. All of the known soy isoflavones separated by HPLC were identified and characterised, and three novel isoflavones were detected and screened out. These minor isoflavones were deduced to be isomers of 6"-O-malonyl isoflavone glycosides, based on the ESI-MS and UV data, in which the malonyl group is attached at a position other than the 6" position of the glycosyl moiety of the molecule. These novel malonyl glycosides are as thermally labile as the 6"-O-malonyl glycosides, being converted into known isoflavone glycosides after heating in aqueous ethanol. The advantages of HPLC-ESI-MS in detection of novel isoflavones from plant extracts are reviewed.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Incidence and clinical significance of CDKN2/MTS1/P16ink4A and MTS2/P15ink4B gene deletions in childhood acute lymphoblastic leukemia.

We have examined the incidence and clinical significance of deletions of two candidate tumor suppressor genes, CDKN2/MTS1/p16ink4A and MTS2/p15ink4B, in pediatric acute lymphoblastic leukemia (ALL). Gene deletion was evaluated in leukemic bone marrow (BM) cells obtained at diagnosis from 105 pediatric ALL patients: 83 with B-cell precursor (BCP-ALL) ALL and 22 with T-ALL. CDKN2/p16 deletion was seen in 23 of the 83 (28%) BCP-ALL and 15 of the 22 (68%) T-ALL cases. A virtually identical pattern of MTS2/p15 deletion was detected in these patients: p15 was deleted in 37 of 38 cases with p16 deletion, and p15 was not deleted in any p16-positive specimens. P16/p15 deletions were significantly related to poor prognosis factors including age under 1 year (P < 0.001), initial white cell counts greater than 50 x 10(9) per liter (P < .001), and T cell phenotype P < .005). Analysis of all 105 patients revealed that the 5-year disease-free survival rate was 68% for patients without p16/p15 deletions and 35% for those with p16/p15 deletions (P < .005). The association between gene deletion at initial diagnosis and unfavorable outcome suggests that loss of these genes is clinically significant and indicates a need for prospective studies of p16/p15 deletion in pediatric ALL patients.

Adolescent↗