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Biomedical subjects

J H Lin

Publications and source records attributed to J H Lin.

At least 235 records · Page 13Linked to original sources
PubMed1994

Dose-dependent pharmacokinetics: experimental observations and theoretical considerations.

Clinically, absorption and elimination of most drugs follow linear kinetics, and pharmacokinetic parameters describing absorption and elimination of a drug do not change over the therapeutic dose range. However, dose-dependent pharmacokinetics have been reported more frequently in preclinical studies, particularly in toxicity studies, where high doses are often employed. This review highlights the major types of dose-dependent pharmacokinetics with unique examples. Before setting out on a pivotal subchronic and chronic toxicity study of a new drug, a pilot study is often performed to establish a dose range in which a reasonable relationship between plasma AUC and dosage exists to ensure sufficient exposure of animals to the drug. Theoretical bases and possible causes of dose-AUC disproportionality are discussed. Factors affecting the distribution and elimination of drugs and causes of dose-dependent tissue distribution and elimination are also discussed. Often, the non-linear kinetics complicate the design of dosage regimens and prediction of efficacy and toxicity. Thus, an understanding of the influence of dose on the pharmacokinetics is important in the evaluation of the efficacy and toxicity of new drugs.

Absorption↗
PubMed1994

Morphologic variation in plasma-sprayed hydroxyapatite-bioactive glass composite coatings in Hank's solution.

Pure hydroxyapatite (HA), pure bioactive glass (BG), and a new series of (HA/BG) composite coatings were plasma-sprayed onto a commercial Ti6A14V substrate. Changes in morphology and phases of these coatings after immersion in Hank's physiologic solution were investigated using XRD and SEM. Results indicated that the as-sprayed BG coating has an essentially amorphous structure with a very rough surface. After 7 days of immersion, the BG surface started to dissolve, and weak XRD peaks of apatite started to develop. Small amounts of CaO, beta-TCP, Ca4P2O5, as well as a glassy film, were found on the as-sprayed pure HA surface, most of which dissolved in 7 days. The XRD intensity of apatite in pure HA slowly increased with immersion time until, on the 10th day, the intensity started to drop, and 10 days later, the intensity rose again. This undiscovered "drop and rise" phenomenon was observed for the HA/BG composite coatings in an even more dramatic way. The presence of HA accelerates the dissolution of bioactive glass.

Biocompatible Materials↗
PubMed1994

On the absorption of alendronate in rats.

Alendronate is an antiosteolytic agent under investigation for the treatment of a number of bone disorders. Since the compound is a zwitterion with five pKa values and is completely ionized in the intestine at the physiological pH, absorption is poor; less than 1% of an oral dose is available systemically in rats. In the present studies, absorption was found to be predominantly in the upper part of the small intestine. Administration of buffered solutions of alendronate (pH 2-11) did not improve absorption. Whereas food markedly impaired the absorption of alendronate, EDTA enhanced absorption in a dose-dependent manner. Pretreatment of rats with ulcerogenic agents, mepirizole, acetylsalicylic acid, or indomethacin, resulted in a 3-7-fold increase in the oral absorption of alendronate. The absorption of phenol red, added as an indicator of intestinal tissue damage, was also increased in rats with experimental peptic ulcers. The enhanced absorption of alendronate observed in rats with experimental peptic ulcers was attributed to the alteration of the integrity of the intestinal membrane.

Administration, Oral↗
PubMed1994

A long lytic cycle in filamentous phage Cf1tv infecting Xanthomonas campestris pv. citri.

In this study the lytic cycle of a filamentous phage is reported. Under normal laboratory cultivation conditions a virulent form could spontaneously and easily arise from a temperate phage. The virulent one could superinfect cells containing Cf1t lysogen. Therefore, we have named it Cf1tv. In a colony formation assay using cells from an infected culture, two types of colonies were observed, small and large. It could be proven that the formation of small colonies is the result of killing during Cf1tv infection. The number of small colony forming units (cfu) increased with infection time and reached a maximum at 16 h after infection, then dropped to the initial cell concentration at 28 h after infection; 28 h were required to kill all infected cells. Large colonies contained uninfected or phage-resistant cells, but no lysogenic cells. Bacterial death was further confirmed by a microculture assay. At 2 h after infection, normal-dividing cells (cfu giving large colonies) contained about 40% of Cf1tv-infected cells, then the percentage decreased with infection time. Slow-dividing cells (infected cfu giving small colonies) initially contained 55% of cells; this percentage increased slightly at 4 h after infection, then decreased at 8 h after infection. Non-dividing cells initially contained 5% of infected cells, then their numbers rapidly increased with time after infection. The cell division was seriously affected and finally stopped. During one-step growth, the latent period was 30 min and there was no burst; phages were released at 30 min after infection and the rate of release increased gradually with time after infection. Phage DNA integration into host chromosome could not be observed.

Bacteriophages↗
PubMed1994

Dose-dependent pharmacokinetics of L-693,612, a carbonic anhydrase inhibitor, following oral administration in rats.

The disposition of L-693,612, a carbonic anhydrase inhibitor, was examined in rats following oral doses of 0.05 to 25 mg/kg. Area under the blood concentration-time curve (AUC) increased linearly with dose up to 0.25 mg/kg. However, the linear range did not extend to 5 and 25 mg/kg doses; AUC rose only 10-fold overall despite a 500-fold increase in dose. A similar pattern of disproportionality occurring after i.v. administration indicated that the nonlinear behavior after oral doses was not due to dose-limited absorption, but rather it arose because blood clearance increased with dose. Concentration-dependent erythrocyte/plasma partitioning arising from saturation of binding to erythrocyte carbonic anhydrase could explain the dose-dependent blood clearance. At blood concentrations (< 25 microM) achieved in the linear dose range, L-693,612 was extensively sequestered in red blood cells, bound to carbonic anhydrase, with a constant low free fraction in plasma available for elimination. At doses which saturated the binding capacity of carbonic anhydrase, blood clearance increased, since for low hepatic extraction compounds, the rate of elimination is dependent upon the free fraction in blood. Dose-dependent increases in distribution volumes were consistent with the view that high-affinity binding to carbonic anhydrase confined this compound largely to blood volume at low doses, but saturation of binding sites increased availability to peripheral tissues after high doses. Increasing the dose had a minimal effect on terminal half-life because it reflected the concentration-time profile during a period of linear distribution into erythrocytes.

Administration, Oral↗
PubMed1994

Uroplakins Ia and Ib, two major differentiation products of bladder epithelium, belong to a family of four transmembrane domain (4TM) proteins.

The mammalian bladder epithelium elaborates, as a terminal differentiation product, a specialized plasma membrane called asymmetric unit membrane (AUM) which is believed to play a role in strengthening and stabilizing the urothelial apical surface through its interactions with an underlying cytoskeleton. Previous studies indicate that the outer leaflet of AUM is composed of crystalline patches of 12-nm protein particles, and that bovine AUMs contain three major proteins: the 27- to 28-kD uroplakin I, the 15-kD uroplakin II and the 47-kD uroplakin III. As a step towards elucidating the AUM structure and function, we have cloned the cDNAs of bovine uroplakin I (UPI). Our results established the existence of two isoforms of bovine uroplakin I: a 27-kD uroplakin Ia and a 28-kD uroplakin Ib. These two glycoproteins are closely related with 39% identity in their amino acid sequences. Hydropathy plot revealed that both have four potential transmembrane domains (TMDs) with connecting loops of similar length. Proteolytic digestion of UPIa inserted in vitro into microsomal vesicles suggested that its two main hydrophilic loops are exposed to the luminal space, possibly involved in interacting with the luminal domains of other uroplakins to form the 12-nm protein particles. The larger loop connecting TMD3 and TMD4 of both UPIa and UPIb contains six highly conserved cysteine residues; at least one centrally located cysteine doublet in UPIa is involved in forming intramolecular disulfide bridges. The sequences of UPIa and UPIb (the latter is almost identical to a hypothetical, TGF beta-inducible, TI-1 protein of mink lung epithelial cells) are homologous to members of a recently described family all possessing four transmembrane domains (the "4TM family"); members of this family include many important leukocyte differentiation markers such as CD9, CD37, CD53, and CD63. The tissue-specific and differentiation-dependent expression as well as the naturally occurring crystalline state of uroplakin I molecules make them uniquely suitable, as prototype members of the 4TM family, for studying the structure and function of these integral membrane proteins.

Amino Acid Sequence↗
PubMed1994

Identification of a non-fluorescent isodicentric Y chromosome by molecular cytogenetic techniques.

A 12 1/2-month-old girl was referred because of short stature, short neck, large internipple distance and simian crease on her right hand. By routine cytogenetic techniques the presence of an unidentifiable marker chromosome and loss of one X chromosome was noted (i.e. 45, X/46, X, mar/47, X, mar, +mar). By fluorescence in situ hybridization (FISH) technique, the marker chromosome was identified as an isodicentric non-fluorescent Y chromosome ((45, X/46, X, idic (Ynf)/47, X, idic (Ynf), +idic (Ynf)). Although the clinical significance of this finding cannot be assessed at present, possible development of gonadoblastoma in such cases is a major concern and warrants follow-up evaluations.

Chromosome Banding↗
PubMed1994

Use of Chinese herbal medicine in veterinary science: history and perspectives.

Veterinary acupuncture has been receiving greater acceptance in veterinary medicine communities throughout the world in recent years. The American Veterinary Medical Association, for example, is beginning to accept acupuncture as a form of veterinary treatment. Another branch of traditional Chinese veterinary practice, herbal medicine, deserves similar recognition throughout the veterinary world. While herbal medicine carries a strong reputation for healing potential in the Orient, this treatment system is new to Western veterinary practices. Chinese herbal medicine should be incorporated into wider veterinary practice only after close scientific examination of these techniques. The authors examine the reasons for investigating Chinese herbal medicine, including the historical background, strategies of development, research plans and prospects for the use of Chinese herbal medicine in veterinary sciences. Potentially, this could lead to a unique combination of traditional and modern medicines, and to links whereby veterinary findings might acquire applications in human medicine.

Animals↗
PubMed1994

Blood-brain barrier permeability and in vivo activity of partial agonists of benzodiazepine receptor: a study of L-663,581 and its metabolites in rats.

L-663,581 [FG 8205; 7-chloro-4,5-dihydro-5-methyl-3-(5-(1-methylethyl)- 1,2,4-oxadiazol-3-yl)6H-imidazo(1,5-A)(1.4)-benzodiazepine-6-one] is an investigational partial agonist of benzodiazepine receptors for possible application in the treatment of anxiety. Previous studies have shown that the drug is eliminated mainly by biotransformation in rats, dogs and monkeys. Two metabolites, mono- and bis-hydroxy analogs were demonstrated to be active in vitro. The potency of benzodiazepine receptor binding (Ki) is 3.7 nM for the parent drug, 3.3 nM for the mono-hydroxylated metabolite and 1.2 nM for the bishydroxylated metabolite, respectively. Although the metabolites are as potent as, or more so than the parent drug in vitro, they are inactive in rats in a conditioned emotional response model. This study was designed to explore the underlying mechanisms responsible for the discrepancy between in vitro and in vivo activity of the metabolites. After i.v. administration of L-663,581 or its preformed metabolites, the metabolites were cleared more slowly than the parent drug. After i.p. administration at the same dose, the areas under the curve of the metabolites were 2 to 5 times that of the parent drug. Thus, the lack of in vivo activity of the metabolites cannot be explained by the absorption and/or elimination kinetics. Brain uptake studies indicated that the permeability of the blood-brain barrier is high for L-663,581 but very poor for the metabolites; the brain extraction ratio was about 0.6 for L-663,581 and less than 0.03 for the metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Grip strength in different positions of elbow and shoulder.

This study investigated the effect of shoulder position on grip strength in 80 men and 80 women. A Jamar dynamometer was used to measure the grip strength in the four testing positions. The four hand strength tests consisted of three positions in which the elbow was maintained in full extension combined with varying degrees of shoulder flexion (ie, 0 degrees, 90 degrees, and 180 degrees) and of one position in which the elbow was flexed at 90 degrees with the shoulder in 0 degrees of flexion. Only the dominant hand was tested. The highest mean grip strength measurement was recorded when the shoulder was positioned at 180 degrees of flexion with elbow in full extension; whereas the position of 90 degrees elbow flexion with shoulder in 0 degrees of flexion had the lowest grip strength score. In addition, the grip strength measured with the elbow in extension, regardless of shoulder position (ie, 0 degrees, 90 degrees, and 180 degrees of flexion), was significantly higher than when the elbow was flexed at 90 degrees with the shoulder positioned at 0 degrees of flexion. Finally, grip strength differed significantly for both sexes and for each age group. The grip values of the standardized 90 degrees elbow flexed position were further analyzed to determine the average performances in the study population. For men, grip strength peaked within the 20 to 39 years age group and gradually declined thereafter. For women, the highest mean grip strength measurement was recorded in the 40- to 49-year-old age group and then deteriorated with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Quantitation of polycyclic aromatic hydrocarbons, 1-hydroxypyrene, and mutagenicity in urine of coal tar-treated psoriasis patients and untreated volunteers.

Coal tar-treated psoriasis patients were used as a model population to test a newly developed enzyme-linked immunosorbent assay (ELISA) for urinary excretion of benzo(a)pyrene and related polycyclic aromatic hydrocarbons (PAHs). The ability of the ELISA to detect exposure was also compared with that of two previously established biomonitoring methods, measurement of urinary 1-hydroxypyrene by high performance liquid chromatography with fluorescence detection and mutagenicity measured by the Salmonella typhimurium mutagenesis assay. Urine samples were collected from 57 patients and 53 untreated volunteers. Urinary excretion of PAH metabolites, measured by competitive ELISA with a monoclonal antibody (4D5), was elevated in patients (mean, 730 +/- 1370 mumol/mol creatinine) compared with untreated volunteers (110 +/- 90 mumol/mol creatinine; P < 0.0001). 1-Hydroxypyrene also was elevated in patients (mean, 547 +/- 928 mumol/mol creatinine) compared with volunteers (mean, 0.14 +/- 0.17 mumol/mol creatinine; P < 0.0001). Much larger differences between mean values in patients and volunteers were observed with the 1-hydroxypyrene assay compared with the PAH metabolite ELISA. No significant effect of smoking could be detected by either assay. Analysis by the Salmonella typhimurium mutagenesis assay indicated elevated mutagenicity in urine from patients (1410 +/- 2750 revertants/mmol creatinine) compared with volunteers (715 +/- 846 revertants/mmol creatinine; P = 0.072). In all subjects, there was a good correlation between the PAH metabolites and both 1-hydroxypyrene (r = 0.717; P < 0.0001) and urinary mutagenicity (r = 0.317; P = 0.004). These results suggest that the ELISA, which easily can be carried out on large numbers of samples, can be used for monitoring urinary excretion of PAHs in a high exposure population. Ongoing studies are designed to determine its applicability to lower exposure populations.

Administration, Topical↗
PubMed1994

[A simplified emulsification method for antigens with oil adjuvants].

In order to enhance the immune response, people usually add adjuvant to the antigen in immunization. Freund's adjuvant is one of the most used. It can prolong the duration of the antigen staying in the body of the animal, and through continuous stimulation of the antigen the production of antibody is increased. This paper describes a few points in facilitating the emulsification of the antigen and making it more effective. The process can be summarized as follows: (1) Force a small amount of adjuvant from syringe B by pushing it into syringe A filled with antigen solution to mingle with the latter. (2) Push the same volume of the mix from syringe A back to syringe B slowly. (3) Repeat the above mixing process until the mixed portion has become milky white. (4) Gradually increase the volume by small amounts and each time do the same mixing until final completion. After immunization with the mixture, potent sera were always obtained. It has become a routine in this laboratory to use such mixture in its immunization tasks.

Adjuvants, Immunologic↗
PubMed1993

Correlation between prolactin secretion and Gs protein expression during sustained cholera-toxin stimulation.

We have studied the chronic effect of cholera toxin (CTX) on prolactin synthesis and secretion in GH3 pituitary-tumour cells. Time-course analysis showed that prolactin secretion increased with time of CTX exposure, reached a peak at 3 h, and decreased thereafter. Prolactin synthesis was also shown to be stimulated by CTX. The basic and forskolin-stimulated cyclic AMP levels of the CTX-treated cells followed a biphasic time response similar to that of prolactin secretion. Exposure of cells to CTX for more than 3 h abolished the subsequent CTX-catalysed ADP-ribosylation in vitro. Moreover, a significant decrease in the pertussis-toxin-catalysed ADP-ribosylation was found after cells were exposed to CTX for longer than 6 h. Western-blot analysis indicated that the amount of Gs alpha (alpha-subunit of Gs) protein increased within 3 h, followed by a gradual decrease to 50% of the control level at 24 h. The accumulation of Gs alpha mRNA increased within 6 h of CTX exposure, and decreased thereafter to 40% of the basal level at 48 h. Our findings that prolonged treatment of CTX induced similar patterns of time responses in Gs alpha protein expression, cyclic AMP production and prolactin secretion indicate that CTX-induced changes in Gs alpha protein levels may be responsible for the cellular response leading to prolactin secretion.

Adenosine Diphosphate Ribose↗
PubMed1993

D-2-amino-5-phosphonovaleate blocks induction of long-term depression of the NMDA receptor-mediated synaptic component in rat hippocampus.

The long-term depression (LTD) of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potential (EPSPNMDA) was studied in an in vitro slice preparation of rat hippocampus. Intracellular recordings were made from CA1 pyramidal cells in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) and picrotoxin (50 microM) which block non-NMDA and GABAA receptors, respectively. Low frequency (1 Hz) synaptic stimulation caused a transient decrease in the amplitude of EPSPNMDA that usually restored to its control level within 15 min after the stimulation. However, pairing of low frequency synaptic stimulation with postsynaptic depolarization induced an LTD of EPSPNMDA. The ESPNMDA LTD could be blocked by D-2-amino-5-phosphonovaleate (D-APV, 20 microM) suggesting that the induction of LTD requires an increase in postsynaptic Ca2+, at least in part, due to synaptic activation of NMDA receptors during concomitant postsynaptic depolarization.

2-Amino-5-phosphonovalerate↗
PubMed1993

Pairing of pre- and postsynaptic activities in hippocampal CA1 neurons induces long-term modifications of NMDA receptor-mediated synaptic potential.

An in vitro slice preparation of rat hippocampus was used to study the long-term modifications of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potential (EPSPNMDA). Intracellular recordings were made from CA1 pyramidal cells in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) and picrotoxin (50 microM) which block non-NMDA and GABAA receptors, respectively. Pairing of low-frequency EPSPNMDA with postsynaptic depolarization induced a long-term depression (LTD) of EPSPNMDA. The maximal reduction of EPSPNMDA amplitude amounted to 81.3% of the control 1 min after the pairing. When low-frequency synaptic stimulation was paired with strong postsynaptic depolarization, a long-term potentiation (LTP) of EPSPNMDA could be induced. These results suggest that the induction of long-term modifications of EPSPNMDA has at least a postsynaptic component.

6-Cyano-7-nitroquinoxaline-2,3-dione↗