Spontaneous disengagement of the Optimed implant.
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Aged↗
Biomedical subjects
D D Kim
Publications and source records attributed to D D Kim.
Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 2. The effect of vehicle and enhancer on skin permeation.
The effects of vehicles and enhancers on the skin permeation of the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC), Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat skin at 37 degrees C. After each drug was saturated in various volume fractions of ethanol (EtOH)/water or EtOH/tricaprylin (TCP) cosolvent system for 48 h at 37 degrees C, an in vitro skin permeation study was conducted using Valia-Chien permeation cells for 30 h. The skin permeation rates of DDC, DDI, and AZT from both EtOH/water and EtOH/TCP cosolvent systems increased as the volume fraction of ethanol was increased, reached maximum values at 50-60% (v/v) of ethanol, and then decreased with further increase of ethanol volume fraction. The EtOH/water cosolvent system seems to enhance the skin permeation of these drugs by increasing both the solubility of drug in the vehicles and partitioning of drug into the skin. The skin permeation enhancing effect of EtOH/TCP seems to be solely due to the increase in partitioning of drug into the skin. Addition of 1.0% (v/v) of permeation enhancers, such as oleic acid (OA) and N-methyl-2-pyrrolidone (NMP), in the EtOH/TCP (50:50) cosolvent system could not significantly increase the permeation rate of these drugs. Incorporation of viscous TCP into ethanol probably reduced the thermodynamic activity of enhancers to distribute from the vehicle to the skin. However, incorporation of 1.0% (v/v) of OA in the EtOH/water (60:40) cosolvent system dramatically enhanced the skin permeation of these drugs while reducing the lag time. The permeation rates of these drugs increased as OA concentration was increased up to 0.3% (v/v) in the EtOH/water (60:40) cosolvent system and reached a plateau with further addition of OA. Using a saturated solution in the EtOH/water (60:40) cosolvent system containing 1.0% (v/v) OA, DDC, and AZT reached the target permeation rate required to maintain a therapeutic system level across hairless rat skin. Although only DDC reached the target permeation rate across human cadaver skin, these results suggest that the mutual enhancement effect of ethanol and OA may make transdermal delivery of dideoxynucleoside-type anti-HIV drugs feasible.
Animals↗
Mutual hairless rat skin permeation-enhancing effect of ethanol/water system and oleic acid.
The mutual hairless rat skin permeation-enhancing effect of ethanol (EtOH)/water systems and oleic acid (OA) was investigated with model lipophilic (estradiol, progesterone, levonorgestrel) and hydrophilic drugs (zalcitabine, didanosine, zidovudine). The aqueous solubility and hairless rat skin permeation rate of each drug, saturated in various compositions of EtOH/water system (with and without OA), was determined at 37 degrees C. The hairless rat skin permeation rates of ethanol from EtOH/water systems (with and without OA) were also measured to investigate the skin permeation-enhancing mechanism of EtOH/water systems and OA. Both saturated solubility and steady-state permeation rates of each drug in EtOH/water systems increased exponentially as the volume fraction of ethanol increased, reached the maximum value, and then decreased with further increases in the ethanol volume fraction. Moreover, the hairless rat skin permeation rate of each drug had a good linear relationship with that of ethanol up to 70% (v/v) of ethanol in the EtOH/water system. The addition of OA in the EtOH/water system (70:30 and 60:40 for lipophilic and hydrophilic drugs, respectively) further enhanced the skin permeation rate of both ethanol and drugs. However, > 2.0% (v/v) OA was required to achieve the plateau level in the skin permeation rate of lipophilic drugs, whereas only 0.3% (v/v) OA was required for hydrophilic drugs. The skin permeation rate of ethanol also increased with the addition of OA in the EtOH/water systems (70:30 and 60:40), reached the plateau level with < 1.0% (v/v) OA, and did not significantly change with higher OA concentration. These results suggest that the addition of OA in the EtOH/water system is a useful method to enhance the hairless rat skin permeation rate of both hydrophilic and lipophilic drugs, with more enhancement for hydrophilic drugs.
Animals↗
Protein kinase C modulates microvascular permeability through nitric oxide synthase.
Protein kinase C (PKC) serves important functions in signal transduction. We hypothesized that PKC modulation of microvascular permeability to macromolecules is mediated by nitric oxide (NO). To test this hypothesis, we stimulated PKC topically with 10(-7) M phorbol 12,13-dibutyrate (PDBu) in the hamster check pouch microcirculation. NG-monomethyl-L-arginine (L-NMMA) at 10(-4) M was superfused in a bicarbonate buffer solution throughout the experiment to inhibit the activity of NO synthase. We evaluated changes in transport of fluorescein isothiocyanate-labeled 150,000 mol wt dextran by integrated optical intensity (IOI) using intravital fluorometry and computer-assisted digital image analysis. Postcapillary areas were recorded. PDBu increased IOI from baseline to a value of 46.8 +/- 6.3 units (+/- SE). Pretreatment with L-NMMA decreased the PDBu-stimulated increment to 10.8 +/- 0.9 units. These results demonstrate that PKC-activated modulation of macromolecular transport operates through a mechanism involving the production of NO.
Animals↗
Transdermal delivery of dideoxynucleoside-type anti-HIV drugs. 1. Stability studies for hairless rat skin permeation.
The stability of dideoxynucleoside-type anti-HIV drugs in solution when in contact with hairless rat skin was investigated in order to study the feasibility of their transdermal delivery. The freshly excised dorsal region of hairless rat skin was mounted on Valia-Chien skin permeation cells, and both epidermis (donor) and dermis (receptor) were extracted with isotonic phosphate buffer (pH 7.4) at 37 degrees C for 24 h. Zalcitabine (DDC), didanosine (DDI), and zidovudine (AZT) were found to be stable in the extract of the epidermis at 37 degrees C for at least 30 h. However, DDC and DDI degraded in the extract of the dermis following first-order kinetics at both 25 and 37 degrees C, while AZT was stable at 37 degrees C for at least 30 h. The degradation mechanism(s) of DDC and DDI was (were) studied by analyzing HPLC chromatograms and by evaluating the drug stability in the extract which was filtered to remove any microbes. An unidentified peak produced by DDC in the dermis extract did not appear when the drug was added to the filtered extract, which suggested a bacterial degradation of DDC. On the other hand, DDI was unstable even in the filtered extract and produced a degradation product which corresponded to hypoxanthine, which suggested that a cutaneous enzyme is also involved in the degradation of DDI. DDC was stabilized by the addition of 0.01% (w/v) of an antibacterial agent, such as thimerosal or gentamicin, in the receptor solution, while DDI was stabilized by 0.01% (w/v) purine nucleoside phosphorylase inhibitor, i.e., p-chloromercuribenzoic acid. These results show the importance of stability studies when designing skin permeation experiments using hairless rat since compounds with similar chemical structures can have different stability profiles when in contact with hairless rat skin.
Administration, Cutaneous↗
Transdermal delivery of zalcitabine: in vitro skin permeation study.
OBJECTIVE: To study the feasibility of transdermal delivery of anti-HIV drugs in order to maintain blood concentration within the therapeutic range for longer duration and to reduce the side-effects associated with high dose administration. DESIGN AND METHODS: The effects of vehicles and enhancers on the skin permeation rate of zalcitabine (ddC) were investigated to determine the maximum permeation rate attainable. In vitro skin permeation of ddC, saturated in various compositions of ethanol/tricaprylin or ethanol/water cosolvent system, with and without enhancer, was studied at 37 degrees C using freshly excised hairless rat skin and human cadaver skin as model skins. RESULTS: The skin permeation rate of ddC from both ethanol/tricaprylin and ethanol/water cosolvent system increased when increasing the volume fraction of ethanol and reached maximum values at 50-60% (vol/vol) of ethanol. Addition of 1.0% (vol/vol) of permeation enhancer, such as oleic acid or N-methyl-2-pyrrolidone, to the ethanol/tricaprylin (50:50) cosolvent system could not significantly increase the permeation rate of ddC. However, addition of 1.0% (vol/vol) of oleic acid in ethanol/water (60:40) cosolvent system dramatically enhanced the skin permeation rate of ddC with reduced lag time. Permeation rate of ddC increased with increasing oleic acid concentration up to 0.7% (vol/vol) in the ethanol/water (60: 40) cosolvent system, and reached a plateau with further addition of oleic acid. Although permeation rate of ddC across human cadaver skin (0.61 mg/cm2/h) was three times lower than that across hairless rat skin (1.88 mg/cm2/h), the maximum permeation rate of ddC attainable, using ddC saturated solution in ethanol/water (60: 40) cosolvent system containing 1.0% (vol/vol) oleic acid, was 4-5 times higher than the target rate (0.14 mg/cm2/h) to maintain the therapeutic blood level. CONCLUSION: The synergistic enhancement effect of ethanol and oleic acid can make transdermal delivery of ddC feasible.
Administration, Cutaneous↗
Indocyanine green angiographic findings in pseudoxanthoma elasticum.
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Angioid Streaks↗
Intravenous regional anesthesia for outpatient foot and ankle surgery: a prospective study.
A prospective study was undertaken in 39 patients undergoing 48 foot and ankle procedures using intravenous regional anesthesia (IVRA). IVRA was administered using 35 cc of 0.33% or 0.5% lidocaine. Single tourniquets inflated to 250 mm Hg were used at the ankle level. No supplemental analgesia or sedation was used. Those requiring supplemental local anesthetic infiltration were defined as IVRA failures. Thirty-one of the 39 patients (79.5%) tolerated the procedures with little or no discomfort, and 8 (20.5%) required additional local infiltration with 1% lidocaine. All 39 patients completed the procedures at the outpatient surgical unit without requiring conversion to other forms of anesthesia. Patchy non-anesthetic areas were noted in 14 patients (36.8%). In 7 patients, because the non-anesthetic areas were excluded from the operative fields, the procedures were completed without discomfort. However, in 8 patients where the non-anesthetic areas were directly involved in the operative fields, supplemental local anesthesia was required. Only 1 of the 39 patients complained of tourniquet pain. IVRA compared favorably with other methods of regional anesthesia in the lower extremity with respect to ease of technique, speed of onset, safety, and patient acceptance. However, it appears that it is less reliable than IVRA in the upper extremity. The reasons for this difference will require further investigation.
Adult↗
Posterior segment changes in membranoproliferative glomerulonephritis.
Membranoproliferative glomerulonephritis is a renal disorder characterized by proliferation of cells and changes in the basement membrane of the glomerulus. The disease is divided into three subtypes: type I, characterized by the presence of subendothelial electrondense deposits; type II, characterized by deposition of electrondense material of unknown origin in the lamina densa of the glomerular basement membrane; and type III, characterized by lesions having both type I and type II qualities. Specific posterior segment changes have been reported with membranoproliferative glomerulonephritis type II. We examined three patients with membranoproliferative glomerulonephritis type II and two patients with type III disease. All three patients with type II disease had Bruch's membrane and retinal pigment epithelial changes, whereas both patients with type III disease had normal posterior segments.
Adult↗
Identification of expression signals of the mycobacteriophages Bxb1, L1 and TM4 using the Escherichia-Mycobacterium shuttle plasmids pYUB75 and pYUB76 designed to create translational fusions to the lacZ gene.
Mycobacterial expression signals were cloned using specially constructed gene fusion shuttle plasmid probes carrying a truncated Escherichia coli lacZ (beta-galactosidase) gene which lacked a promoter, a ribosome binding site, and an ATG start codon. Libraries of mycobacteriophage Bxb1, L1 and TM4 DNAs were constructed, and introduced by electroporation into Mycobacterium smegmatis and the 'bacille Calmette-Guérin' (BCG). Clones carrying mycobacterial expression sequences were detected by their blue colour or characteristic fluorescence when plated on media containing chromogenic or fluorogenic substrates. Varying degrees of beta-galactosidase expression were observed, and one Bxb1 expression signal was identified where beta-galactosidase expression is repressed in phage lysogens.
Cloning, Molecular↗
Congenital bowing of the ulna and aggressive fibromatosis.
The association of skeletal anomalies and aggressive fibromatosis has been documented. Isolated bowing of the ulna is rare, yet its occurrence, particularly in conjunction with congenital dislocation of the radial head, has been documented. This article presents two cases of ulnar bowing in which the patients subsequently developed aggressive fibromatosis. We feel that aggressive fibromatosis may be a latent manifestation of congenital bowing of the ulna. The course of the disease appears to be of an aggressive nature, and patients who present with bowing of the ulna should be followed for the potential development of this disease.
Adolescent↗
Complete thrombospondin mRNA sequence includes potential regulatory sites in the 3' untranslated region.
The nucleotide sequence of human thrombospondin (TS) mRNA has been determined from human fibroblast and endothelial cDNAs. The sequence of 5802 bp begins 110 bp upstream from the initiator codon and includes the entire 3' untranslated region (UTR) of the mRNA. The coding region (3510 bp) specifies a protein of 1170 amino acids with all of the known features of the TS subunit (Frazier, W. A. 1987. J. Cell Biol. 105:625-632). The long 3' UTR of 2166 nucleotides is extremely A/T-rich, particularly in the latter half. It contains 37 TATT or ATTT(A) sequences that have been suggested as mediators of the stability of mRNAs for cytokines, lymphokines, and oncogenes (Shaw, G., and R. Kamen. 1986. Cell. 46:659-667). Another unusual feature of the 3' UTR of TS mRNA is a stretch of 42 nucleotides of which 40 are thymidines (uridine in the mRNA) including an uninterrupted sequence of 26 thymidines. This region is flanked by two sets of direct repeats suggesting that it may be an insertion element of retrotranscriptional origin. Comparison of the 3' untranslated region of TS mRNA with the GenBank data base indicates the greatest degree of similarity with an alpha-interferon gene which contains a number of the TATT/ATTT consensus sites. The degree of similarity between the TS and interferon sequences is the same in regions of the interferon gene corresponding to its coding and noncoding regions suggesting that most of the TS 3' UTR may be derived from an interferon gene or pseudogene. The features of the TS mRNA 3' UTR provide a potential explanation for the rapid regulation of TS message observed in cultured cells in response to PDGF and suggest that TS is a member of a group of proteins which are intimately involved in the control of cell growth and differentiation.
Amino Acid Sequence↗
Acetate causes endothelium-independent increases in cyclic AMP in rat caudal artery.
The mechanism of the vasorelaxant action of acetate is unknown. Because cyclic nucleotides have been linked to vasorelaxation in vascular smooth muscle, we studied the effects of acetate on tissue adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) levels in rat caudal artery. Acetate (4 mM) induced an increase in tissue cAMP levels (control: 5.1 +/- 0.67, acetate: 7.1 +/- 0.97 pmol/mg protein, P less than 0.05), with the increase noted as early as 15-30 s after acetate exposure, and peaking at 60 s. The time course of the cAMP response was compatible with the vasorelaxant effect of acetate against an arginine vasopressin (AVP, 2 X 10(-9) M) contraction. Both the increase in cAMP and the vasorelaxant effect were completely blocked by 10(-3) M 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Acetate increased cAMP levels in 3-isobutyl-1-methylxanthine (IBMX)-treated tissue with an effective concentration producing 50% of the maximum response (EC50) of 1.5 mM, similar to the relaxant EC50 (without IBMX) of 2.2 mM against an AVP contraction. In other experiments, the effect of acetate on cAMP was shown to be independent of endothelium. In contrast, acetate had no effect on tissue cGMP levels, whether the endothelium was present or absent. The results suggest that acetate causes an increase in tissue cAMP levels that is not dependent on presence of a functioning endothelium. The changes in cAMP may be contributory to the vasorelaxant effect of acetate in the caudal artery.
1-Methyl-3-isobutylxanthine↗
Recurrence of papillary thyroid carcinoma presenting as a focal neurologic deficit.
Papillary-follicular thyroid carcinoma usually remains localized to the thyroid bed and, in cases of metastasis, almost always involves the lung, bone, or liver. The two patients described here presented with papillary carcinoma and neurologic dysfunction. Total body iodine 131 scans disclosed cerebral uptake, and cerebral masses were confirmed by computed tomographic scan. Both patients presented diagnostic and therapeutic dilemmas, and ultimately underwent craniotomy. One patient's cerebral metastasis recurred and was treated by a second craniotomy. The other patient received postoperative external cerebral radiotherapy and a novel intraoperative treatment: implantation of 22 iodine 125 seeds in the tumor bed, estimated to yield 16,000 rad (160 Gy) in one year. To date, cerebral metastases have not recurred in the latter patient, although tumor has reappeared in other sites. There is little reported in the medical literature concerning cerebral metastases of thyroid carcinoma, and the present report reviews this experience and discusses treatment alternatives.
Adenocarcinoma↗
Recombinant BCG as a candidate oral vaccine vector.
Bacille Calmette-Guerin (BCG), currently the most widely used vaccine in the world, was originally administered for many years as an oral vaccine. The low frequency of serious complications, inexpensive production, and adjuvanticity make BCG an ideal candidate for a recombinant vaccine vehicle. Although mycobacteria are slow growing and not yet well characterized genetically, we have recently developed technology for the genetic manipulation of BCG and other mycobacteria. Phage and plasmid systems based on a shuttle strategy to manipulate DNA in Escherichia coli and transfer it to mycobacteria have been developed. We have established that the aminoglycoside phosphotransferase gene can be used as an effective selectable marker in the mycobacteria and that a foreign antigen from Mycobacterium leprae can be expressed in BCG. Furthermore, a thorough analysis of mycobacterial expression sequences has been undertaken to optimize the expression of foreign antigens in BCG. We constructed an expression probe shuttle plasmid with beta-galactosidase as reporter gene, and have used it successfully to identify multiple mycobacteriophage DNA sequences with varying levels of constitutive or regulable promoter activity. Further genetic advances required for development of recombinant BCG into an effective recombinant vaccine vehicle, including possibilities for oral administration, are adumbrated.
Administration, Oral↗
The acute effects of hematoporphyrin derivative photoradiation on tumor and liver capillary blood flow.
The acute effects of photoradiation after administering hematoporphyrin derivative (Hpd) on capillary blood flow were studied in intrahepatic tumors and normal liver. The tumors were solitary Walker carcinosarcomas implanted within the livers of Sprague-Dawley rats. Capillary flow was measured by a laser doppler monitor with its probe positioned over the tumor or over normal liver. Within a minute after intraportal Hpd injection (1.7 mg), capillary flow in the tumors began to decrease. Minimal levels of flow were maintained for as long as 15 minutes after Hpd injection with no observed recovery of flow back to control levels. Ratio of minimal flow/control flow averaged 0.36. Similar results were seen in studies on normal liver tissue. These studies demonstrate the extremely rapid vasoactive effects caused by photoradiation of Hpd. Vasoconstriction, vascular stasis and ischemia have proven to be important mechanisms in producing tumor cell destruction by photodynamic therapy.
Animals↗