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J S Roth

Publications and source records attributed to J S Roth.

At least 19 recordsLinked to original sources
PubMed2001

Evaluation of a fluorogenic derivatization method for the reversed-phase HPLC analysis of 2'-beta-fluoro-2',3'-dideoxyadenosine, a new anti-AIDS drug.

High sensitivity (10(-7) to 10(-9) M) reversed-phase high-performance liquid chromatography (HPLC) analysis of adenine nucleosides and nucleotides, especially in a biological matrix, is difficult using only ultraviolet detection. Derivatization coupled with fluorescence detection has been investigated as a means of enhancing sensitivity for the reversed-phase HPLC analysis of 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA), an experimental, acid-stable, anti-AIDS drug. The reaction of chloroacetaldehyde with the adenine base has been employed to form fluorescent 1,N(6)-etheno derivatives of F-ddA and 5'-deoxyadenosine, which is used as an internal standard. These derivatives give an analytically useful fluorescence emission at 416 nm after excitation at 230, 265, or 275 nm. Derivatization, fluorescence detection and reversed-phase chromatography have been optimized for the analysis of nanomolar concentrations of F-ddA in human plasma. This method has potential for the measurement of F-ddA at low concentration and in limited volume samples from in vivo biological studies.

Anti-HIV Agents↗
PubMed2001

Laparoscopic pancreatic cystgastrostomy: the lesser sac technique.

Management of pancreatic pseudocysts has remained largely unchanged during the past century. Excision and drainage procedures remain the mainstay of therapy for large, persistent, or symptomatic pseudocysts. Laparoscopic approaches to the management of pancreatic pseudocysts have been previously described. The lesser sac approach is an effective means of creating a hemostatic cystgastrostomy through a single posterior gastrotomy. This procedure is performed by creating a cystotomy and posterior wall gastrotomy through which an endoscopic stapler is applied. The cystotomy-gastrotomy is closed using laparoscopically placed sutures. An endoscope is inserted into the stomach and pseudocyst at the conclusion of the procedure to ensure an airtight anastomosis. The lesser sac approach to pancreatic cystgastrostomy allows for a minimally invasive approach to the management of pancreatic pseudocysts using a single gastrotomy.

Aged↗
PubMed2000

A pilot study of new approaches to teaching anatomy and pathology.

PURPOSE: Minimally Invasive Surgery (MIS) has impacted patient care as well as medical training. New medical education opportunities have emerged with MIS. In this pilot study we explore the role of live, interactive MIS to augment and strengthen specific segments of the undergraduate medical curriculum. METHODS: Laparoscopic cholecystectomy (LC) was selected to demonstrate upper abdominal anatomy and pathology. Second year medical students (n=100) in the course of their GI pathology classes attended live LC telesurgery-the telesurgery student group (TSG). Because of technical difficulties, a second class of medical students (n=90) was shown the tape of the MIS procedure one year later instead of the live surgery-the videotape surgery group (VSG). Background clinical information was provided by the program director and the durgeon. During the live and taped LC broadcast living anatomy was demonstrated and a diseased gallbladder was resected. TSG students were able to ask questions of the program director and the surgeon and vice versa using telesurgery technology. After the procedure, the surgeon met with the students for further discussion. VSG students were able to ask questions of the program director during and after the program. Both groups of students completed a pre- and posttest using remote audience responders. Students' responses from the two groups were compared for selected test and evaluation items. RESULTS: Pre-test (Cronbach's alpha=.10) and post-test (Cronbach's alpha =.28) data were obtained from 73 students in the TSG and.22 and.54 respectively from 69 students in the VSG. A significant increase in laparoscopic anatomy knowledge was observed from pretest to posttest for the VSG (31-55%) and from the TSG (30-61%). The majority of VSG students (68%) indicated the method used to teach was outstanding, and 87% indicated that the program was outstanding in keeping their interest. This is contrasted with only 24% of the TSG group responding that the teaching method was outstanding, and 41% indicated that the program was outstanding in keeping their interest. CONCLUSIONS: Medical students can productively be exposed to surgical methods and living anatomy using telesurgery. The high regard the TSG students had for this program suggests that it can be used effectively to teach and inspire medical students. The positive results have encouraged us to have a backup instructional method such as a tape of the MIS procedure, it apparently does not have the positive impact of live surgery.

Anatomy↗
PubMed2000

Determination of lodenosine and its major metabolite in human plasma by liquid chromatography/electrospray ionization tandem mass spectrometry.

A sensitive and selective method for the determination of 2'-beta-fluoro-2',3'-dideoxyadenosine (lodenosine, F-ddA), an experimental anti-AIDS drug, and its major metabolite, 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), in human plasma was developed and validated. The procedure employs two internal standards and a simple ultrafiltration step followed by chromatography on a Betasil C(18) minibore column. An in-line valve is used to remove salts before reaching the ion source. Detection is by electrospray ionization tandem mass spectrometry with selected reaction monitoring. The method has a limit of quantitation of 4 ng ml(-1) (16 nM) for F-ddA and 8 ng ml(-1) (32 nM) for F-ddI with a linear range up to 2000 ng ml(-1) (7.9 microM) for each. Predicted concentrations from a three-day validation study were within 5% of the nominal values for F-ddA and 16% for F-ddI. Intra- and inter-assay precision, as measured by relative standard deviation, was 13% or better for both compounds. To achieve good reproducibility, many variables related to the electrospray ionization were optimized for both precision and sensitivity. The method was successfully employed to analyze samples and evaluate plasma pharmacokinetics from a Phase I clinical trial.

Anti-HIV Agents↗
PubMed2000

Minilaparoscopically assisted placement of ventriculoperitoneal shunts.

BACKGROUND: Ventriculoperitoneal (VP) shunting remains the preferred treatment for hydrocephalus. Laparoscopic techniques to aid in the placement of the peritoneal portion of the catheter have been reported previously. We describe a minilaparoscopic VP shunt (MLVPS) insertion technique that facilitates directed placement of the peritoneal portion of the catheter in most patients, including those with obese abdomens previously subjected to surgery. In this study we review our experience with MLVPS placement. METHODS: All cases of MLVPS insertions at the University of Kentucky Medical Center and Lexington VA Hospital performed between February 1998 and March 1999 were reviewed retrospectively. A total of 27 patients (13 males and 14 females) ranging in age from 4 to 81 years (mean, 41 years) underwent VP shunting. The MLVPS insertion was performed via a 2-mm laparoscope and a separate 2-mm incision for catheter insertion using a venous introducer kit. In patients who had prior abdominal surgery, a 5-mm direct-view trocar was used. RESULTS: The MLVPS procedure was successful in 27 patients (100%). The mean number of prior shunts was 2 (range, 0-28). Of the 27 patients, 16 (59%) had undergone previous abdominal surgery. The mean operative time was 76 min (range, 19-155 min). There were no intra- or postoperative complications, and no mortalities. The follow-up period extended from 1 to 12 months. CONCLUSIONS: Findings show MLVPS placement to be safe and feasible. It allows accurate, directed placement of the VP shunt with a 2-mm laparoscope and a second 2-mm incision for shunt insertion. The procedure is associated with reduced trauma to the abdominal wall and minimal postoperative ileus. Long-term follow-up assessment of shunt function is planned.

Adolescent↗
PubMed1999

2'-beta-fluoro-2',3'-dideoxyadenosine, lodenosine, in rhesus monkeys: plasma and cerebrospinal fluid pharmacokinetics and urinary disposition.

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA, lodenosine) is a nucleoside analog that was rationally designed as a more chemically and enzymatically stable anti-AIDS drug than its parent compound 2', 3'-dideoxyadenosine or didanosine. Plasma and cerebrospinal fluid (CSF) pharmacokinetics of this compound and its major metabolite, 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), were studied in three rhesus monkeys after a single 20 mg/kg dose administered as an i.v. push. F-ddA exhibited a mean residence time of 0.17 h in plasma and its plasma concentration time profile appeared to be biexponential. The majority of plasma exposure was from F-ddI, with a mean parent drug area under the curve (AUC) to metabolite AUC ratio of 0.16. CSF levels were low, with a mean CSF AUC to plasma AUC ratio of 0.068, with approximately one-quarter of this exposure in CSF due to unchanged drug. Urinary excretion accounted for half of the drug administered with the majority recovered as the metabolite, F-ddI. In a separate experiment, one monkey received a 20 mg/kg i.v. dose of F-ddI. The total dideoxynucleoside plasma exposure was greater than it was after administration of F-ddA; however, the CSF AUC to plasma AUC ratio was a factor of 4 lower (0.017). Thus, F-ddA central nervous system penetration is at least comparable to that of didanosine, indicating that this experimental drug has potential as an addition to currently approved AIDS therapies.

Animals↗
PubMed1998

Determination of 2'-beta-fluoro-2',3'-dideoxyadenosine, an experimental anti-AIDS drug, in human plasma by high-performance liquid chromatography.

2'-Beta-fluoro-2',3'-dideoxyadenosine (F-ddA, lodenosine) is an experimental anti-AIDS drug currently being evaluated in a Phase I clinical trial. A simple and specific HPLC method with UV detection, suitable for use in clinical studies, has been developed to determine both F-ddA and its deaminated catabolite, 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI) in human plasma. After inactivation of plasma HIV by 0.5% Triton X-100, the compounds of interest are isolated and concentrated using solid-phase extraction. Processed samples are separated by use of a pH 4.8 buffered methanol gradient on a reversed-phase phenyl column. The method has a linear range of 0.05-5 microg/ml (0.2-20 microM) and intra-assay precision is better than 8%. Analyte recovery is quantitative and plasma protein binding is minimal. In addition, drug and metabolite levels measured in Triton-treated human plasma remain stable for at least 5 months when samples are stored frozen without further treatment. Compound concentrations determined after samples are processed and then frozen for up to 1 month before analysis are also unchanged.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Lipophilic, acid-stable, adenosine deaminase-activated anti-HIV prodrugs for central nervous system delivery. 3. 6-Amino prodrugs of 2'-beta-fluoro-2',3'-dideoxyinosine.

A series of 6-substituted amino analogs of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl) purines (F-ddN) has been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds are intended to be more lipophilic than the currently approved anti-HIV drugs for better blood-brain barrier penetration. Subsequent adenosine deaminase (ADA)-catalyzed hydrolysis of these prodrugs in the brain is expected to produce the anti-HIV agent, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)hypoxanthine (F-ddI). The new compounds, synthesized from the corresponding 6-chloro analog, include F-ddN which contain methylamino, ethylamino, dimethylamino, hydroxylamino, methoxyamino, benzyloxyamino, hydrazino, and nitro substituents in the 6-position. The 6-nitro analog was isolated as an unexpected product during the preparation of the 6-chloro derivative. Among the analogs with anti-HIV activity, the ethylamino and dimethylamino compounds are ca. 100 times more lipophilic than ddI or F-ddI. As expected, 2'-fluoro substitution protects the compounds from acid-catalyzed glycosylic cleavage. Only the hydroxylamino and nitro analogs underwent any nonenzymatic hydrolysis at pH 1.0 or 7.4. This reaction, however, results in hydrolysis of the group in the 6-position rather than glycosylic bond cleavage. ADA catalyzes the hydrolysis of the 6-substituents at rates which vary from slightly slower (NO2, 1.7x) to much slower (NHEt, 5000x) than F-ddA. The 6-dimethylamino analog is the only compound which possesses anti-HIV activity (ED50 18 microM) without ADA hydrolysis. With the exception of the two inactive alkoxyamino compounds, the other prodrugs exhibited cellular protection in the HIV-1/PHA-PBM system with IC50 potencies of 7-40 microM.

Adenosine Deaminase↗
PubMed1995

Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the rat.

2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine dideoxynucleoside with in vitro anti-HIV activity, has been selected by the NCI as a clinical trial candidate. A recent report that high, single doses of F-ddA produce cardiotoxicity in rats prompted the present investigation whose objective was to quantitate this effect and establish a relationship between this toxicity and F-ddA plasma concentrations. Microscopic examination of cardiac tissues for degenerative lesions established the effects of F-ddA and ddA on three iv schedules [daily x 1(2.5-250 mg/kg); daily x 5(125, 250 mg/kg), and BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg) using 8- to 12-week old female Sprague-Dawley rats. For both F-ddA and ddA, the group mean severity of the cardiac lesions was dose-dependent and proportional to the measured plasma concentrations of the undeaminated parent drugs. F-ddI and ddI, were essentially nontoxic in this study (iv, 250 mg/kg, daily x 1 and daily x 5), since plasma concentrations exceeding 2 mM produced only minimal cardiac lesions. The cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250 mg/kg (daily x 1) and usually was greater than that of ddA at any given dose. This is a consequence of the fact that F-ddA is deaminated 20 times more slowly than ddA, resulting in higher plasma concentrations of F-ddA relative to ddA at any given time for any given dose. Neither F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily x 5) than when administered only once, suggesting that rat cardiotoxicity is related Cmax rather than total exposure. In this most sensitive species, the formation of cardiac lesions above the background level is associated with i.v. F-ddA administration when the F-ddA plasma concentration approaches 300 microM, 30-50 times the anticipated therapeutic level in humans.

Administration, Oral↗
PubMed1994

Simultaneous measurement of the cell-differentiating agent hexamethylene bisacetamide and its metabolites by gas chromatography.

Hexamethylene bisacetamide (HMBA) is a potent in vitro differentiating agent that has clinical potential as an anticancer drug both as a single agent and as a component of combination therapy. A sensitive and efficient GC method for the isolation, derivatization, and measurement of both HMBA and its two major metabolites in plasma and urine in a single analysis is described. In situ carbamylation of the biological sample with diethylpyrocarbonate forms the urethane derivative of the basic N-acetyl diaminohexane metabolite and allows analyte isolation and concentration by solid-phase extraction. Subsequent formation of the n-butyl ester of 6-acetamidohexanoic acid, the major metabolite, provides a derivatized biological extract that can be rapidly analyzed by temperature-programmed GC. The quantitative extraction and the efficient derivatization steps provide a limit of quantitation of 0.05 mM (10 micrograms/ml) for all analytes with a precision better than 8% for the range of in vitro activity (0.1-2.0 mM). This method is amenable to automation and is well-suited for the analysis of clinical samples.

Acetamides↗
PubMed1994

Occult tooth fragments spontaneously extruded after six months.

Fracture of one or more teeth is a frequent complication of trauma to the oral cavity. Broken teeth that are not accounted for are often presumed to be swallowed or lost. We report a case of fracture of incisors that were not located on physical examination following the trauma but were discovered six months later as hard, perforating papulonodules on the lower lip.

Adult↗