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J S Roth

Publications and source records attributed to J S Roth.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Chemistry and anti-HIV properties of 2'-fluoro-2',3'-dideoxyarabinofuranosylpyrimidines.

The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'-dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compounds is a potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after greater than 24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.

Animals↗
PubMed1991

Phase I bioavailability and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered via nasogastric tube.

A Phase I clinical trial and pharmacological study of nasogastrically administered hexamethylene bisacetamide, a polar-planar compound with in vitro differentiating activity, was conducted in 14 adult patients with refractory cancer. Hexamethylene bisacetamide was administered as a 5% (w/v) solution via a nasogastric or gastrostomy tube every 4 h for 5 days, followed in 21 days by a 5-day continuous i.v. infusion at the same daily dose. Parenteral drug administration was then continued at the same interval in the absence of disease progression or unacceptable toxicity. Three patients each were treated at doses of 12 and 24 g/m2/day, while eight patients received a dose of 30 g/m2/day. Toxicity was comparable for both routes of drug administration at the above doses. Nasogastrically administered hexamethylene bisacetamide was well tolerated at the lower doses, whereas neurotoxicity and nausea and vomiting were the major, but manageable, toxicities at 30 g/m2/day. Metabolic acidosis, renal dysfunction, mucositis, and thrombocytopenia were the other commonly observed drug toxicities at this dose. No objective tumor responses were observed. Hexamethylene bisacetamide was rapidly absorbed from the gastrointestinal tract with a mean measured bioavailability of 99 +/- 15%. Pharmacokinetic parameters for hexamethylene bisacetamide and plasma concentrations of the two major metabolites, N-acetyl-1,6-diaminohexane and 6-acetamidohexanoic acid, were similar for either route of administration in individual patients. Hexamethylene bisacetamide exhibited apparent monoexponential plasma elimination after either nasogastric or parenteral administration with 27 to 60% of the administered dose being excreted in the urine as parent compound. Based on its demonstrated complete bioavailability and tolerability, nasogastric administration of hexamethylene bisacetamide can be directly and safely substituted for the comparable i.v. dose.

Acetamides↗
PubMed1990

Isolation of a complementary DNA encoding the catalytic subunit of protein kinase A and studies on the expression of this sequence in rat hepatomas and regenerating liver.

A complementary DNA (cDNA) clone (B4) encoding the catalytic subunit of a cAMP-dependent protein kinase (PKAc) was isolated from a lambda gt10 rat brain cDNA library, using a synthetic oligonucleotide probe whose sequence was based on the known amino acid sequence of a bovine cardiac PKAc. Sequence analysis of this clone revealed a region of 1002 nucleotides which encodes a protein that is 92% homologous to amino acids 17-350 of the bovine cardiac PKAc protein. This clone lacks coding sequences for amino acids 1-16 of the latter protein. Nevertheless, it provided a useful probe to analyze expression of the related gene in a variety of systems. Northern blot analyses using a 32P-labeled probe prepared from a 0.6-kilobase PstI fragment of clone B4 revealed an abundant 4.6-kilobase band in rat brain RNA and lesser amounts of this 4.6-kilobase RNA in rat heart and liver. A 4.6-kilobase RNA was also detected in RNA samples obtained from mouse fibroblasts. This probe also detected homologous RNA in a variety of nonrodent species. In subsequent experiments, this cDNA was used as a probe to elucidate the role of PKAc in post-surgical hepatic regeneration and diethylnitrosamine-induced hepatomas in the rat. These experiments revealed that, following partial hepatectomy, PKAc mRNA is decreased 3-fold by 12 h, returning to normal by 72 h; hepatomas showed no consistent pattern of change in PKAc mRNA levels as compared to controls. Our results indicate that this cDNA encodes an isoform of PKAc which is distinct from PKAc-alpha isolated by Uhler et al. (Proc. Natl. Acad. Sci. USA, 83: 1300-1304, 1986) but highly homologous to PKAc-beta isolated by Showers and Maurer (J. Biol. Chem., 261: 16288-16291, 1986), that depression of cAMP-dependent protein phosphorylation may be an important mechanism in the regeneration of mature rat liver but is not a consistent alteration in chemically induced hepatoma, and that this cDNA is useful as a probe for the study of the role of PKAc gene expression in growth control, particularly in rodent species.

Amino Acid Sequence↗
PubMed1990

Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV.

2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.

Antiviral Agents↗
PubMed1988

A pediatric phase I and pharmacokinetic study of spirohydantoin mustard.

A pediatric Phase I and pharmacokinetic study of the lipophilic alkylating agent spirohydantoin mustard (SHM) was conducted in 23 patients. The dose-limiting toxicity of SHM was neurological with disorientation, delirium, or hallucinations occurring in 9 of 23 patients. These symptoms were partially reversible and preventable with physostigmine. In 17 patients who were evaluable for response to treatment (14 of whom had central nervous system malignancies), no objective tumor responses were observed. Pharmacokinetic evaluation of SHM revealed a t1/2 alpha of 1.7 +/- 0.7 min, t1/2 beta of 16 +/- 8.3 min, and total body clearance of 2134 +/- 735 ml/min/m2. Measureable peak plasma levels were less than 40% of that which produces cytotoxicity in vitro against monolayer cultures of rat 9L brain tumor. Over 90% of SHM was protein bound, greatly limiting the free drug available for central nervous system penetration. SHM cerebrospinal fluid to plasma ratios were less than 0.047. The above suggests that in spite of its lipophilicity, SHM may not reach clinically significant levels in the central nervous system at clinically tolerable doses.

Adolescent↗
PubMed1988

Pyrimidine dideoxyribonucleosides: selectivity of penetration into cerebrospinal fluid.

Cerebrospinal fluid (CSF)/plasma ratios of 1 to 30% were obtained in rhesus monkeys for the 3'-azido- and 2',3'-dideoxy-analogs of thymidine, deoxycytidine and deoxyuridine. Penetration of thymidine and deoxyuridine analogs was much greater than for deoxycytidine analogs. Octanol/buffer partition coefficients varied more than 30-fold, but did not correlate with CSF entry. Plasma protein binding was insignificant for all compounds. The presence or absence of the azido group at position 3' did not appear to influence the extent of CSF penetration. Although we do not fully understand the mechanistic basis for the penetration of these nucleosides into the CSF, it is apparent that the structural specificity is related more closely to the nucleobase than the sugar. Based upon elimination rates from the CSF after direct intrathecal injection, the differences in net penetration are determined by influx rather than efflux processes.

Animals↗