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PubMed2001

SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase.

Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (K(i) = 0.19 microM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2, IL-2, IFN-gamma, TNF-alpha, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-alpha and inhibited anti-CD3-induced apoptosis of CD4(+) CD8(+) thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.

Adenosine Triphosphate↗
PubMed2000

Illegal or legitimate use? Precursor compounds to amphetamine and methamphetamine.

The interpretation of methamphetamine and amphetamine positive test results in biological samples is a challenge to clinical and forensic toxicology for several reasons. The effects of pH and dilution of urine samples and the knowledge about legitimate and illicit sources have to be taken into account. Besides a potentially legal prescription of amphetamines, many substances metabolize to methamphetamine or amphetamine in the body: amphetaminil, benzphetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Especially the knowledge of potential origins of methamphetamine and amphetamine turns out to be very important to prevent a misinterpretation of the surrounding circumstances and to prove illegal drug abuse. In this review, potential precursor compounds are described, including their medical use and major clinical effects and their metabolic profiles, as well as some clues which help to identify the sources.

Amphetamines↗
PubMed1995

Interstitial laser photochemotherapy with new anthrapyrazole drugs for the treatment of xenograft tumors.

Photodynamic therapy (PDT) with lasers and new dyes has gained popularity in recent years as a minimally invasive technique with high tumoricidal effects in vitro and in some cancer patients. However, because new laser dyes are not FDA approved at present, the clinical evaluation of PDT may be years away. During the past 6 years we have used laser alone for photothermal ablation in both preclinical studies and in a large number of patients with an observed 60% tumor response rate. The 40% treatment failure led us to explore the possibility of combined therapy with lasers and standard chemotherapeutic drugs. We have recently tested a promising preclinical alternative using implantation of a bare 600-microns KTP 532 laser fiberoptic in multiple tumor sites 30 min after intratumor injection of the anthrapyrazole DUP-941. As a control, this drug was injected in 3 sites of P3 human squamous cell tumor transplants in nude mice, which led to tumor stasis without regression. Similar 400-600 mm3 tumors exposed to laser illumination alone (0.8 W for 5 sec) at multiple sites resulted in tumor regrowth after 10 weeks in 80% of the animals. However, combining interstitial laser illumination with intratumor DUP-941 injections led to complete tumor regression in 85% of the mice. We propose that intratumor drug injection followed by interstitial laser fiberoptic treatment represents a potentially useful new method for tumor ablation in advanced cancer patients.

Animals↗
PubMed1997

Laser chemotherapy of human carcinoma cells with three new anticancer drugs.

A new experimental therapy for squamous carcinoma was tested by sensitizing human tumor cells with light-sensitive anticancer drugs followed by laser illumination at visible or infrared wavelengths. The anthrapyrazole DUP-941 and the isoquinoline derivative DUP-840 were compared with the dianthraquinone hypericin. P3 human squamous carcinoma cells were incubated for 2 h with the drugs at escalating doses ranging from 5 to 100 micrograms/ml, then exposed to visible green 532-nm or infrared 1064-nm light at 300 J output from a KTP/Nd:YAG laser. Tumor cell toxicity measured by in vitro MTT viability assays was minimal after DUP-840 uptake but was slightly enhanced by infrared laser emissions. By contrast, the strong tumoricidal effects seen after DUP-941 uptake were amplified over 10-fold by 532-nm light and up to 2-fold by 1064-nm light. Hypericin-sensitized tumor cells were killed after 532 nm irradiation even at the lowest drug dose but were not affected by 1064-nm illumination. The results suggest that laser chemotherapy with drugs sensitive to photothermal energy could become a useful new treatment modality for cancer.

Anthracenes↗
PubMed1987

Lipoxygenase inhibitor nafazatrom fails to attenuate postischaemic ventricular dysfunction.

The role of lipoxygenase activation in the genesis of postischaemic myocardial dysfunction was investigated in open chest dogs undergoing a 15 min occlusion of the left anterior descending artery followed by 4 h of reperfusion. Treated animals (n = 9) received nafazatrom, a potent lipoxygenase inhibitor, 10 mg.kg-1 orally 4 h before occlusion followed by intravenous boluses of 1.5 mg.kg-1 and 0.5 mg.kg-1 5 min before occlusion and 1 min before reperfusion respectively. Control animals (n = 10) received saline. No discernible haemodynamic effects were produced by the drug. Collateral flow to the ischaemic zone (radioactive microspheres) was 0.14(0.02) ml.min-1.g-1 in the control group and 0.16(0.05) ml.min-1.g-1 in the treated group. The size of the occluded bed as determined by postmortem perfusion was 25.5(0.8)% of the left ventricle in the control and 24.3(1.3)% in the treated group. Histological examination showed a decrease in neutrophil infiltration of the non-ischaemic myocardium and, to a lesser extent, of the reperfused myocardium in nafazatrom treated animals, suggesting lipoxygenase inhibition. Systolic wall thickening (an index of regional function) was assessed using an epicardial pulsed Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions. Though treated animals showed less dyskinesis during coronary occlusion (p less than 0.05), recovery of function was not enhanced over controls and in both groups the reperfused myocardium was still dyskinetic at 4 h. Thus nafazatrom failed to improve postischaemic ventricular dysfunction, suggesting that leukotrienes do not contribute importantly to this phenomenon.

Animals↗
PubMed1994

Urinary methamphetamine concentration following famprofazone administration.

A 37-year-old man had a considerable concentration of methamphetamine in his urine, but he denied taking any abused drug. It was found that he took a pain killer that contains famprofazone, a relatively strong analgesic whose metabolites include methamphetamine and amphetamine. The human urinary metabolism of famprofazone was investigated. Immunoassay was used as a preliminary test, and gas chromatography with flame-ionization detection and gas chromatography-mass spectrometry were used for quantitation and confirmation.

Adult↗
PubMedDate not supplied

Identification of new urinary metabolites of famprofazone in humans.

Urinary metabolites of famprofazone following oral administration in humans were identified by gas chromatography-mass spectrometry with electron impact-ionization and comparison with the spectra and retention times of authentic standards. The metabolites were determined following selective derivatization with N-methyl-bis-trifluoroacetamide (MBTFA) and N-methyl-N-trimethyl silyl trifluoroacetamide (MSTFA). Famprofazone was rapidly and extensively metabolized by N-dealkylation, beta-hydroxylation, and p-hydroxylation. The major metabolite, representing approximately 15% of the dose, was methamphetamine. The other metabolites, which were present in minor amounts, were amphetamine, norephedrine, norpseudoephedrine, ephedrine, pseudoephedrine, p-hydroxyamphetamine, p-hydroxymethamphetamine, and p-hydroxydemethyl famprofazone.

Acetamides↗
PubMed2003

Metabolic profile of amphetamine and methamphetamine following administration of the drug famprofazone.

There are a several drugs that lead to the production of methamphetamine and/or amphetamine in the body which are subsequently excreted in the urine. These drugs raise obvious concerns when interpreting positive amphetamine drug testing results. Famprofazone is an analgesic found in a multi-ingredient medication (Gewodin) used for pain relief. Two Gewodin tablets (50 mg of famprofazone) were administered orally to healthy volunteers with no history of amphetamine, methamphetamine, or famprofazone use. Following administration, urine samples were collected ad lib for up to six days, and pH, specific gravity, and creatinine values were determined. In order to determine the quantitative excretion profile of amphetamine and methamphetamine, samples were extracted using liquid-liquid extraction, derivatized with heptafluorobutyric anhydride, and analyzed by gas chromatography-mass spectrometry (GC-MS). The ions monitored were 91, 118, 240 for amphetamine and 254, 210, 118 for methamphetamine. Amphetamine-d(6) and methamphetamine-d(11) were used as internal standards. Peak concentrations for amphetamine ranged from 148 to 2271 ng/mL and for methamphetamine 615 to 7361 ng/mL. Concentrations of both compounds peaked between 3 and 7 h post-dose. Amphetamine and methamphetamine could be detected (limit of detection = 5 ng/mL) at 121 and 143 h post-dose, respectively. Using a cutoff of 500 ng/mL, all subjects had individual urine samples that tested positive. One subject had 14 samples above the cutoff with the last positive being detected over 48 h post-dose. The profile of methamphetamine and amphetamine enantiomers was also determined using liquid-liquid extraction, derivatization with N-trifluoroacetyl-l-prolyl chloride and analysis by GC-MS. Data showed the famprofazone metabolites amphetamine and methamphetamine to be both d- and l-enantiomers. The proportion of l-methamphetamine exceeded that of its d-enantiomer from the first sample collected. Initially, the proportion was approximately 70% l-methamphetamine and this proportion increased over time. Amphetamine results showed l- and d-amphetamine were virtually the same in the early samples with the proportion of l-amphetamine increasing as time progressed. Forensic interpretation of drug testing results is a challenging critical part of forensic drug testing area because of the potential repercussions the results found may have on an individual's life. The finding of each enantiomers by itself differentiates famprofazone use from the most commonly abused form of methamphetamine and all medicinal methamphetamine available in the U.S., which is either d-methamphetamine (prescription medication) or l-methamphetamine (Vicks inhaler). Coupling this information with the concentrations of amphetamine and methamphetamine helps to determine the potential for use of this drug.

Administration, Oral↗
PubMed2004

Metabolic profile of famprofazone following multidose administration.

One of the 14 different drugs known to be metabolized to methamphetamine and/or amphetamine is famprofazone, a component in the multi-ingredient formulation Gewodin. Because of its conversion to methamphetamine and amphetamine, which can result in positive drug-testing results, the excretion pattern of these metabolites is critical for proper interpretation of drug-testing results. Multiple doses of famprofazone were administered to healthy volunteers with no previous history of methamphetamine, amphetamine, or famprofazone use. Following administration, urine samples were collected ad lib for nine days, and pH, specific gravity, and creatinine values were determined. To determine the methamphetamine and amphetamine excretion profile, samples were extracted, derivatized, and analyzed by gas chromatography-mass spectrometry (GC-MS). Peak concentrations of methamphetamine ranged from 5327 to 14,155 ng/mL and from 833 to 3555 ng/mL for amphetamine and were reached between 12:22 and 48:45 h post initial dose. There were 15-19 samples per subject that were positive under HHS testing guidelines, with the earliest at 03:37 h post initial dose and as late as 70:30 h post last dose. Methamphetamine and amphetamine were last detected (LOD > or = 5 ng/mL) up to 159 h and 153 h post last dose for methamphetamine and amphetamine, respectively. GC-MS was also used to determine the enantiomeric composition of methamphetamine and amphetamine. This analysis revealed both enantiomers were present in a predictable pattern.

Adult↗
PubMed1986

Interference with tumor cell-induced degradation of endothelial matrix on the antimetastatic action of nafazatrom.

The antithrombotic compound nafazatrom was evaluated in several in vivo and in vitro assays to elucidate the mechanism of its antimetastatic activity. C57BL/6 mice bearing B16 amelanotic subcutaneous tumors treated with 100 mg nafazatrom/kg/day exhibited a sixfold reduction in metastatic pulmonary lesions compared to lesion numbers in controls. The reduction in metastatic lesions was not accompanied by changes in primary tumor growth, and up to 1 microgram nafazatrom/ml did not inhibit tumor cell proliferation in vitro. Treatment of C57BL/6 mice with nafazatrom prior to iv inoculation of tumor cells failed to inhibit lung colony formation. In vitro exposure of exponentially growing B16 amelanotic cells to nafazatrom (1 microgram/ml for 72 hr) in culture did not change their ability to adhere to endothelial cell monolayers. B16 amelanotic cells degraded the matrix material of bovine endothelial cell monolayers; a heparin sulfate proteoglycan appeared to be the predominant matrix component released by these tumor cells, as judged by resistance to chondroitin ABC lyase and sensitivity to heparitinase and pronase degradation. Nafazatrom (1 microgram/ml for 72 hr) inhibited the solubilization of matrix components by approximately 60%. Tumor cell degradation of matrix components is an important event in the pathogenesis of metastasis. Thus the interference with this process appears to provide an explanation for the inhibition of malignant cell dissemination in vivo by nafazatrom.

Animals↗
PubMed1994

Topoisomerase II inhibition and cytotoxicity of the anthrapyrazoles DuP 937 and DuP 941 (Losoxantrone) in the National Cancer Institute preclinical antitumor drug discovery screen.

BACKGROUND: The cumulative cardiotoxicity of anthracyclines is thought to result from the generation of free radicals. New DNA topoisomerase II inhibitors less prone to redox reactions, such as mitoxantrone and more recently the anthrapyrazoles, were developed to circumvent this toxicity. PURPOSE: Two anthrapyrazoles currently in clinical evaluation, DuP 941 (Losoxantrone) and DuP 937, were compared to other topoisomerase II inhibitors with respect to their cytotoxic potency and selectivity and with respect to topoisomerase II inhibition. METHODS: Cytotoxicity was tested in the 60 cell lines of the National Cancer Institute preclinical antitumor drug discovery screen (NCI screen). The potency of anthrapyrazoles to inhibit purified topoisomerase II was determined. The specificity of drug-induced topoisomerase II pattern of cleavage, one of the cellular determinants of cytotoxicity, was investigated in human c-myc DNA. RESULTS: Using the COMPARE analysis, we found that the most closely related cytotoxic profiles in the NCI screen were between the anthrapyrazoles and mitoxantrone. Among topoisomerase II inhibitors, the cytostatic potency was by decreasing order: mitoxantrone; doxorubicin, which was slightly greater than DuP 941, azatoxin; DuP 937; and amsacrine, which was much greater than VP-16. The potency of mitoxantrone and anthrapyrazoles to generate DNA double-strand breaks, by induction of the topoisomerase II cleavable complexes in nuclear extracts, was in agreement with cytotoxicity. Sequencing of drug-induced topoisomerase II cleavages in c-myc DNA showed a common cleavage pattern for anthrapyrazoles and mitoxantrone. This pattern was different from the patterns obtained with other topoisomerase II inhibitors. CONCLUSION: At the molecular and cellular levels, anthrapyrazoles are potent topoisomerase II inhibitors closely related to mitoxantrone. IMPLICATIONS: These results validate the COMPARE analysis using the NCI screen to predict molecular mechanisms of drug action. Anthrapyrazoles, which are unlikely to produce free radicals, might be useful in the same indications as mitoxantrone, especially for patients with cardiac risks, for pediatric patients, and for patients treated with intensified protocols.

Anthraquinones↗
PubMed1986

A clinical trial of nafazatrom (Bay g 6575) in advanced cancer.

Nafazatrom (Bay g 6575) has been shown to be a potent inhibitor of tumor metastasis in preclinical models. It is believed to work by stimulating endogenous prostacyclin production. The drug has also been shown to inhibit the growth of certain experimental tumors, to be cytostatic for certain cell lines in tissue culture, and to induce differentiation in HL-60, neuroblastoma, and Friend erythroleukemia cell lines. Furthermore, no toxicity has been seen in animals or human volunteers. We report here a clinical trial of oral nafazatrom at five dose levels in patients with advanced cancer. Thirty patients with a wide variety of advanced malignancies were treated for 26-638+ days (median 82 days). No tumor responses were seen. Toxicity included two cases with mild skin rashes, one case with nausea and vomiting, and one case with diarrhea. Nafazatrom is a safe and well-tolerated agent. Maximum activity would be predicted to occur in the adjuvant treatment of cancer and we feel that further efforts should proceed to identify the appropriate dose for such a trial.

Adult↗
PubMedDate not supplied

Reduction of acute myocardial ischemia in rabbit hearts by nafazatrom.

The effects of oral nafazatrom pretreatment (10 mg/kg, twice a day, for 10 days) on myocardial ischemia were studied in the rabbit heart during 6-h occlusion of the left anterior descending coronary artery (LAD). The tension-time index (TTI), hemodynamics, and ischemia size were determined (Evan's blue-triphenyltetrazolium chloride staining with planimetry). In drug-vehicle controls, left ventricular (LV) and peripheral pressures and LV dP/dtmax decreased, while heart rate, end-diastolic pressure, the TTI, and electrocardiographic ST segments increased. Hemodynamics were nearly unaltered in the nafazatrom-pretreated animals, except for a heart rate elevation during the initial phase of LAD occlusion. In drug-treated hearts, 45 +/- 6% of the LAD perfusion region at risk was ischemic, showing a patchy distribution. In vehicle controls, 82 +/- 4% (p less than 0.02 vs. nafazatrom pretreatment) of the LAD-perfused myocardial regions was transmurally ischemic, showing a uniform pattern. Thus, nafazatrom pretreatment prevented most hemodynamic changes following LAD occlusion in the rabbit heart. Significant amounts of the muscle remained normoxic within the nonperfused arterial regions. These results indicate that the inhibition of lipoxygenase enzymes by nafazatrom may delay the development of ischemic damage to the heart following acute coronary artery occlusion.

Acute Disease↗
PubMed1985

Arachidonic acid cascade and the generation of ischemia- and reperfusion-induced ventricular arrhythmias.

This article reviews the evidence we found in our study that the local generation of thromboxane and prostacyclin is one important factor involved in determining the severity of the ventricular arrhythmias that result from acute myocardial ischaemia and subsequent reperfusion. The hypothesis examined is that thromboxane release, presumably from platelets, is harmful in the early stages of ischaemia (perhaps because this induces further platelet aggregation and/or a reduction in blood flow as a result of both active vasoconstriction and of mechanical obstruction) and that prostacyclin generation (presumably mainly from endothelial cells) is beneficial at this time. The evidence is that in anaesthetised greyhound dogs, blockade of the thromboxane receptor (AH 23848) or inhibition of thromboxane synthesis (with a variety of "specific" inhibitors of thromboxane synthetase such as dazoxiben, dazmegrel, and "low-dose" aspirin) slightly reduces the severity of ischaemia-induced arrhythmias and markedly increases survival after myocardial reperfusion by reducing reperfusion-induced ventricular fibrillation (e.g., from 80% in control dogs to less than 20% in treated dogs). The evidence that prostacyclin generation is helpful in this situation comes from studies with locally infused prostacyclin or iloprost and with nafazatrom, a drug that increases the amount of prostacyclin released into local coronary venous blood soon after the onset of myocardial ischaemia; these procedures also reduce the number of ventricular extrasystoles occurring during ischaemia and the incidence of reperfusion-induced ventricular fibrillation. These findings do not imply that arachidonic acid derivatives are the only, or even the main, biochemical factor involved in the generation of these arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effects of nafazatrom and indomethacin on experimental myocardial ischemia in the anesthetized dog.

The anti-ischemic effects of nafazatrom (10 mg/kg intraduodenally) have been studied in a canine model of myocardial infarction. Nafazatrom was given 30 min before and 2 h after occlusion of the left anterior descending coronary artery (LAD). Effects were compared with those after intravenous indomethacin (10 mg/kg) treatment. Infarct size was measured at 6 h of coronary occlusion by postmortem tetrazolium staining. Myocardial ischemia was reduced after nafazatrom administration, whether related to total left ventricle (18 +/- 3.3 vs. 30.7 +/- 4.8%; p less than 0.05) or to the LAD vessel area at risk for infarction (51.4 +/- 4.0 vs. 82.5 +/- 4.5%; p less than 0.01). Salvage with nafazatrom occurred in the subepicardial and endomural tissues without lateral protection. Indomethacin had no effects on infarction. The LAD occlusion-induced hemodynamic consequences were reduced at 15 min by nafazatrom and remained unchanged by indomethacin. During the following experimental course, no differences were noted between the groups. At 6 h, blood flow in the nonoccluded circumflex artery increased by 12.6 +/- 3.2 ml/min (p less than 0.05) following nafazatrom treatment. Thus, nafazatrom reduced ischemia by a mechanism unrelated to changes in hemodynamics. Most likely, this was due to 5-lipoxygenase inhibition. This may shift arachidonic acid metabolism to cyclooxygenase products and prevent release of deleterious lipoxygenase products by neutrophils during ischemic injury.

Anesthesia↗
PubMed1998

Anthrapyrazoles and interstitial laser phototherapy for experimental treatment of squamous cell carcinoma.

Interstitial laser therapy (ILT) is an effective palliative treatment for advanced head and neck cancer, but recurrence often is seen at the margin. The objective of the current study was to test combined drug and laser therapy as an experimental approach for improved treatment of human squamous cell carcinoma (SCCA). Human SCCA tumor transplants were grown in nude mice and injected with the photosensitive anthrapyrazole CI-941 before ILT. Intralesional drug injections alone at levels ranging from 60 to 1200 microg/gm of tumor induced a growth delay at the higher doses, but recurrence was seen in all 35 tumors tested. SCCA tumor transplants injected with 240 microg/gm CI-941 followed after 4 hours by ILT with the KTP532 laser led to a complete response rate of 72% (21/29) compared with 45% (13/29) for ILT alone. Laser chemotherapy was a significant improvement compared with ILT when partial and complete responses were combined (P < 0.03). The results provide preclinical evidence that laser chemotherapy may become a useful minimally invasive treatment for advanced squamous cell carcinoma of the head and neck.

Animals↗