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PubMed2001

[Separation and determination of ephedrine alkaloids and 2,3,5,6-tetramethyl pyrazine in Ephedra herba by HPLC].

A sensitive and reliable high performance liquid chromatographic method(HPLC) has been developed for the first time for the simultaneous determination of the active ingredients of ephedrine alkaloids and 2,3,5,6-tetramethyl pyrazine (TMP) in Ephedra herba crude drug and two Chinese traditional medicines (Xiao-er qingfeiwan and Lu-si kewan). The HPLC assay was performed on a reversed phase C18 column (Nova-Pak C18, 3.9 mm i.d. x 150 mm) by using methanol-0.02 mol/L KH2PO4-acetic acid-triethyl amine (4:96:0.2:0.01, V/V) as mobile phase for the ephedrine alkaloids analysis and methanol-H2O-acetic acid (35:65:0.5, V/V) as mobile phase for TMP analysis. Regression equations revealed the linear relationships (correlation coefficients: 0.991-0.998) between the peak area of each constituent (E, PE, NE, NPE, TMP) and its concentration. The detection limits for E, PE, NE, NPE and TMP were 0.4 mg/L, 0.1 mg/L, 0.03 mg/L, 0.02 mg/L and 0.03 mg/L, respectively, and the recoveries ranged between 92%-103%. The contents of E, PE, NE, NPE, TMP in Ephedra herba, traditional medicine Xiao-er qingfeiwan and Lu-si kewan were determined respectively. The relative standard deviations (RSD) of the contents ranged between 1.1%-3%.

Alkaloids↗
PubMed2002

Pharmacokinetic changes of intravenous 2-(allylthio) pyrazine, a chemoprotective agent, in rats with acute renal failure induced by uranyl nitrate.

It was reported that the total body clearance (CL) of 2-(allylthio)pyrazine (2-AP) was significantly faster after intravenous administration of 2-AP to rats pretreated with 3-methylcholanthrene (an inducer of CYP1A1/2 and 2E1 in rats) than that in control rats. It was also found that the CYP2E1 increased 2-4 times in rats with acute renal failure induced by uranyl nitrate (U-ARF) compared with those in control rats. Therefore, it could be expected that the pharmacokinetics of 2-AP could be changed in rats with U-ARF. After intravenous administration of 2-AP, 50 mg/kg, to rats with U-ARF, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of 2-AP was significantly smaller (1030 versus 1360 microg min/ml) and this could be due to significantly faster CL of 2-AP (48.4 versus 36.8 ml/min/kg). This could be due to increased CYP2E1 in rats with U-ARF. More studies are required to find increased metabolite(s) of 2-AP in rats with U-ARF.

Acute Kidney Injury↗
PubMed1978

[Tricyclic homologs of piperazine. III. Synthesis of 4-substituted hexahydro-1H-2,6-methanopyrrolo[1,2a]pyrazines].

The Authors describe the synthesis of some quaternary salts of the hexahydro-1H-2,6-methanopyrrolo[1,2-a]pyrazines mono or disubstituted at carbon-4. These were obtained directly by cyclization of the corresponding diazabicyclooctanes, by formation of a substituted ethylenic bridge between the two nitrogen atoms. The compounds were pharmacologically screened; the hypothesis of enhancement of curare-like activity in comparison with the unsubstituted derivatives was not confirmed.

Animals↗
PubMed1990

[Effect of penicillamine and tetramethyl pyrazine on the hypoxic pulmonary hypertension in rats].

Penicillamine (P) and tetramethyl-pyrazine (T) were administered to treat experimentally hypoxic pulmonary hypertension in rats exposed to hypoxia of 380 torr for up to 21-days. The results of this study showed: Hypoxia increased RVP, the RV/LV + S ratio, the MT% and the MA%. P and T all prevented the hypoxia-induced increases in RVP, the RV/LV + S ratio, but the effect of T on the pulmonary artery remodeling induced by hypoxia was weaker than that of P. The MT% and the MA% were significantly lower in H/P group than in H group (P less than 0.01, P less than 0.05; respectively). Although the MT% was lower in H/T group than in hypoxia group (P less than 0.05), there was no statistical difference in the MA% between H/T group and H group (P greater than 0.05). The MT% and the MA% were significantly lower in H/PT group than in H group (P less than 0.01, P less than 0.01, respectively), and there was no statistical difference in MA% between H/PT group and N group (P greater than 0.05). It was concluded that P prevented primarily pulmonary artery remodeling induced by hypoxia and T inhibited mainly hypoxic pulmonary vasoconstriction response, so prevented partially hypoxic pulmonary hypertension and right ventricular hypertrophy.

Animals↗
PubMed1990

Antitumor activity of ethyl 5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido [3,4-b]pyrazin-7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) against selected tumor systems in culture and in mice.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin- 7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) was evaluated for antitumor activity against a spectrum of tumor systems in culture and in mice. NSC 370147 was cytotoxic to a variety of mouse and human cell lines at nanomolar concentrations. The compound exhibited good in vivo antitumor activity against several murine tumors (P388 and L1210 leukemia, colon 11/A and 36, mammary 16/C, and M5076 sarcoma). Activity was largely independent of route of administration but favored a prolonged treatment schedule. NSC 370147 was as active against murine leukemia sublines resistant to Adriamycin, amsacrine, vincristine, melphalan, cisplatin, methotrexate, and CI-920 (a topoisomerase II inhibitor) as against the corresponding parental lines. Only the 1-beta-D-arabinofuranosylcytosine-resistant P388 subline exhibited any cross-resistance to NSC 370147. NSC 370147 has a spectrum of activity similar to that of vincristine and, unlike vincristine, is active against multidrug-resistant cell lines. Therefore, NSC 370147 is a candidate for clinical trial because of its favorable activity compared to vincristine, its effectiveness against multidrug-resistant cells, and its retention of activity for p.o. administration.

Animals↗
PubMed1988

[UV-spectrophotometry in drug control. 41. Drug substances with chromophores and auxochromes in monocyclic compounds (pyrazolone, pyrazolidine, pyridazine, pyrimidine and pyrazine) and bicyclic compounds (benzoxazole, imidazole, benzthiazole and indene)].

The results of a systematic examination of the spectra of 15 drug substances with chromophores and auxochromes in monocyclic (pyrazolone, pyrazolidin, pyridazine, pyrimidine and pyrazine) and bicyclic compounds (benzoxazol, imidazole, benzthiazole and indene) in the UV and visible range were evaluated. Influences of substituents and solvents on shifts of the E, K, B and R bands were discussed.

Benzothiazoles↗
PubMedDate not supplied

Studies on pyrazine derivatives. Part XIII. synthesis and tuberculostatic activity of some 6-alkyl-amino- and 6-dialkylhydrazinopyrazine-2-carboxylic acids derivatives.

6-RNH- and 6-R2NNH-pyrazine-2-carbothioamides 1--3, 5, 6, 9 and 14 were obtained from 2-cyano-6-chloropyrazine. In the in vitro screening the thioamides were active against Myc. tuber. H37Rv at the conc. range of 15.6--250 microgram/cm3. The most active thioamides 1 and 8, however, do not act in experimental tuberculosis in guinea pigs.

Amines↗
PubMed1982

Inhibition of mitosis and anticancer activity against experimental neoplasms by ethyl 5-amino-1,2-dihydro-3-[(N-methylanilino)methyl]-pyrido[3,4-b]pyrazin-7-ylcarbamate (NSC 181928).

Ethyl 5-amino-1,2-dihydro-3-[N-methylanilino)methyl]pyrido[3,4-b]pyrazin-7-ylcarbamate (NSC 181928) is reported to be active against several experimental neoplasms. The experimental data obtained in the present study indicate that it causes the accumulation of cells at mitosis with both cultured cells and ascites cancer cells in vivo. This effect was observed with L1210, P388, colon cancer 26, colon cancer 38, and H.Ep. 2 cells in culture and with L1210 cells and P388 cells in mice. The agent was also active in vitro and in vivo against a line of leukemia P388 cells that are resistant to vincristine.

Animals↗
PubMedDate not supplied

Studies on the quantitative structure-activity relationships in pyrazine carbothioamide derivatives.

Quantitative relationships were studied between tuberculostatic potency in vitro and structure parameters of pyrazine carbothioamides. The activity of the compounds was found to be dependent on the parameters related both to the size of the substituent and electronic properties of the molecule. An equation was obtained, statistically significant on the 99% level, which described about 71% of variance of activity data for the compounds under study as a function of molar refractivity of the substituent and the wave length at which absorption maximum occured.

Amides↗
PubMed1993

[Effects of toxins, apamine, charybdotoxin and iberiotoxin on the relaxation of the smooth muscular fiber induced by imidazo(1,2-a)pyrazine derivative].

Experiments have been performed in order to analyse the mechanism whereby SCA40, a new imidazo[1,2-a]pyrazine derivative relaxes airway smooth muscle. We investigated the effect of different toxins, known to be K(+)-channel blockers on guinea-pig smooth muscle relaxant activity of SCA40. The small conductance Ca(2+)-activated K(+)-channel blocker apamin (100 nM) did not antagonize the relaxant activity of SCA40 in 1 microM carbachol-contracted isolated guinea pig trachea. The large conductance Ca(2+)-activated K(+)-channel blocker, iberiotoxin (30, 60 and 180 nM) antagonized the relaxant activity of SCA40 in an apparently competitive manner. The concentration-relaxation curves to SCA40 were shifted to the right with no significant alteration in the maximum response. The relaxant activity of SCA40 in 1 microM carbachol-contracted isolated trachea was antagonized by both charybdotoxin (60 nM) and iberiotoxin (60 nM), but the antagonism induced by iberiotoxin appears to be more potent than that induced by charybdotoxin. It is concluded that the potent relaxant activity of SCA40 on guinea-pig airway smooth muscle in vitro involves a charybdotoxin and iberiotoxin sensitive K(+)-channel.

Animals↗
PubMed1995

Inhibition of human immunodeficiency virus type 1 replication by 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, an in vivo metabolite of oltipraz.

Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication in vitro (ED50 approximately 10 microM), undergoes extensive metabolism in vivo. Most of the orally administered drug undergoes opening of the dithiolethione ring, reduction, recyclization, and methylation to form 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine ("metabolite III"). We report here that metabolite III inhibits viral replication in vitro (ED50 approximately 25 microM) in acutely infected H9 and CEM T cell lymphoma cell lines. Although both metabolite III and oltipraz were able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in the chronically infected U1 promonocytic leukemia cell line, only metabolite III was able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in chronically infected ACH-2 T cell lymphoma cells. The results with ACH-2 cells suggest that oltipraz inhibits an early stage of the viral life cycle, whereas metabolite III affects human immunodeficiency virus type 1 replication at a step distal to viral integration. This is consistent with the finding that oltipraz inhibits reverse transcriptase, whereas metabolite III does not. Although the mean ED50 for metabolite III in acutely infected peripheral blood mononuclear cells was 18 microM, the ED50 was below 5 microM in three of eight independent experiments. Studies of metabolite III in combination with oltipraz in acutely infected peripheral blood mononuclear cells demonstrated significant antiviral synergy. These results raise the possibility that the in vitro potency of oltipraz may underestimate its antiretroviral activity in vivo. Based on these results, the pharmacokinetics of oltipraz and metabolite III will be compared with the pharmacodynamic effects of orally administered oltipraz in a forthcoming phase I/II trial of oltipraz in patients with p24 antigenemia.

Antiviral Agents↗
PubMed1993

Long-term treatment with the antidepressants fluoxetine and desipramine potentiates endocrine responses to the serotonin agonists 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI).

Various endocrine responses to 5-hydroxytryptamine (serotonin, 5-HT) agonists were used to assess serotonergic receptor function after chronic treatment with the antidepressants fluoxetine (10 mg/kg), a 5-HT uptake blocker and the norepinephrine uptake blocker desipramine (DMI, 5 mg/kg). Both were injected (i.p.) once a day for 21 days. DOI (5-HT1C/2 agonist, 0-5 mg/kg i.p.) and 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) (less selective, but predominantly a 5-HT1C agonist, 0-20 mg/kg i.p.) were administered 18 hr after the final antidepressant injection and 30 min before decapitation. Chronic treatment with both fluoxetine and DMI produced a potentiation in most hormone responses to the 5-HT agonists (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) and MK-212, although there were several differences in individual hormone responses to the two 5-HT agonists. Fluoxetine and DMI potentiated the MK-212- and DOI-induced increase of plasma oxytocin levels and potentiated the effect of DOI on plasma adrenocorticotropic hormone (corticotropin) and prolactin levels. In contrast, the effect of the high dose of MK-212 on plasma prolactin concentration was reduced by both antidepressants. Only MK-212 increased vasopressin levels and this effect was potentiated by fluoxetine, but not by DMI. Fluoxetine also significantly increased the resting level of plasma vasopressin. DMI potentiated the effect of MK-212 on plasma renin concentration. Pretreatment with fluoxetine significantly increased (38%) the Bmax for the 5-HT1C/2 agonist sites ([125I]DOI) in the hypothalamus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Phase I evaluation and pharmacokinetic study of pyrazine-2-diazohydroxide administered as a single bolus intravenous injection in patients with advanced solid tumors.

The sodium salt of pyrazine-2-diazohydroxide (PZDH; NSC 361456) was identified as an active congener of the antitumor lead pyridine-2-diazotate with enhanced chemical stability under physiological conditions. In a phase I trial of PZDH administered as a single i.v. bolus injection, 19 patients with refractory solid tumors received 44 courses of therapy at dose levels ranging from 50 to 350 mg/m2. No objective responses to PZDH were noted. Myelosuppression characterized by prolonged, delayed onset leukopenia and thrombocytopenia was the dose limiting toxicity. A maximum tolerated dose of 350 mg/m2 was identified for this treatment schedule. Nonhematological toxicity was limited to severe nausea and vomiting, experienced by all patients treated at the lower doses, although reasonably well controlled when antiemetics were given prior to chemotherapy. The plasma pharmacokinetics of PZDH was evaluated following a single course of therapy in 16 patients. Drug levels were monitored using a specific capillary gas chromatographic assay with a 1-ng/ml lower limit of quantitation. In patients treated with doses greater than 50 mg/m2, the concentration of PZDH in plasma declined in a distinctly triexponential manner and remained above 1.5 ng/ml for at least 8 h. However, the initial decay phase, characterized by a harmonic mean half-life of 3.9 +/- 3.5 (SD) min (range, 2.2-6.3 min), was the primary determinant of drug disposition, as indicated by its 85.5-93.1% contribution to the area under the plasma concentration-time profiles from time zero to infinity. The harmonic mean terminal half-life increased with escalations in dose from 2.7 +/- 0.8 h (n = 2) at 100 mg/m2 to 8.5 +/- 3.0 h at 350 mg/m2 (n = 6). Total plasma drug clearance was very similar in patients treated with doses of 50-250 mg/m2, exhibiting a mean value of 42.5 +/- 7.8 liters/h/m2 (n = 10); however, it was significantly lower at the 350 mg/m2 dose level, 27.2 +/- 6.6 liters/h/m2 (n = 6; P < 0.002), denoting a departure from linear pharmacokinetic behavior. The rather low steady state apparent volume of distribution, which ranged from 6.0 +/- 1.5 (50 mg/m2, n = 2) to 12.7 +/- 8.0 (350 mg/m2, n = 6) liters/m2, was indicative of limited distribution of the drug into body tissue. The absence of objective antitumor effects should not discourage continued evaluation of PZDH against solid tumors selected for probable sensitivity as indicated by preclinical testing. A dose of 250 mg/m2 on a single i.v. bolus schedule is recommended for these phase II trials.

Adult↗
PubMed1996

[Effect of tetramethyl pyrazine on coronary vasoconstriction induced by endothelin-1 in dogs].

The purpose of this study was to determine the antagonistic effect of tetramethyl pyrazine (TMP), a sort of chinese herbal medicine, on coronary vasoconstriction induced by endothelin-1 (ET-1) in closed chest dogs. ET-1 at doses of 50, 75 and 100 pmol was selectively administered into left main coronary artery and coronary angiogram was performed in 1, 3 and 10 minutes after intracoronary administration of ET-1. After a 60 minute interval ET-1 administration and coronary angiogram were repeated in two groups in group A with 5 dogs intravenous infusion of saline solution was administered while in group B with 4 dogs TMP was infused at a dose of 80 mg/kg. Blood pressure of intra-femoral artery, heart rate and ECG were monitored during the experiment. The study demonstrated that coronary vessel diameter significantly decreased by 17% (P < 0.02) in group A and 20% (P < 0.02) in group B, associated with ischemia in ECG (4/5 in group A and 3/4 in group B) after intracoronary administration of ET-1. Endothelin-1 induced coronary vasoconstriction and ischemic changes in ECG were significantly inhibited by intravenous TMP. The coronary diameter increased by 20% (P < 0.03) after administration of TMP, comparing with the control group. Heart rate had an increased response to TMP. In conclusion this study demonstrated that intracoronary administration of ET-1 caused significant myocardial ischemia through coronary vasoconstriction, which was inhibited by TMP. TMP significantly dilated coronary artery.

Animals↗