Platelet activating factor receptors drive CXC chemokine production, neutrophil influx and edema formation in the lungs of mice injected with Tityus serrulatus venom.

Lung injury is a common finding and a frequent cause of death in cases of severe human envenoming by scorpion sting. The present work investigated the effects of pretreatment with a platelet activation factor receptor (PAFR) antagonist and a CXCR2 inhibitor on the lung injury induced by subcutaneous injection of Tityus serrulatus venom (TsV) in mice. Lung injury was assessed by evaluating the extravasation of Evans blue dye, as an index of increased vascular permeability, the neutrophil accumulation (mieloperoxidase activity), the concentration of tumor necrosis factor-alpha (TNF-alpha) and the chemokine KC in the lung after TsV administration. Neutrophil influx was preceded by the production of KC and dependent on CXCR2, as shown by the ability of repertaxin, a CXCR2 inhibitor, to prevent an increase of MPO activity in the lung. Repertaxin had no effect on TsV-induced lethality. The PAFR antagonist (UK-74,505) significantly reduced TsV-induced vascular permeability changes and neutrophil influx in the lungs. The inhibition of neutrophil influx was associated with inhibition of the production of the CXCR2-active chemokine KC. UK-74,505 had no effect on the lethality induced by TsV. In conclusion, these results show that the influx of neutrophils in the lungs of mice injected with TsV is dependent on the activation of PAFR and on PAFR-dependent production of the chemokine KC as well as activation of CXCR2 on neutrophils. Although lung injury may contribute to late lethality after TsV envenoming, acute lethality is not modified by inhibitors of neutrophil influx.     

Acute toxicity of cyclohexylmethylphosphonofluoridate (CMPF) in rhesus monkeys: serum biochemical and hematologic changes

 Changes in serum biochemical and hematological parameters were studied in 20 male rhesus monkeys following acute poisoning by the organophosphate nerve agent cyclohexylmethylphosphonofluoridate (CMPF or GF). Animals were challenged with 5×LD50 GF (233 μg/kg, IM) following pretreatment with pyridostigmine (0.3–0.7 mg/kg per 24 h) and treated with atropine (0.4 mg/kg, IM) and either 2-PAM (25.7 mg/kg, IM) or HI6 (37.8 mg/kg, IM) at the onset of clinical signs or at 1 min after exposure. Muscle fasciculations, tremors, or convulsions occurred in 19 of 20 animals. Serum biochemical and hematologic parameters were analyzed 2 days and 7 days after exposure and compared to pre-exposure baseline values. Significant increases in creatine kinase (CK), lactate dehydrogenase (LD), aspartate transaminase (AST), alanine transaminase (ALT) and potassium ion (K⁺), associated with damage to striated muscle and metabolic acidosis, occurred in both oxime-treated groups 2 days after exposure. Total protein, albumin, red blood cell (RBC) count, hemoglobin concentration (Hb) and hematocrit (Hct), were decreased in both oxime-treated groups at 7 days. The results demonstrate that animals exposed to a single high dose of GF and treated with standard therapy exhibit changes in serum biochemical and hematological indices directly and indirectly associated with their clinical presentations. Received: 15 November 1993 / Accepted: 29 August 1994     

Effect of total and partial nephrectomy on the elimination of ciprofloxacin in humans

BackgroundRenal cell carcinoma (RCC) is the most common form of kidney cancer. Surgery is a standard procedure to resect the tumor during total (TN) or partial (nephron-sparing) nephrectomy (PN). Ciprofloxacin is most often administered at the usual intravenous dose of 100–400 mg/12 h. The application of such low doses of ciprofloxacin as 200 mg/24 h carries the risk of achieving subtherapeutic concentrations even in patients with limited renal function. The aim of the study was a comparison of concentrations and pharmacokinetics for ciprofloxacin at steady-state in patients after total and partial nephrectomy and evaluation of the effectiveness of the iv dose 200 mg/24 h against the theoretical value of MIC, 0.5 μg/ml.MethodsThe research was carried out on two groups of patients after nephrectomy: total (group 1, n = 21; mean [SD], age, 62.9 [14.4] years; weight, 76.0 [14.6] kg; creatinine clearance, clcr, 90.7 [22.2] ml/min) and partial (group 2, n = 15; 61.7 [9.3] years; 87.8 [16.4] kg; CL_CR, 107.8 [36.4] ml/min). The patients were treated with ciprofloxacin in the dose of 200 mg/24 h (iv). Plasma concentrations of ciprofloxacin at steady state were measured with validated HPLC method with UV detection.ResultsThe mean values of plasma concentrations of ciprofloxacin at steady state in group 1 and 2 were: C^ss_max, 2.012 and 1.345; C^ss_min, 0.437 and 0.244 μg/ml, respectively. The main pharmacokinetic parameters for ciprofloxacin in group 1 and 2 were as follows: AUC_(0–last), 30.9 [17.9] and 19.5 [8.7] μg h/ml; AUMC_(0–last), 177.91 [11.1] and 91.9 [66.5] μg h²/ ml; _t1/2β, 13.9 [7.7] and 9.8 [3.3] h; MRT, 16.5 [12.1] and 9.77 [5.4] h; V_d, 115.0 [67.2] and 142.2 [78.7] l; CL, 6.2 [3.3] and 10.8 [5.7] l/h, respectively. With the assumed MIC = 0.5 μg/ml, the values of C^ss_max/MIC < 10 and AUC/MIC < 125 were obtained in all the patients.ConclusionIn our patients we observed significant differences in some pharmacokinetic parameters of ciprofloxacin after two types of nephrectomy.     

Unaltered [3H]GBR-12935 binding after chronic treatment with dopamine active drugs

Rats were injected intraperitoneally with haloperidol 0.5 mg/kg, raclopride 1 mg/kg, bromocriptine 2.5 mg/kg,d-amphetamine 2.5 mg/kg, or cocaine 10 mg/kg twice daily for 21 days. The animals were sacrificed 72 h after last injection. Control rats were injected with saline, following the same schedule. The radioligand [³H]GBR-12935 was used as a presynaptic marker for dopamine neurites. There were no significant differences in [³H]GBR-12935 binding to striatum between drug-treated rats and controls.     

Ascorbic acid decreases the antifungal effect of fluconazole in the treatment of candidiasis

• 1 The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro.
• 2 The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated.
• 3 The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125–64 µg/mL) were also investigated. The in vitro effects of two anti‐oxidants, namely N‐acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA.
• 4 Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose‐dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA.
• 5 In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose‐dependently decreased the activity of FCZ.
• 6 The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.

     

Neonatal death and lung injury in rats caused by intrauterine exposure to O,O,S-trimethylphosphorothioate

O,O,S-Trimethyl phosphorothioate (OOS-TMP) is an impurity present in a number of widely used organophosphorus insecticides and has been recognized as a potent lung toxicant. OOS-TMP was given p.o. to pregnant rats on gestation day (G) 20 at 0.5, 2.5, 10 and 40 mg/kg. Control dams or pair-fed dams (pair-fed to 40 mg/kg) received 2 ml/kg corn oil. Neonates from treated dams died within 72 h after delivery in a dose-related manner: 100% at 40 mg/kg, 86% at 10 mg/kg, 15% at 2.5 mg/kg, 1% at 0.5 mg/kg, with 3% in controls and 2% in neonates from pair-fed dams. Neonates from treated (40 or 10 mg/kg) and control dams were cross-fostered. The cross-fostering did not affect mortality of neonates from either dosed dams or from control dams. Disposition of OOS-TMP was studied by using [³H]-OOS-TMP at 0.5, 2.5 and 10 mg/kg. Concentrations of OOS-TMP equivalent in fetal lung were about one half of those in mothers at all doses. In another set of experiments, dams (five dams for each dose) were dosed on G 20 with OOS-TMP p.o. at 0, 0.5, 2.5, 10, and 40 mg/kg or pair-fed (pair-fed to 40 mg/kg) and the fetuses were delivered by cesarean section (C-section) on G 23. In neonates from dams dosed with 10 and 40 mg/kg, cyanosis occurred within 4 h after C-section. Histopathological examination revealed dose-related proliferation of type II pneumocytes in dams and proliferation of interstitial cells and delayed septal/capillary development in neonates. However, we could not detect these changes in control fetuses or in fetuses from pair-fed dams. Even at 0.5 mg/kg we found changes in pulmonary morphology in dams and neonates. In other organs such as, liver, brain, spleen, adrenal gland and kidney, we could not detect any morphological changes at 40 mg/kg in either dams or neonates. Thus it was concluded that OOS-TMP caused lung injury in neonates by intrauterine exposure and elicited a lethal response in the neonates.     

黄芪皂苷甲对血浆cAMP及再生肝DNA合成的影响

Astragalus saponin 1, one of the components isolated from Astragalus membranaceus Bge was found to induce accumulation of cAMP in rabbit plasma at the ip dose of 10mg/kg. The increase of cAMP started at 30 rain and reached maximum in 0.5～4h after a single injection. The effect of the component on DNA biosynthesis in partially hepatectomized mice seemed to be significant. The component was also shown to enhance the incorporation of [³H] TdR into the regenerating liver in mice.     

Anticonvulsant activity in photosensitive baboons,Papio papio,of two new 1,5 benzodiazepines

Two new 1,5 benzodiazepines have been evaluated acutely as anticonvulsants in baboons, Papio papio, with photosensitive epilepsy. BAU 426 (8-Chlor-6-[2-chlorphenyl]-4H-s-triazolo-[4,3-a] [1,5-benzodiazepin-5-[6-H]on) and BAU 500 (analogue of BAU 426 with [2-trifluor methylphenyl] substituted for [2-chlorphenyl]), 0.1–5.0 mg/kg, were administered i.v. to baboons with and without priming with D,l allylglycine.BAU 426 or BAU 500, 0.1–0.2 mg/kg, produced partial or transient protection against photically induced myoclonus or epileptic responses. Complete protection, in the absence of signs of sedation or acute neurological toxicity, was seen 1–4 h after 0.5–2 mg/kg. EEG changes typical of benzodiazepines were seen for 1–3 h and clinical signs of sedation with some muscular hypotonia were evident for 1 h after either drug, 5 mg/kg.Clinical trials are required to determine if these compounds are superior to 1,4 benzodiazepines as anticonvulsants.     

Evaluation of the concomitant use of methotrexate and curcumin on Freund's complete adjuvant-induced arthritis and hematological indices in rats

Objective:

To evaluate the concomitant administration of methotrexate and curcumin for antiarthiritic activity in rats.

Materials and Methods:

Arthritis was induced in rats following a single subplantar injection of Freund''s complete adjuvant (0.1 ml). Rats were divided into six groups of six animals each. Group I and II were control injected with saline and Freund''s complete adjuvant (0.1 ml), respectively. Group III arthritic rats were treated with curcumin (100 mg/kg, i.p.) on alternate days. Group IV received methotrexate (MTX) (2 mg/kg, i.p.) once in a week. Group-V and VI were treated with MTX (1 mg/kg, i.p.) once in a week and after 30 min received curcumin (30 mg/kg and 100 mg/kg, thrice a week, i.p.) from 10^th to 45^th days, respectively. Body weight and the paw volume was measured on 9^th, 16^th, 23^rd, 30^th, 37^th, and 45^th days. Determination of complete blood cell counts, hemoglobin concentration, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin concentration was determined on the 46^th day.

Results:

An improvement in body weight and a significant (P < 0.05) reduction in arthritis was observed with the combination treatment as compared to the positive control. A significant improvement in the hematological profile was also observed in rats treated with curcumin and methotrexate.

Conclusion:

The study showed a significant anti-arthritic action and protection from hematological toxicity with the combination treatment of methotrexate and curcumin.     

Effects of Tityus serrulatus scorpion venom on lung mechanics and inflammation in mice

The present study evaluated the effects of an intramuscular injection of Tityus serrulatus venom (TsV) (0.67 μg/g) on lung mechanics and lung inflammation at 15, 30, 60 and 180 min after inoculation. TsV inoculation resulted in increased lung elastance when compared with the control group (p < 0.001); these values were significantly higher at 60 min than at 15 and 180 min (p < 0.05). Resistive pressure (ΔP₁) values decreased significantly at 30, 60 and 180 min after TsV injection (p < 0.001). TsV inoculation resulted in increased lung inflammation, characterised by an increased density of mononuclear cells at 15, 30, 60 and 180 min after TsV injection when compared with the control group (p < 0.001). TsV inoculation also resulted in an increased pulmonary density of polymorphonuclear cells at 15, 30 and 60 min following injection when compared to the control group (p < 0.001). In conclusion, T. serrulatus venom leads to acute lung injury, characterised by altered lung mechanics and increased pulmonary inflammation.     

Modulation of Th1/Th2 cytokine production by selective and nonselective phosphodiesterase inhibitors administered to mice

Phosphodiesterase (PDE) inhibitors can modulate the functions of immune cells, including T lymphocytes, due to increased intracellular levels of cyclic nucleotides. The drugs (aminophylline, milrinone and sildenafil) were administered once or five times at 24 h intervals at the following doses: 20 mg/kg, im, 1 mg/kg, im and 1 mg/kg, po, respectively.Th1 and Th2 cytokine levels (IL-2, IFN-γ, IL-4, IL-5, TNF) were determined 12, 24 or 72 h after the last administration of the drugs. A commercial BD^TM Cytometric Bead Array Mouse Th1/Th2 Cytokine Kit (CBA) was used to determine the levels of Th1/Th2 cytokines in the serum.Neither of the PDE inhibitors under investigation administered once changed IFN-γ, TNF and IL-4 production. A single dose of aminophyl-line decreased the production of IL-2 (after 12 h). A single dose of milrinone did not affect Th1/Th2 cytokine secretion. Sildenafil administered once decreased the production of IL-2 (after 72 h). A temporary enhancement in the level of IL-5 was observed 12 h after a single dose of sildenafil. No changes in Th1 and Th2 cytokine production were observed after five doses of PDE inhibitors under investigation. These results indicate that nonstimulated lymphocytes Th1 and Th2 exhibited a slight sensitivity to aminophylline and sildenafil. The drugs under investigation were ineffective inhibitors of Th1/Th2 cytokine production.     

Distribution and metabolism of O-Ethyl O-4-nitrophenyl phenylphosphonothioate after a single oral dose in one-week old chicks

The toxicokinetics and metabolism of a single 1 mg (2.7 Ci/kg) oral dose of uniformly phenyl-labeled [¹⁴C]EPN (O-ethyl O-4-nitrophenyl [¹⁴C]phenylphosphonothioate) have been studied in 1-week old chicks. One control and three treated chicks were killed at each of the following time intervals: 0.5, 2, 4, 8, and 12 days. Radioactivity was rapidly absorbed from the gastrointestinal tract and distributed in all tissues. ¹⁴C in tissues reached a peak of 16.9% of the dose after 0.5 day and decreased to 0.6% at 4 days. The tissues of the gastrointestinal tract had the highest concentration of radioactivity, followed by bile and liver. Among nervous tissues, concentration of ¹⁴C was highest in the peripheral nerves. The spinal cord had the next highest concentration, while the brain had the least. After 4 days 91.3% of the ¹⁴C had been eliminated in the combined urinary-fecal excreta. By the end of the 12-day experiment this percentage reached 93.1%. No ¹⁴C was detected in the expired CO₂. Following the oral administration of [14C]EPN, a monophasic body level curve was observed. The half-life for the elimination of ¹⁴C from chick body was 16 h, corresponding to a rate constant of 0.04 h^–1. Most of the excreted ¹⁴C materials were identified as O-ethyl phenylphosphonic acid, phenylphosphonic acid, and O-ethyl phenylphosphonothioic acid.     

Altered metabolism of serotonin in the brain of the rat after chronic ingestion of d-amphetamine

Dextro-amphetamine at doses of 1 mg/kg/day was administered intragastrically to rats for one month. At 18 h after the final dose, a small (16%) increase of brain serotonin concentration was found as well as an increase (30%) of the synthesis and degradation of [³H] serotonin formed from intracisternally injected exogenous [³H]-l-tryptophan.This study was supported by USPHS Grant MH 16674-02.     

Amphetamine Decreases α2C-Adrenoceptor Binding of [11C]ORM-13070: A PET Study in the Primate Brain

Background:

The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands.

Methods:

We explored the use of the novel α_2C-adrenoceptor antagonist PET tracer [¹¹C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [¹¹C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys.

Results:

Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [¹¹C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [¹¹C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [¹¹C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP _ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP _ND values by 31–50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata.

Conclusions:

Together, these results indicate that [¹¹C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect.     

Mechlorethamine (NTG) effects on the erythrocytic and leukocytic blood parameters during experimentally induced pleuritis in rats

BackgroundAccording to cytotoxic and mutagenic properties, nitrogranulogen (NTG) changes the character of inflammatory reactions. Our previous studies have shown that NTG can enhance immunological defense reactions, because of its high affinity to DNA, and causes disorders in the synthesis of acute phase proteins (e.g., haptoglobin, transferrin, fibrinogen and complement protein C3) [15]. The aim of the current studies was to determine the influence of three different NTG doses: 5 µg/kg b.w. (body weight), 50 µg/kg b.w. and 600 µg/kg b.w. (cytotoxic dose) on the values of hematological blood parameters: RBC, HGB, HCT, RDW, MCV, MCH, MCHC, PLT, MPV, PCT, PDW, WBC, NEUT, LYMPH, MONO, EOS and BASO in pleuritis-induced rats.MethodsThe animals were randomized into five groups: Group I – control group; Group II – IP (induced pleuritis) group; Group III – NTG5 group; Group IV – NTG50 group; Group V – NTG600 group. The blood was collected from all the groups at the 24^th h, 48^th h, and 72^nd h after the initiation of the carrageenin-induced inflammatory reaction.ResultsThese investigations have revealed that NTG administered at the dose of 5 µg/kg b.w. caused the drop of the leukocyte and lymphocyte numbers and the rise of the neutrophil number at the 72^nd h of the experimental-induced inflammatory reaction. Moreover, the dose of: 5 µg/kg b.w. was an immunomodulatory property and it also increased the erythrocytic parameters. On the contrary, NTG applied at the doses of 50 µg/kg and 600 µg/kg b.w. contributed to the drop of both: the erythrocytic and leukocytic parameters during the whole time of the inflammatory reaction.ConclusionsThe results suggest that nitrogranulogen affects the erythropoiesis.     

The biotransformation of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. After oral or intravenous doses (0.25?mg/kg) of [¹⁴C]lormetazepam to rats, most of the urinary radioactivity was associated with polar components and < 1% dose was excreted as unconjugated lormetazepam. About 30% of an oral dose was excreted in rat bile as a conjugate of lormetazepam and about 50% dose as polar metabolites. Plasma also contained mainly polar metabolites, and unchanged lormetazepam represented at most 10% of total plasma radioactivity after an oral dose.

2. Almost all the radioactivity in dog, rhesus monkey and rabbit urine, after oral or intravenous doses (0.5–0.7?mg/kg) of [¹⁴C]lormetazepam, was associated with conjugated material. In the dog there were only two major components, conjugates of lormetazepam and lorazepam (N-desmethyl-lormetazepam) which accounted for about 24% and 14% respectively of the oral dose in the 0–24?h urine. The same two conjugated components were also present in dog bile. Conjugated lormetazepam was the only major component in monkey and rabbit urine and accounted for about 60% dose in the 0–24?h urine of each species, while conjugated lorazepam accounted for only about 0.5% and 4% respectively.

3. Dog and monkey plasma contained mostly conjugated material after oral and intravenous doses (0.05–0.07?mg/kg of [¹⁴C]lormetazepam. Dog plasma after an oral dose contained conjugates of both lormetazepam and lorazepam with peak concn. at 1?h of 130 and 47 ng/ml respectively. Concn. of these conjugates in plasma declined with apparent terminal half-lives of about 17 and 27?h respectively after oral doses, and 13?h in both cases after intravenous doses. Conjugated lormetazepam was the only major component in monkey plasma representing a peak concn. of 180 ng/ml at 1?h after an oral dose, and declined with an apparent terminal half-life of about 11?h after oral or intravenous doses.

4. Lormetazepam crosses the placental ‘barrier’ of rabbits: its concn. in the foetus were similar to those in maternal plasma after intravenous doses.     

The effect of sodium chromate pretreatment on mercuric chloride-induced nephrotoxicity

Sodium chromate (20 mg/kg, s.c.), which in male rats inflicted necrotic damage mainly in the p₁ region (proximal part of the proximal convoluted tubules), protected against proximal tubular necrosis induced by 0.5 or 3.0 mg Hg²⁺/kg in the P₂ (distal part of the proximal convoluted tubules) and P₃ (pars recta part of the proximal tubules) regions. Histochemical staining for mercury indicated that chromate increased mercury deposition in those cells of the p₁ region which were unaffected by chromate (had intact brush border) but did not decrease mercury deposition in the most severely affected P₃ region. Chromate pretreatment actually increased mercury deposition in the kidneys of animals killed 24 h after the injection of 0.5 mg Hg²⁺. The protective effect was mutual. Cellular proliferation and fibrosis observed 4–5 days after chromate were prevented by injecting 0.5 mg Hg²⁺/kg 3 days after chromate treatment.     

The metabolic fate of tizoprolique acid in baboons

1. After oral administration of the anti-lipolytic drug [¹⁴C]tizoprolique acid (2-propyl-5-carboxy1[4-¹⁴C]thiazole), to baboons (60?mg/kg), the radioactivity was well absorbed and rapidly excreted. During 6 and 24?h respectively, 60±25% (S.D.) and 90±2% were excreted in the urine.

2. Plasmaconcn. of ¹⁴C reached a max. (182±65, range 85–221 ±g equiv./ml) at 1–1.5?h after an oral dose, and declined rapidly with an apparent half-life of about 0.5?h. A mean of 77±7% of the ¹⁴C in peak plasma samples was bound to plasma proteins, somewhat less than that of [¹⁴C]tizoprolique acid (84±5%).

3. Tissue concn. of ¹⁴C were highest in an animal killed at 0.5?h after an oral dose, but were lower than those in plasma in all tissues examined except the kidneys.

4. The major metabolite of tizoprolique acid was its glycine conjugate, which accounted for about 80% dose excreted in the 24h urine. About 2% dose was excreted as unchanged drug. About 70% and 20% respectively of plasma ¹⁴C were associated with the unchanged drug and its glycine conjugate during the period 15?min to 4h after dosing.     

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration

1. Z-7760 (S(?)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy- 1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. ³H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 μCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total ³H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma ³H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma ³H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given ³H-Z-7760 p.o. (0.4?mg and 40 μCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with ³H-Z-7760 (0.4?mg and 400 μCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% ³H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100?mg/kg, 40 μCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.     

Hesperidin potentiates the neuroprotective effects of diazepam and gabapentin against pentylenetetrazole-induced convulsions in mice: Possible behavioral,biochemical and mitochondrial alterations

Aim:

Epilepsy is a chronic neurological disorder with complex pathophysiology. Several evidences suggest a role of oxidative stress and mitochondrial dysfunction in pathophysiology of epilepsy. Hesperidin (Hesp) acts as a powerful anti-oxidant agent against superoxide, singlet oxygen, and hydroxyl radicals. Thus, this study was undertaken to evaluate the possible neuroprotective mechanism of Hesp against pentylenetetrazole (PTZ)-induced convulsions in mice.

Materials and Methods:

Sixty males Laca mice (20-25 g) were randomly divided into 10 treatment groups (n = 6). Seven days pretreatment of Hesp (100, 200 mg/kg, p.o.) was carried out before PTZ (80 mg/kg, intraperitoneal [i.p.]) challenge, whereas diazepam (DZP) (0.2, 0.5 mg/kg) and gabapentin (Gbp) (10, 20 mg/kg) were administered i.p. 30 min before PTZ administration, that is, on 7^th day. Following PTZ challenge, severity of convulsions (onset of jerks, myoclonic seizures, extensor phase and death), brain anti-oxidant enzyme levels and mitochondrial complex enzymes activities were estimated.

Results:

Single i.p. PTZ (80 mg/kg) challenge demonstrated severe convulsions, oxidative damage (raised lipid peroxidation [LPO], nitrite concentration as well as depleted reduced glutathione, superoxide dismutase and catalase levels), and depletion of mitochondrial enzyme Complex (I, II, IV) activities. Hesp (200 mg/kg), DZP (0.5 mg/kg) and Gbp (20 mg/kg) pretreatments attenuated PTZ induced behavioral, biochemical and mitochondrial alterations. However, administration of Hesp (100 mg/kg) in combination with DZP (0.2 mg/kg) or Gbp (10 mg/kg) potentiated their neuroprotective effect, which was significant as compared to their effects in PTZ treated animals.

Conclusion:

Hesp possesses potent anticonvulsant activity which might be mediated through modulation of gamma-amino butyric acid/benzodiazepine receptor action.KEY WORDS: Mitochondrial dysfunction, myoclonic jerks, oxidative stress, seizure