Pharmacokinetic interaction between ϵ-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine

After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ?-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.     

Pharmacodynamic interaction of 3α-hydroxymasticadienonic acid and diligustilide against indomethacin-induced gastric damage in rats

The aims of the study were to evaluate the pharmacodynamic interaction between 3α-hydroxymasticadienonic acid and diligustilide (DLG), isolated from the plants Amphiptherygium adstringens and Ligusticum porteri, respectively, using the indomethacin-induced gastric injury model, as well as their individual gastroprotective efficacy in this model. Male Wistar rats were orally administered with 3α-hydroxymasticadienonic acid, DLG or the mixture of 3α-hydroxymasticadienonic acid-DLG (at a fixed-ratio combination of 1:1, 1:3, and 3:1). Thirty minutes later, the gastric damage was induced by a single oral dose of indomethacin (30 mg/kg). Three hours later, the gastric injury (mm²) was determined. 3α-hydroxymasticadienonic acid and DLG as individual compounds showed a gastroprotective effect against indomethacin-induced gastric damage (p < .05). The effective dose (ED₅₀) values for each compound were 6.96 ± 1.25 mg/kg for 3α-hydroxymasticadienonic acid and 2.63 ± 0.37 mg/kg for DLG. The isobolographic analysis performed showed that the combination exhibited super-additive interaction as the experimental ED₅₀ values (Zexp) were lower than theoretical additive dose values (Zadd; p < .05). Our results identify the super-additive (synergist) interaction between 3α-hydroxymasticadienonic acid and DLG and the gastric safety of both compounds in the indomethacin—induced gastric injury model, suggesting their potential in the future as a strategy to decrease the gastric damage associated to the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).     

Reduced clearance of ε-acetamidocaproic acid in rats with acute renal failure induced by uranyl nitrate

Objectives Anti-ulcer drugs are frequently used in patients with acute renal failure (ARF). Zinc acexamate is ionized to zinc and ε-acetamidocaproic acid and free EACA exerts a potent therapeutic effect in treating gastric or duodenal ulcers with few side effects. Thus, pharmacokinetic changes in rats with acute renal failure induced by uranyl nitrate (U-ARF rats) were investigated in this study. Methods The in-vivo pharmacokinetics and in-vitro hepatic/intestinal metabolism of EACA were assessed using control and U-ARF rats. The mechanism of urinary excretion of EACA was further investigated in rats. Key findings After intravenous and oral administration of zinc acexamate to U-ARF rats, there were significant increases in the values of the area under the curve (AUC) and decreases in the values for time-averaged renal and nonrenal clearances (Cl(r) and Cl(nr) , respectively) compared with control rats. Slower Cl(nr) was partly due to a decrease in the metabolism in liver and/or intestine. Slower Cl(r) could have been due to urine flow rate-dependent timed-interval renal clearance, decrease in organic anion transporter-mediated renal excretion (drug interaction with probenecid and decrease in the relative contribution of net secretion compared with glomerular filtration in U-ARF rats) and/or impaired kidney function. Conclusions The pharmacokinetics were significantly altered in U-ARF rats due to the changes in both the hepatic/intestinal metabolism and urinary excretion.     

Pharmacokinetics and first-pass effects of ϵ-acetamidocaproic acid after administration of zinc acexamate in rats

1. Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg^?1) and oral (100?mg kg^?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg^?1) and oral (20, 50, and 100?mg kg^?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg^?1 were evaluated in rats.

2. After oral administration of ZAC (20?mg kg^?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.

3. Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml^?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.

     

Interleukin 1β-induced inhibition of gastric acid secretion involves glutamate,NO and cGMP synthesis in the brain

This study examines the role of a central pathway involving glutamate receptors, nitric oxide (NO) and cGMP in the acute inhibitory effects of central interleukin 1beta on pentagastrin-stimulated acid production.The acid-inhibitory effect of central interleukin 1beta was prevented by intracisternal (i.c.) microinjections of interleukin 1beta together with the NMDA receptor antagonist, dizocilpine maleate (MK-801). Intracisternal co-administration of the nitric oxide synthase inhibitor, N(G)-nitro- L-arginine methyl esther ( L-NAME) or 1H-[1,2,4]oxazodiolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase (sGC) blocker, both reversed the hyposecretory effect of central interleukin 1beta. Peripheral administration of endotoxin significantly reduced pentagastrin-stimulated gastric acid secretion. I.c. pre-treatment with the interleukin 1 receptor antagonist, IL-1ra, failed to restore acid secretory responses in these rats. In addition, endotoxin did not modify the levels of endogenous mRNA for IL-1beta in the brainstem.We conclude that central glutamate receptors are involved in the acid inhibitory effect of centrally administered interleukin 1beta. This central pathway involves synthesis of NO, which acts on the enzyme sGC. However, endogenous interleukin 1beta does not seem to be involved in the inhibition of gastric acid secretion elicited by peripheral endotoxin.     

Therapeutic role and its mechanism of gypenosides on delayed healing of experimental gastric ulcer induced by NCTC11637 strain HP in rats

AIM: To investigate the adverse action of Helicobacter pylori(HP) (NCTC11637 strain ) and the therapeutic effect ofGypenosides (GP) isolated from Gynostemma pentaphyllum onulcer healing in rats. METHODS: After ulcer induction byacetic acid in the stomach, rats were divided into 4 groups. Theywere eithe given ig with distilled water or with CagA ( ) andVacA ( ) NCTC1163HP (1 mg·kg~(-1)·d~(-1) ) alone or togetherwith GP (15 or 45 mg·kg~(-1)·d~(-1) ) for 9 d. The changes of     

Tumor necrosis factor alpha (TNF-α) blockage reduces acute inflammation and delayed wound healing in oral ulcer of rats

Inflammopharmacology - Oral traumatic ulcers (OTU) are common in dental routine, and the control of proinflammatory cytokines, such as the tumor necrosis factor-alpha (TNF-α), may interfere...     

Intracerebroventricular injection of a TRH analogue, γ-butyrolactone-γ-carbonyl-l-histidyl-prolinamide induces gastric lesions and gastric acid stimulation in rats

Summary The effects of TRH and its biologically stable analogue, -butyrolactone--carbonyl-l-histidyl-l-prolinamide (DN-1417), on gastric mucosa and acid secretion were examined in rats. Intracerebroventricular (ICV) injection of DN-1417 (0.1–10 g) caused a dose-dependent gastric lesion in the corpus and antrum 6 h after administration. The gastric lesions produced by 1 g of DN-1417 were more severe than those produced by ICV TRH (10 g), intravenous DN-1417 (200 g) and stress. Although the lesion-generating effect of TRH (10 g) tended to be reduced 6 h after the injection, that of DN-1417 (1 g) was sustained during 6 h. Atropine (0.1 and 1 mg/kg s.c.) inhibited DN-1417-induced gastric lesions in a dose-related manner while sulpiride (10 and 30 mg/kg s.c.), haloperidol (1 mg/kg i.p.), phentolamine (1 and 5 mg/kg s.c.) and yohimbine (5 mg/kg s.c.) did not prevent the lesions. ICV DN-1417 also stimulated basal gastric acid secretion and the effect was stronger and longer-lasting than that of TRH. Atropine (0.1 mg/kg s.c.) stopped DN-1417-stimulated gastric acid secretion. In conclusion, the possibility that TRH may be involved in the CNS modulation of gastric mucosal integrity deserves further attention. The enhanced potency of action of DN-1417 over TRH could make ICV injection of this peptide a useful tool for inducing centrally-mediated gastric lesions in rats.     

Absence of interaction between δ9-tetrahydrocannabinol (δ9-THC) and cannabidiol (CBD) in aggression,muscle control and body temperature experiments in mice

Summary In this report we give the results of some experiments on the effects of the hashish constituents ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) on mice. THC produced a dose dependent depression of aggression in isolated mice and a dose dependent depression of body temperature in group caged mice. The drug did not alter motor co-ordination. CBD showed a small, not significant influence on aggressiveness, and no influence on body temperature and muscle control. The same experiments were carried out with combinations of THC and CBD in several dosages.In these experiments no interaction between both compounds was seen. This means that there can only be an additive action and not potentiation in the pharmacological sense. It also means that the in vitro inhibition by CBD of the drug metabolizing enzymes, responsible for biotransformation of THC, is not strong enough to result in changed effects of THC in the living animal.     

Concomitant use of mirtazapine and cimetidine: a drug–drug interaction study in healthy male subjects

Objective: The objective of this study was to examine the pharmacokinetics and the tolerability/safety of mirtazapine and cimetidine separately and in combination following oral administration of multiple doses. Methods: This was a double-blind, placebo-controlled, two-period cross-over, multiple-dose pharmacokinetic interaction study in 12 healthy male subjects. They received either cimetidine (800 mg b.i.d.) or placebo in combination with (commercially available, racemic) mirtazapine (30 mg nocte). Cimetidine and placebo were administered for 14 days, with mirtazapine added during days 6–12 of each period. Serial blood samples for kinetic profiling were taken on day 5 and day 12 for cimetidine and on days 12–14 for mirtazapine. Results: The co-administration of cimetidine resulted in a statistically significant increase in the area under the curve (AUC_0–24) and C_max of mirtazapine (54% and 22% respectively). The AUC_0–24 of demethylmirtazapine increased only slightly, and there was no effect on C_max. The elimination half-lives for both mirtazapine and its demethyl metabolite were unaffected by cimetidine co-administration. The trough and average plasma concentrations during the steady state were elevated during cimetidine treatment (62% and 54%, respectively). Mirtazapine had no effect on the pharmacokinetics of cimetidine. Conclusion: Co-administration of cimetidine (800 mg b.i.d.) and mirtazapine (30 mg nocte) resulted in increased steady-state plasma levels of mirtazapine (C_ss,min= +61%, P < 0.05; C_ss,av=+54%, P < 0.05), probably as a result of increased bio-availability. The C_max (+22%, P < 0.05) and AUC_0–24 (+54%, P < 0.05) also increased. Due to the variability of the mirtazapine plasma levels in patients, the clinical meaning of these increases is probably limited. Co-administration of mirtazapine did not alter cimetidine pharmacokinetics. Received: 24 November 1999 / Accepted in revised form: 15 May 2000     

Alleviation of bone markers in rats induced nano-zinc oxide by qurecetin and α-lipolic acid

The purpose of this study was to evaluate the potential protective effect of qurecetin (Qur) and α-lipolic acid (ALA) to modulate the perturbation of bone turnover which is induced by nano-zinc oxide (n-ZnO). Rats were fasted overnight and randomly divided into two groups: G1, normal healthy animals and the other rats were administered zinc oxide nanoparticles orally by guava in a dose of 600?mg/kg body weight/d for 5 sequential days in Wistar albino male rats. N-ZnO-exposed animals were randomly sub-divided into three groups: G2, n-ZnO-exposed animals; G3, n-ZnO-exposed animals co-treated with Qur (200?mg/kg daily); and G4, n-ZnO-exposed animals co-treated with ALA (200?mg/kg). Qur and ALA were administered orally by guava daily for three sequential weeks from the beginning of the experiment. The results revealed a significant reduction of nitiric oxide (NO) and serum level and comet assay in n-ZnO exposure rats after treatment of Qur and ALA. It was found the alteration of pro-inflammatory markers (tumor necrosis factor alpha; TNF-α, interleukin-6; IL-6 and C-reactive protein; CRP), bone alkaline phosphatase (B-ALP, bone formation marker), and C-terminal peptide type I collagen (CTx, bone resorption marker) levels compared with the normal group. Co-administration of Qur and ALA in n-ZnO-exposed rats significantly alleviated the mentioned alterations of biochemical parameters. These results suggest that Qur and ALA as antioxidant agents may be a candidate for preventive and treatment applications of impaired bone markers induced bone loss caused by nano-particles of metal oxide.     

Evaluation of metabolomic profiling against renal toxicity in Sprague–Dawley rats treated with melamine and cyanuric acid

Melamine-induced renal toxicity is associated with crystal formation in the kidney following exposure to melamine and cyanuric acid. However, metabolomic profiling of intact kidney tissue after chronic intake of melamine and cyanuric acid (M?+?CA) mixtures has rarely been studied. The present study investigated the melamine-induced renal toxicity by determining metabolites in the kidney through [¹H]nuclear magnetic resonance. Melamine (63?mg/kg) and cyanuric acid (6.3?mg/kg) were co-administered to rats via oral gavage for 30?days. The mixture of M?+?CA (63/6.3?mg/kg) induced nephrotoxicity, as determined by increased blood urea nitrogen (BUN) and creatinine levels. The kidney weights were significantly increased in the animals treated with M?+?CA (63/6.3?mg/kg). The histological analysis revealed epithelial degeneration and necrotic cell death in the proximal and distal tubules. Furthermore, various metabolites were altered in both renal medullar and cortical tissues. In the medullar tissues, asparagine, choline, creatinine, cysteine, ethanolamine, glucose, isoleucine, glutamine, and myo-inositol levels were elevated, but glucitol, phenylalanine, tyrosine, and sn-glycero-3-levels were reduced. In the cortex, ethanolamine, hypoxanthine, isoleucine and o-phosphoethanolamine levels were increased, whereas formate, glucose, glutathione, threonine, and myo-inositol levels were decreased, suggesting the M?+?CA-induced renal cell injury. These data suggest that a mixture of M?+?CA-induced metabolites may be useful biomarkers for the detection of kidney injury.     

In vitro inhibition of UGT1A3, UGT1A4 by ursolic acid and oleanolic acid and drug–drug interaction risk prediction

1.?Ursolic acid (UA) and oleanolic acid (OA) may have important activity relevant to health and disease prevention. Thus, we studied the activity of UA and OA on UDP-glucuronosyltransferases (UGTs) and used trifluoperazine as a probe substrate to test UGT1A4 activity. Recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as a probe reaction for other UGT isoforms.

2.?UA and OA inhibited UGT1A3 and UGT1A4 activity but did not inhibit other tested UGT isoforms.

3.?UA-mediated inhibition of UGT1A3 catalyzed 4-MU-β-d-glucuronidation was via competitive inhibition (IC₅₀ 0.391?±?0.013?μM; K_i 0.185?±?0.015?μM). UA also competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC₅₀ 2.651?±?0.201?μM; K_i 1.334?±?0.146?μM).

4.?OA offered mixed inhibition of UGT1A3-mediated 4-MU-β-d-glucuronidation (IC₅₀ 0.336?±?0.013?μM; K_i 0.176?±?0.007?μM) and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation (IC₅₀ 5.468?±?0.697?μM; K_i 6.298?±?0.891?μM).

5.?Co-administering OA or UA with drugs or products that are substrates of UGT1A3 or UGT1A4 may produce drug-mediated side effects.     

Use of methimazole and risk of acute pancreatitis: A case–control study in Taiwan

Objective:

Some cases of acute pancreatitis have been reported to be associated with use of methimazole. The aim of this study was to investigate the relationship between use of methimazole and risk of acute pancreatitis on the basis of a systematic analysis.

Methods:

This was a population-based case–control study analyzing the database of the Taiwan National Health Insurance Program. There were 5764 individuals aged 20–84 years with a first attack of acute pancreatitis from 1998 to 2011 as the cases and 23,056 randomly selected sex- and age-matched individuals without acute pancreatitis as the controls. Use of methimazole was categorized as “never use” and “ever use.” We estimated the relative risk of acute pancreatitis associated with the use of methimazole by calculating the odds ratio (OR) with 95% confidence interval (CI) using a multivariable logistic regression model.

Results:

After adjustment for confounding factors, the OR of acute pancreatitis was 0.91 in individuals with ever use of methimazole, when compared with individuals with never use of methimazole (95% CI, 0.60–1.38). Unlike methimazole use, alcohol-related disease, biliary stone, cardiovascular disease, chronic obstructive pulmonary disease, diabetes mellitus, hepatitis B, hepatitis C, and hypertriglyceridemia were factors significantly associated with acute pancreatitis.

Conclusions:

Our study does not detect a substantial association between the use of methimazole and risk of acute pancreatitis on the basis of systematic analysis. There appears to be a discrepancy between case reports and our systematic analysis about the association between the use of methimazole and risk of acute pancreatitis.KEY WORDS: Acute pancreatitis, alcoholism, biliary stone, diabetes mellitus, methimazole     

Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days: relationship between cell cycle aberration and carcinogenesis

Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28?days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen, p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex?+?OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα-immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G(2). OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G(2)/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G(2) arrest in the target tubular cells.     

γ-Hydroxybutyric acid (GHBA) induces pacemaker activity and inhibition of substantia nigra dopamine neurons by activating GABAB-receptors

Summary In the present study the actions of -hydroxybutyric acid (GHBA) on dopaminergic neurons in the rat substantia nigra (SN) were pharmacologically analysed utilising extracellular single unit recording techniques. Intravenous administration of GHBA was associated with several effects on the neuronal activity of nigral dopamine (DA) neurons. Low doses (<200 mg/kg) of GHBA produced a slight excitation of the neurons, concomitant with a regularised firing rhythm and lack of burst activity. In higher doses GHBA produced an even higher degree of regularisation but, in contrast to low doses, an inhibition of firing rate. Administration of the GABA_B-receptor agonist baclofen, in all essential respects, mimicked the effect of GHBA on the firing of nigral DA neurons. Both the regularisation of the firing pattern and inhibition of firing rate produced by systemic administration of GHBA were antagonised by the GABA_B-receptor antagonist CGP 35348 (200 mg/kg, i.v.).Our observations show that GHBA affects the firing pattern of nigral DA neurons in doses considerably lower than those required to inhibit the firing rate of the neurons. This action, as well as the decreased firing rate observed after high doses of GHBA, are mediated via activation of GABA_B-receptors. Correspondence to: G. Engberg at the above address     

Do indomethacin and cimetidine or Cu(cimetadine)2 affect the nature of superoxide dismutase activity in the liver of copper-deficient rats?

1. Control and copper-deficient rats were treated with: (i) indomethacin; (ii) indomethacin in the presence of cimetidine; and (iii) indomethacin in the presence of Cu(cimetidine)₂. The levels of copper, zinc and manganese as well as the nature of superoxide dismutase activity in the liver were studied.2. Copper deficiency caused a decrease of enzyme SOD activity, EDTA-insensitive (by 84%) and the appearance of nonenzyme SOD-like activity, EDTA-sensitive. The levels of copper and zinc decreased by 67% and 40% and the manganese level increased by 53%.3. The above-mentioned treatments (i, ii, iii) of copper-deficient rats induced a progressive increase of enzyme SOD activity (by 19, 90 and 176%, respectively) without, however, changing nonenzyme SOD-like activity. It was only indomethacin treatment in the presence of Cu(cimetidine)₂ that increased the copper level in control (by 82%) and copper-deficient (by 182%) rats.4. The liver contained 4 CuZnSOD- and 1 MnSOD-isoenzymes, whose number and position on the gel were affected neither by copper deficiency nor by indomethacin treatment in the presence of Cu(cimetidine)₂. Copper deficiency significantly increased the MnSOD-band and reduced the CuZnSOD-bands, particularly that with pI ∼ 5.7. Indomethacin in the presence of Cu(cimetidine)₂ changed neither the MnSOD-band nor the reduced CuZnSOD-band with pI ∼ 5.7, but restored to normal all the other CuZnSOD-bands.