Acetaminophen nephrotoxicity in male Wistar rats

Acute acetaminophen (APAP) nephrotoxicity was studied in male Wistar rats 1 h after different APAP single doses (200, 500 and 1000 mg/kg body wt, i.p.). Significant impairments in glomerular filtration rate (GFR) and clearance ofp-aminohippuric acid (Cl_PAH) were observed in a dose-dependent way, although tubular parameters measured, water and electrolyte fractional excretion, remained at control values, while the urine to plasma osmolality ratios (U_osm/P_osm) were diminished in APAP-1000 rats (control=2.93 ±0.20, APAP-1000=1.40±0.04). The time course of renal function was also studied in APAP-1000 mg/kg-treated animals; parallel impairments were observed in GFR, Cl_PAH and tubular functions. Maximal alteration was observed at 16 h and restorement began at 24 h post-injection. Glucose renal handling, either at low or at high tubular glucose loads, remained at control values. Thus, our data suggest that the early stage of acetaminophen nephrotoxicity might be due to renal hemodynamic changes which might induce an alteration in tubular function principally in distal structures of medullary tissue, as shown by the U_osm/P_osm results. These effects occurred coupled with a diminution in hepatic glutathione (GSH) levels at every APAP dose and in renal GSH levels in APAP-1000 mg/kg-treated rats. Moreover, renal damage was observed both in the presence or absence of hepatic damage.     

Studies on protective effect of Cyperus Scariosus extract on acetaminophen and CCl4-induced hepatotoxicity

• 1.1. The hepatoprotective activity of aqueous-methanolic extract of Cyperus scariosus (Cyperaceae) was investigated against acetaminophen and CCl₄-induced hepatic damage.
• 2.2. Acetaminophen produced 100% mortality at a dose of 1 g/kg in mice while pretreatment of animals with plant extract (500 mg/kg) reduced the death rate to 30%.
• 3.3. Acetaminophen at a dose of 640 mg/kg produced liver damage in rats as manifested by the rise in serum levels of alkaline phosphatase (ALP), glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) to 430 ± 68, 867 ± 305 and 732 ± 212 IU/1 (n = 10) respectively, compared to respective control values of 202 ± 36, 59 ± 14 and 38 ± 7.
• 4.4. Pretreatment of rats with plant extract (500 mg/kg) significantly lowered (P < 0.05) the respective serum ALP, GOT and GPT levels to 192 ± 31, 63 ± 9 and 35 ± 8.
• 5.5. The hepatotoxic dose of CCl₄ (1.5ml/kg; orally) raised serum ALP, GOT and GPT levels to 328 ± 30, 493 ± 102 and 357 ± 109 IU/1 (n = 10) respectively, compared to respective control values of 177 ± 21, 106 ± 15 and 47 ± 12.
• 6.6. The same dose of plant extract (500 mg/kg) was able to significantly prevent (P < 0.05) CCl₄-induced rise in serum enzymes and the estimated values of ALP, GOT and GPT were 220 ± 30, 207 ± 95 and 75 ± 38, respectively.
• 7.7. The plant extract also prevented CCl₄-induced prolongation in pentobarbital sleeping time confirming hepatoprotectivity.
• 8.8. These results indicate that the Cyperus scariosus possesses hepatoprotective activity and thus, rationalizes the folkloric use of this plant in hepato-biliary disorders.

     

Convulsive Effect of Theophylline in Conscious and Anaesthetized Guinea-pigs

Abstract: In urethane-anaesthetized guinea-pigs, the effect of theophylline (theo) on heart rate, arterial blood pressure, respiration rate and limb movements were recorded. Continuous intravenous infusion of theo initially increased the respiratory and heart rates and lowered the arterial blood pressure. After infusion of about 50 mg/kg of theo, the cardiovascular effects reached a maximum and were then only slightly changed until the terminal stage. A tonic stretching of the limbs (at 155 ± 15 mg/kg) preceded generalized seizures of clonic tonic convulsions which were recorded after infusion of 367 ± 25 mg/kg of theo. At this stage, respiration was highly irregular. PaO₂ started to fall and PaCO₂ to rise, while a plasma acidosis developed rapidly. The convulsions progressed in frequency and intensity and were terminally associated with respiratory and cardiovascular collapse. The convulsive effects of theophylline were similar to those observed in conscious guinea-pigs after 250 mg/kg of theo orally. The present findings agree with the view that the convulsive effect is a primary life-threatening action of theophylline. The method described may be of use in the search for new, less toxic xanthine drugs.     

Renal Effects of α-Adrenoceptor Blockade During Furosemide Diuresis in Conscious Rats

Abstract: Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective α-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n=6) was compared with time control animals (n=9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n=9), 0.3 (n=6), 1.0 (n=7) and 3.0 mg/kg/hr (n=6). Phentolamine infusion reduced noepinephrine-induced increase in blood pressure at all three dose levels (n=5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FE_Li) increased to 65±3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52±3% during furosemide alone. At steady-state conditions (120–180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FE_Li=48±2% versus 39±1%> in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular α-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.     

Survival of Verapamil-Poisoned Rats Treated with Triiodothyronine

Life-threatening toxicity due to calcium channel blocker ingestion is commonly encountered by emergency medicine physicians and toxicologists. Despite a vast array of research on its treatment, results have proven inconsistent. The goal of this study is to evaluate potential vasopressor effects of triiodothyronine (T3) in rats poisoned with verapamil. Following anesthesia and intubation, ten Sprague–Dawley rats were given intravenous verapamil infusion of 10 mg/kg/h. This dose was titrated until a mean arterial pressure (MAP) of 50–55 mmHg was achieved and maintained for a period of at least 5 min. The verapamil infusion was then maintained at that rate. Five rats were randomized to receive a T3 bolus of 0.4 mcg/kg preceding an infusion of 1.5 mcg/kg/day which was doubled every 2 min until any of the following endpoints: systolic blood pressure of 100 mmHg, an elapsed time of 60 min, or death. The other five received an equal volume of normal saline solution. The primary outcome measure was survival with secondary outcomes of MAP and heart rate. The T3 group did have a slightly longer, yet not statistically significant, average time to cessation of electrical activity—30.0?±?14.4 min versus 23.8?±?9.5 min in the placebo group. Average MAP decreased nearly identically in the two groups. Heart rates were not reliable indicators of toxicity in this rat model as there was little decrease until immediately prior to death in most animals. Despite significant variability in toxicity among individual animals, no statistically significant difference in survival time, heart rate, or MAP was found between groups treated with T3 and those receiving saline.     

Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis

Objective: Mitiglinide, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and α-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients.

Research design and methods: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 – 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb_A1c), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters.

Results: The final dose of mitiglinide was 22.9 ± 8.9 (mean ± s.d.) mg (0.41 mg/kg) daily. Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and Hb_A1c levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed.

Conclusions: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment.     

The prevention of acetaminophen-induced hepatotoxicity by the interferon inducer poly(rI·rC)

When mice were pretreated with the interferon inducer poly(rI·rC) for 24 hr, the mortality caused by acetaminophen was significantly reduced. Acetaminophen doses up to 600 mg/kg which killed 100% of the saline-treated control mice caused no deaths in poly(rI·rC)-treated animals. Even doses as high as 900 mg/kg acetaminophen killed only 38% of the animals. Histological examination of the livers demonstrated that acetaminophen-induced necrosis was decreased in poly(rI·rC)-treated animals compared to controls. Significant protection against necrosis was observed even with doses as high as 900 mg/kg acetaminophe. Following a dose of 300 mg acetaminophen, 0.67 ± 0.5 nmol/mg protein were covalently bound to liver protein in control mice compared to 0.33 ± 0.02 nmol/mg protein bound in poly(rI·rC)-treated mice. This protective effect of poly(rI·rC) did not result from an increase in hepatic glutathione content; in fact, the glutathione level was depressed in animals treated with poly(rI·rC). Since cytochrome P-450 levels were depressed in these experiments, it is concluded that poly(rI·rC) depresses the cytochrome P-450 species responsible for the formation of the toxic metabolite and less reactive species are available for binding to cell macromolecules. It is likely that the toxicity of acetaminophen will be decreased considerably during viral infections which promote the formation of interferon.     

Cardiovascular and respiratory effects induced by a purified scorpion toxin (tityustoxin) in unanesthetized rats

Intravenous injection of a purified scorpion toxin (tityustoxin) into unanesthetized rats induced acute pulmonary edema, which was directly related to the dose and the time of intoxication. To study the cardiovascular and respiratory effects evoked by an edematogenic dose of the toxin (1 mg/kg), the following parameters were recorded in unanesthetized rats: systolic, diastolic and mean arterial pressure; central venous pressure; electrocardiogram; respiratory movements. The toxin induced acute systolic and diastolic hypertension, bradycardia and bradypnea. During a 1 hr period, the systolic, diastolic and mean arterial pressure fell progressively to control values, whereas the central venous pressure did not change significantly. The cardiac and respiratory rates remained lower than the control values during a 1 hr period. Several changes in the respiratory pattern were recorded, such as gasping, prolonged and labored expiration, ataxic rhythm and noisy inspiration with the mouth open. These respiratory changes were explained, in part, by the presence of edema in the lungs and froth in the trachea. From a group of 24 rats, 6 died 18 – 30 min after tityustoxin injection. The cause of death was apnea. The female rats were more susceptible to pulmonary edema and death than the male rats.     

Comparison of inhalation toxicity studies of gentamicin in rats and dogs

Abstract

Nebulized gentamicin solution was administered to rats (nose-only) and dogs (face mask) for 14 days with a 14-day recovery period. Control groups of each were exposed to saline aerosols. Mean estimated inhaled lung doses of gentamicin were 39, 123 and 245?mg/kg for rats (deposited doses 6, 17 and 34?mg/kg) over 30, 90 and 180?min, respectively. Since dogs do not tolerate exposures as long as rats, inhaled lung doses were limited to 7, 14 and 41?mg/kg (deposited doses of 1, 3 and 8?mg/kg) over 15, 30 and 60?min. Comparable doses were achieved at the low dose for rats and high dose for dogs. Serum AUCs (14?±?2?µg/mL*h (mean?±?SD) at 6?mg/kg in rats and 11?±?7?µg/mL*h at 8?mg/kg in dogs) showed comparable exposure between the two, implying similar absorbed doses and confirming similar deposited lung doses. Rat exposures resulted in dose-related lung pathology (including low dose) manifested as upper respiratory tract irritant reactions with alveolar histiocytosis, inflammation, airway epithelial metaplasia and lymphomegaly in lung tissue. This was associated with high lung tissue gentamicin levels 24?h post-dose on Day 14 (375?±?33?µg/g at deposited dose of 6?mg/kg). Dose-related kidney tubular necrosis (a well-known toxicity of parenteral gentamicin) was observed, but no test-article related effects on lung histopathology in dogs (even at highest deposited dose of 8?mg/kg) and low levels of lung tissue gentamicin (42?±?11?µg/g) 24?h post-dose on Day 14.     

硫辛酸对酒石酸锑钾解毒作用的研究

本文研究了国产硫辛酸对酒石酸锑钾的解毒作用.结果证明硫辛酸对酒石酸锑钾的急性及亚急性毒性均有非常显著的解毒作用.小白鼠腹腔注射酒石酸锑钾后,立即以130毫克/公斤的硫辛酸灌胃或皮下注射,可分别使酒石酸锑钾的急性LD₅₀提高1.6和1.9倍.在急性试验中,酒石酸锑钾为LD₉₅时,2-3分子硫辛酸可对抗1分子酒石酸锑钾;在亚急性试验中,酒石酸锑钾为LD₅₀时,1分子硫辛酸即可对抗1分子酒石酸锑钾.腹腔注射酒石酸锑钾LD₅₀后3小时皮下注射硫辛酸,可完全保护小白鼠免于死亡.硫辛酸性质稳定,口服吸收良好,在锑剂中毒出现症状后仍然有效,值得在临床试用.     

Pulmonary and cardiovascular effects of mefloquine methanesulfonate

Mefloquine methanesulfonate (WR-142, 490·CH₃SO₃H), a highly effective antimalarial agent, when infused at a dose rate of 1 mg/kg/ min for 20 min in the anesthetized dog, caused either little or no effect on the pulmonary and cardiovascular parameters measured during this drug infusion or in the following 3-hr observation period. However, dose rates of 2 and 3 mg/kg/min of mefloquine MS for 20 min did produce pulmonary and cardiovascular changes. The respiratory parameters which were observed to change were: (1) tidal volume, which fell during the drug infusion but then returned to control values during the remaining portion of the observation period; (2) respiratory rate, which rose during the drug infusion, but returned to control values; (3) dynamic airways resistance, which decreased during drug administration, but then rose above control values; (4) small gradual changes in blood p_O2 and p_CO2. The cardiovascular parameters observed to change were: (1) arterial blood pressure, which decreased during the drug infusion, but returned rapidly to control values; (2) cardiac contractile force, which diminished during the drug infusion and returned toward control values later in the observation period; (3) central venous pressure, which rose transiently during drug administration; (4) pulmonary artery pressure, which rose initially, but tended to decrease late in the observation period and returned to control values within a 24-hr period. The magnitude of the effects of mefloquine MS appeared to be more dependent on the dose rate of drug delivery than on the total dose delivered.     

Cadmium and vascular reactivity in the rat.

The effect of multiple doses of cadmium on insulin secretion from the perfused pancreas was studied. In addition, urine and plasma glucose, plasma immunoreactive insulin, and the rate of evolution of respiratory ¹⁴CO₂ after administration of [UL-¹⁴C]d-glucose were determined. The treated groups received two dose levels, 0.25 or 0.50 mg Cd/kg, ip every second day for 70 doses. Multiple doses of 0.50 mg/kg caused an inhibition in the amount of insulin secreted from the perfused pancreas, whereas multiple doses of 0.25 mg/kg caused a partial inhibition that was not statistically significant. With the exception of the plasma insulin concentration in animals receiving multiple doses of 0.50 mg/kg, statistically significant differences in the plasma glucose, plasma insulin, and insulinogenic index were not detected. A high glucose concentration as well as a high concentration of ¹⁴C in the urine of treated animals was found. Treated animals expired smaller amounts of ¹⁴CO₂ than the controls. Animals receiving the higher dose showed significantly lower weights than either the controls or the animals receiving the lower dose, which did not differ significantly from each other.     

Cannabinoid CB(1) receptor blockade enhances the protective effect of melanocortins in hemorrhagic shock in the rat

Activation of peripheral cannabinoid CB(1) receptors contributes to hemorrhagic hypotension, and endocannabinoids produced by macrophages and platelets may be mediators of this effect. A number of studies have provided evidence that functional links exist in the mechanisms of action of cannabinoids and opioid peptides; and opioids too play an important role in the pathophysiology of hemorrhagic hypotension and shock. On the other hand, melanocortin peptides, which are the main endogenous functional antagonists of opioid peptides, have an antishock effect in animals and humans. Thus, we investigated whether an interaction exists between endocannabinoids and the endogenous opioid/antiopioid system also in a condition of hemorrhagic shock and, particularly, whether the blockade of cannabinoid CB(1) receptors potentiates the antishock effect of melanocortins. Urethane-anesthetized rats were stepwise bled until mean arterial pressure decreased to, and stabilized at, 21-23 mm Hg. In this model of hemorrhagic shock, which caused the death of all control rats within 30 min after vehicle (tween 80, 5% in saline) injection, the intravenous (i.v.) bolus injection of the cannabinoid CB(1) receptor antagonist N-piperidino-5-[4-chlorophenyl]-1-[2,4 dichlorophenyl]-4-methyl-3-pyrazolecarboxamide (SR141716A) increased mean arterial pressure, pulse pressure, respiratory rate and survival rate in a dose-related manner (0.1-3 mg/kg), an almost complete recovery of mean arterial pressure, pulse pressure and respiratory rate, and 100% survival at the end of the observation period (2 h), occurring with the dose of 3 mg/kg. The melanocortin ACTH-(1-24) (adrenocorticotropin) also produced in a dose-related manner (0.02-0.16 mg/kg i.v.) a restoration of cardiovascular and respiratory functions, and increased survival rate, an almost complete recovery and 100% survival at the end of the observation period (2 h) occurring with the dose of 0.16 mg/kg. When a subactive dose of SR141716A (0.2 mg/kg; 30% survival) was associated with a subactive dose of ACTH-(1-24) (0.02 mg/kg; 12% survival), a complete reversal of the shock condition was obtained with 100% survival at the end of the 2-h observation period. The present results show that the concurrent inhibition of both endogenous opioid and cannabinoid systems produces a reversal of hemorrhagic shock more effective than that produced by the inhibition of either of them. These data suggest that functional interactions between endocannabinoids and opioid/antiopioid are at work also in the pathophysiology of hemorrhagic shock.     

Stimulation of glucose release of the rat kidney in vivo by epinephrine and isoprenaline.

In anesthetized rats the glucose release of the kidneys was estimated from the glucose concentrations in the arterial and renal venous plasma, urinary glucose excretion and the total renal plasma flow. Net renal glucose release was found in control experiments. The glucose release of the kidneys decreased with rising arterial plasma glucose values. Epinephrine (220 mug/kg s.c.) and isoprenaline (10 mu/kg s.c.) enhanced arterial plasma glucose levels and increased mean renal glucose production significantly. The enhanced arterial plasma glucose levels and increased mean renal glucose production significantly. The enhanced glucose release after isoprenaline could be abolished by propranolol (1 mg/kg s.c.). The glycogen content of the kidney was found to be too small to account for the observed renal glucose release by glycogenolysis. Therefore, these in vivo data indicate enhanced renal gluconeogenesis after adrenergic stimulation. This effect is thought to be mediated by the beta-adrenergic receptors.     

Methyl mercury: acute toxicity, tissue distribution and decay profiles in the guinea pig

Acute toxicity studies with methyl mercuric chloride showed that the guinea pig was quite susceptible to methyl mercury intoxication. LD50 values were 5.5 mg Hg/kg ip and 16.5 mg Hg/kg po. One to 2 weeks after dosing, several animals began to display signs of neurotoxicity.Tissue distribution and pharmacodynamic studies with radiolabeled methyl mercuric chloride ([²⁰³Hg]CH₃HgCl) at 1 and 10 mg Hg/kg revealed that while most tissues decreased in mercury concentration from day 1 to day 7, cerebrum, cerebellum and muscle showed a delayed uptake of the alkyl mercurial. In CNS tissue the concentration of mercury decreased in the order cerebrum > cerebellum > spinal cord. Kidney and liver consistently contained the highest levels of mercury, and plasma the lowest, during the 49-day sampling period. One week after dosing the blood: brain ratios were less than 1. The tissue concentration of mercury was generally directly proportional to the dose administered; however, mercury levels in the gall bladder were significantly higher than anticipated on 5 of the 7 sacrifice days.Most of the tissues displayed a biphasic decay profile with a half-life of 2–3 days for the initial rapid phase of decline. This initial phase was followed by a slower tissue excretion rate for which the mean half-life for mercury was 15 ± 0.9 days and 15 ± 0.8 days for the low and high dose, respectively. The similarity of these values again indicates no dose-related effects.     

Evaluation of the Effectiveness of Sugammadex for Verapamil Intoxication

Previous studies have shown that medications from the cyclodextrin family bind to verapamil. The aim of our study was to determine whether sugammadex could bind to verapamil and prevent the cardiovascular toxicity of that drug. Twenty‐eight sedated Wistar rats were infused with verapamil at 37.5 mg/kg/h. Five minutes after the start of infusion, the animals were treated with a bolus of either 16 mg/kg, 100 mg/kg or 1000 mg/kg sugammadex. The control group was treated with an infusion without sugammadex. The heart rate and respiratory rate were monitored, and an electrocardiogram was recorded. The primary end‐point was the time to asystole. The verapamil infusion continued until the animals arrested. The asystole time for the S16 group was significantly longer compared to those for the control and S1000 groups (p < 0.05). The asystole time for the S1000 group was significantly shorter than those for all of the other groups (p < 0.05). Reflecting these data, there was a near doubling of the mean lethal dose of verapamil from 13.57 mg/kg (S.D. ±8.1) in the saline‐treated rats to 22.42 mg/kg (S.D. ±9.9) in the sugammadex 16 group (p < 0.05). However, for the sugammadex 1000 group, the mean lethal dose was found to be 6.28 ± 1.11 mg/kg. This dose is significantly lower than those for all of the other groups (p < 0.05). We found that treatment with 16 mg/kg sugammadex delayed verapamil cardiotoxicity in rats. However, 1000 mg/kg sugammadex accelerated verapamil cardiotoxicity in rats. Further studies must be conducted to investigate the interaction between verapamil and sugammadex.     

The behavioral effects of cocaine: rate dependency or rate constancy.

The behavioral effects of cocaine were studied in squirrel monkeys trained to press a response key under an 8-min fixed-interval (FI) schedule of electric shock presentation. Overall mean rate of responding increased at 0.03--0.3 mg/kg (i.m.) and decreased at 1.0--3.0 mg/kg. Increased responding during the initial and middle periods of the fixed-interval accounted for the increase in overall mean rate; response rate during the final two min of the interval did not increase at any dose. An analysis based on response rate during individual 1-min segments of the 8-min interval showed that the rate during the interval became more uniform, and the pattern of positively accelerated responding became more linear, as dose increased. At 0.3--1.0 mg/kg, response rate was relatively constant and independent of the control, pre-drug rate of responding.     

KNT009安全性药理学研究

目的:观察KNT009对小鼠神经系统、犬心血管系统及呼吸系统的影响。方法:实验均分高、中、低剂量组及空白对照和阳性对照共5个组,小鼠实验给药组分别单次慢速静脉注射(iv)KNT009 160、80和40 mg/kg,加替沙星80 mg/kg,观察动物的自发活动和爬杆能力;犬实验给药组分别单次慢速iv KNT009 40、20 和10 mg/kg,加替沙星20 mg/kg,观察药物对犬血压、ECG、呼吸频率及节律的影响。结果:单次慢速iv KNT009对小鼠自发活动和爬杆能力无明显影响。单次慢速iv KNT009可降低犬收缩压、舒张压、平均动脉压,减慢心率,延长QT间期,使犬呼吸频率减慢,呼吸幅度加大,且均存在量效关系,3 h后上述指标基本恢复正常,加替沙星也有类似变化。结论:KNT009对心血管和呼吸系统有一定的影响,可使血压下降,心率减慢,QT间期延长,呼吸频率减慢,呼吸幅度加大。     

The action of reserpine, 6-hydroxydopamine,and bretylium on digitalis-induced cardiotoxicity

This study determined whether the protective effect of reserpine against ouabain-induced ventricular arrhythmias in the cat is due to an action of the drug on the adrenergic nerve terminal. Rescrpine (5 mg/kg i.p.) administered 24 h prior to ouabain (2 μg/kg per min i.v., until death) increased the dose of ouabain to produce premature ventricular contractions, ventricular tachycardia, and death from 77.3 ± 5.2 to 105.0 ± 6.0; 84.9 ± 5.2 to 132.7 ± 9.1; and 108.8 ± 4.0 to 165.7 ± 10.4 μg/kg, respectively (P<0.05). When 6-hydroxydopamine (6OHDA; 20 mg/kg i.v.) was given 3 days prior to the experiment, the protective effect of reserpinc was not evident. When bretylium (20 mg/kg i.v., 2 h prior to ouabain) was administered to animals previously treated with reserpine, the dose of ouabain which produced premature ventricular contractions, ventricular tachycardia, and death was increased to 109.0 ± 72 146.1 ± 12.6; and 165.8 ± 7.6 μg/kg, respectively (P<0.05). However, the magnitude of this protective action was similar to that produced by rcserpine alone. Lathers et al. (Fed. Proc. 40, 672, 1981) reported that bretylium alone provides protection of a similar order of magnitude as reserpine. Thus, the effects of rescrpine and bretylium were not additive: this indicates that the two agents may be acting on the same locus or they may be acting at different sites with the action of one drug masking or blocking the action of the other. Since 60HDA prevented the action of rcserpine on ouabain-induced ventricular arrhythmia and since 60HDA only produces degeneration of adrenergic nerve terminals, it is probable that the protective effect of both reserpine and bretylium is due to an action at the adrenergic nerve terminal. The heart rate and blood pressure were not involved in the antiarrhythmic effects of rcserpine.     

Effect of ciprofloxacin on the hypoprothrombinemic activity of warfarin in rats

The interaction between the fluoroquinolone ciprofloxacin and the oral anticoagulant warfarin was investigated in male Wistar rats in two phases. In phase I, the optimum oral dose of warfarin was determined to be 0.1 mg/kg in rats. This dose prolonged the prothrombin time (PT) 1.5–2 times the control values. On phase II, for a period of 5 consecutive days, three groups of animals received daily oral doses of one of the following treatments: warfarin sodium 0.1 mg/kg (group I), ciprofloxacin 20 mg/kg (group II), or a combination of ciprofloxacin and warfarin (group III). PT was determined for all animals before and after each treatment. Ciprofloxacin serum concentrations were measured using an HPLC assay. The mean PT before treatment was 12.3 ± 2.8 seconds. One hour after the last treatment in the three groups, the PT of the combination group was significantly higher than that of both of the warfarin and the ciprofloxacin groups (32.7 ±10 vs. 18.9 ± 5.2 and 14.4 ±0.9 seconds, respectively). Whereas, 3 days after the last treatment, the PTs were found to be 15.8 ± 1.1, 18.6 ±0.7 and 14.6 ± 2 seconds for the combination, warfarin and ciprofloxacin groups, respectively. Interestingly, animals in group three seemed to recover more rapidly and fully on day 8. The results indicate that this interaction is serious and could be fatal if not monitored, however it is reversible if ciprofloxacin is discontinued.