Anticonvulsant activity of felbamate in amygdala kindling model of temporal lobe epilepsy in rats

PURPOSE: Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE). METHODS: The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, afterdischarge (AD) duration and seizure duration either at the focal seizure threshold, or after suprathreshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test. RESULTS: FBM at doses of 12.5-50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 microA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses. CONCLUSIONS: FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE.     

Anticonvulsant activity of novel derivatives of 2- and 3-piperidinecarboxylic acid in mice and rats

The relative ability of derivatives of 2-piperidinecarboxylic acid (2-PC; pipecolic acid) and 3-piperidinecarboxylic acid (3-PC; nipecotic acid) to block maximal electroshock (MES)-induced seizures, elevate the threshold for electroshock-induced seizures and be neurotoxic in mice was investigated. Protective index (PI) values, based on the MES test and rotorod performance, ranged from 1.3 to 4.5 for 2-PC benzylamides and from < 1 to > 7.2 for 3-PC derivatives. PI values based on elevation of threshold for electroshock-induced seizures and rotorod performance ranged from > 1.6 to > 20 for both types of derivatives. Since preliminary data indicated that benzylamide derivatives of 2-PC displace [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine (TCP) binding to the phencyclidine (PCP) site of the N-methyl-D-aspartate (NMDA) receptor in the micromolar range and such low affinity uncompetitive antagonists of the NMDA receptor-associated ionophore have been shown to be effective anticonvulsants with low neurological toxicity, the 2-PC derivatives were evaluated in rat brain homogenates for binding affinity to the PCP site. Although all compounds inhibited [3H]TCP binding, a clear correlation between pharmacological activity and binding affinity was not apparent. Select compounds demonstrated minimal ability to protect against pentylenetetrazol-, 4-aminopyridine- and NMDA-induced seizures in mice. Corneal and amygdala kindled rats exhibited different sensitivities to both valproic acid and the nonsubstituted 2-PC benzylamide, suggesting a difference in these two models. Enantiomers of the alpha-methyl substituted benzylamide of 2-PC showed some ability to reduce seizure severity in amygdala kindled rats.     

Effect of endurance training on pancreatic enzyme activity in rats

Immunoglobulin G (IgG) of Indian soft-furred rat, Millardia meltada, was purified by an immunoaffinity chromatography and antibodies against it was raised in rabbit. Using this rabbit anti-M. meltada IgG antibody, sensitivity of enzyme-linked immunosorbent assay (ELISA) to measure parasite-specific antibodies in the sera of M. meltada was markedly enhanced than the previous method using rabbit anti-mouse IgG and rabbit anti-rat IgG antibodies, which could cross-react to M. meltada IgG. Since M. meltada could effectively produce circulating antibodies against two intestinal helminths, Strongyloides venezuelensis and Nippostrongylus brasiliensis, the high susceptibility of this animal to an array of parasites seems to be not due to general immunological deficiency.     

Angiotensin-converting enzyme inhibitors

ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 receptor antagonists.     

Angiotensin I converting enzyme activity in adriamycin induced nephrosis in rats

Activity of the dipeptidyl hydrolase angiotensin converting enzyme (ACE) has been observed to be altered by treatment with adriamycin (ADR). We used an animal model of ADR nephrotoxicity to study the effects on ACE in serum, urine and tissues on days 5, 10, 15, 20, 25 and 30 after ADR administration. Both glomerular and tubular injury occurred as evidenced by heavy proteinuria, albuminuria and increased urine N-acetyl glucosaminidase (NAG) excretion. Serum ACE was significantly elevated on days 20, 25 and 30. Of great interest was the excretion of ACE in urine of treated rats which ran parallel with the total protein excretion above the barely detectable levels found in controls. ACE activity increased in kidney, adrenal gland and liver on days 15, 20, 25 and 30. Heart and brain ACE levels increased on days 25 and 30. Increased ACE activity in aorta and lungs occurred on days 20, 25 and 30. ACE activity decreased in kidney, aorta, heart and brain on days 5 and 10. These observations strongly suggest a contribution of various tissues to elevate the serum ACE level. Urinary ACE may be of potential use as an index for renal glomerular and tubular damage.     

Anticonvulsant activity and inhibition of cellular respiratory activity by substituted imidazolocarbamides

Several 1-(1-aryl-2-mercaptoacetylimidazole)-3-alkylcarbamides were synthesized and characterized by their sharp melting points, elemental analyses, and IR spectra. These substituted imidazolocarbamides possessed anticonvulsant activity, which was reflected by the 20-80% protection observed with these compounds against pentylenetetrazol-induced convulsions in mice. These substituted imidazolocarbamides selectively inhibited the in vitro oxidation of nicotinamide adenine dinucleotide (NAD)-dependent oxidations of pyruvate, alpha-ketoglutarate, beta-hydroxybutyrate, and NADH by rat brain homogenates. However, NAD-independent oxidation of succinate was not affected. The anticonvulsant activity possessed by 1-(1-aryl-2-mercaptoacetylimidazole)-3-alkylcarbamides had no relationship to their ability to inhibit cellular respiratory activity.     

Oxidative defense enzyme activity and mRNA levels in lenses of diabetic rats

This study examines the mRNA expression and enzyme activity of oxidative defense enzymes during the course of streptozotocin-induced hyperglycemic cataract development. Diabetes was produced in 5-wk-old male Sprague-Dawley rats by administering streptozotocin ip and mRNA expression and enzyme activity were monitored on d 4, 8, 12, 16, 20, 40, 60, and 80; concomitantly, the onset and progress of cataract was followed by digital image analysis. Peak enzyme activity and mRNA expression were attained between d 20 and 40. Although catalase and glutathione peroxidase maintained high levels of mRNA expression through d 60, induction of CuZu-superoxide dismutase was transient, with the activity and mRNA levels returning to baseline values by d 40. There was a pronounced increase in aldose reductase activity, which gradually declined to basal levels by d 60; however, the mRNA levels remained unaltered. Other changes included a progressive loss of lenticular transparency, which declined to 40% of control by d 80. The role of antioxidant defense enzymes and, more interestingly, aldose reductase in combating oxidative stress in diabetic cataractogenesis is discussed.     

Lysosomal enzyme activity in the serum of rats with experimental lead poisoning

Examination of the effect of experimental lead poisoning on permeability of lysosomal membranes in albino rats demonstrated activation of lysosomal enzymes (alpha-manosidase and beta-acetylglucosaminidase) in the blood serum as soon as the third day after daily administration of lead acetate (20 mg/kg). Apparently damage of the lysosomal membrane played an important role in the pathogenesis of lead poisoning.     

Anticonvulsant effects of dipotassium clorazepate on hippocampal kindled seizures in rats

OBJECTIVE: To determine the reliability of some commonly used outcome measures in patients with rheumatoid arthritis. METHODS: We studied 22 consecutive patients with rheumatoid arthritis enrolled in a clinical trial in a tertiary care center. The study design consisted of a test-retest, in which the same rheumatologist evaluated all of the patients twice, with an interval between evaluations of 90 to 120 minutes. Statistical analysis of the data consisted of calculation of the weighted Kappa (kw) and the intraclass correlation coefficient (ICC). RESULTS: For the Ritchie articular index, kappa w = 0.83, ICC = 0.49, p < 0.0001; tender joint count, kappa w = 0.82, ICC = 0.49, p < 0.0001; physician's global assessment, kappa w = 0.79, ICC = 0.48, p < 0.0001; disease activity score, kappa w = 0.79, ICC = 0.49, p < 0.0001; utilities, kappa w = 0.71, ICC = 0.48, p < 0.0001; swollen joint count, kappa w = 0.7, ICC = 0.47, p < 0.0001; patient's global assessment, kappa w = 0.58, ICC = 0.44, p < 0.0001; pain kappa w = 0.45, ICC = 0.41, p < 0.0001. CONCLUSIONS: The reliability of most of the outcome measures was good. It was higher for those measurements evaluated by a rheumatologist and for the composite indexes. Those requiring patient participation need to be improved.     

Time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic drug-metabolizing enzyme activity in rats

The time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic cytochrome P450-dependent drug-metabolizing capacity (cytochrome P450 and b5 content, activity of aminopyrine N-demethylase, p-nitroanisole O-demethylase, aniline hydroxylase and benzphetamine N-demethylase) and on the pharmacokinetics of antipyrine have been determined in rats. Measurement of enzyme activity and antipyrine (after intravenous injection of 20 mg kg(-1)) were performed 2, 24 and 96 h after a single intraperitoneal injection of endotoxin (1 mg kg(-1)) and after repeated doses (once daily for 4 days). The contribution of tumour necrosis factor alpha (TNFalpha) to the endotoxin-induced changes was also examined in rats pretreated with granulocyte colony-stimulating factor (G-CSF). The systemic clearance of antipyrine and the activity of hepatic cytochrome P450-dependent drug-metabolizing enzymes were dramatically reduced 24 h after a single injection of endotoxin, but had returned to control levels by 96h. The magnitudes of these decreases in these measurements after repeated doses of endotoxin were similar to those seen 24h after the single dose. The systemic clearance of antipyrine correlated significantly with cytochrome P450 content and aminopyrine N-demethylase activity. In histopathological experiments, moderate hypertrophy of Kupffer cells was observed, with no evidence of severe liver-tissue damage. G-CSF pretreatment suppressed the increased plasma concentrations of TNFalpha produced 2 h after single endotoxin injection, but did not eliminate the endotoxin-induced decrease in the systemic clearance of antipyrine, suggesting that TNFalpha is not the sole component responsible for the reduction of cytochrome P450-mediated drug-metabolizing enzyme activity. These results provide evidence that a single intraperitoneal injection of 1.0 mgkg(-1)K. pneumoniae endotoxin in rats reduces hepatic P450 and b5 levels, and reduces the activity of various cytochrome P450-mediated drug-metabolizing enzymes without causing severe liver-tissue damage. This suggests that the effect of endotoxin on hepatic cytochrome P450-mediated drug-metabolizing isozymes is non-selective.     

Natural plant enzyme inhibitors: Part II-protease inhibitors of seeds

Systolic time intervals (STI) were recorded in 8 healthy male volunteers before, during, and after 30-s exposures to +3 Gz, +5 Gz, and +7 Gz acceleration. Heart rate (HR) increased at all +Gz levels, as did the HR corrected QSIc interval, left ventricular ejection time (LVETc), preejection period (PEPc) and PEP/LVET. These changes in STI were also proportional to the +Gz level. At the higher +Gz levels, PEPc and PEP/LVET continued to increase early in the recovery period, but HR and all STI returned to control after 60 s of recovery. Although physiological variables other than myocardial contractility, such as preload and afterload may influence STI during +Gz the effects of +Gz on stroke volume (SV) and cardiac output (CO) were estimated using previously described relationships between STI and invasively determined indices of cardiovascular function. In general CO increased as SV decreased. During recovery, HR and CO fell and CO remained slightly below control levels, primarily because estimated SV remained low. This study demonstrates the feasibility of using STI to estimate noninvasively the transient changes in cardiovascular function during +Gz acceleration.     

Lack of involvement of bradykinin in the vascular sympathoinhibitory effects of angiotensin converting enzyme inhibitors in spontaneously hypertensive rats

1. The aim of this study was to investigate the contribution of endogenous bradykinin to the vascular sympathoinhibitory effects exerted by angiotensin I converting enzyme inhibitors (ACEIs) in the spontaneously hypertensive rat (SHR). 2. Adult SHRs were treated daily for 8 days with either perindopril (3 mg kg-1), or a selective angiotensin II AT1 receptor antagonist, losartan (10 mg kg-1) both given orally--these two doses being equipotent in inhibiting angiotensin I (AI)-induced vascular responses--or distilled water (controls). After pithing, the animals were instrumented for determination of blood pressure, heart rate, cardiac output, regional (renal, mesenteric, hindlimb) blood flows (pulsed Doppler technique) and corresponding vascular resistances. Afterwards, half of the animals of each group were given the selective bradykinin B2 receptor antagonist, icatibant, used in a dose (10 micrograms kg-1, i.v.) that achieved B2 receptor blockade, the other half received saline (10 microliters kg-1, i.v.). Haemodynamic responses to increasing frequencies of spinal cord stimulation were then measured. 3. Pressor and vasoconstrictor responses to AI were significantly and similarly reduced in both perindopril- and losartan-treated groups. Perindopril and losartan both decreased to a similar extent the pressor and vasoconstrictor responses to electrical stimulation of the spinal cord. 4. In the dose used, icatibant did not affect any of the investigated haemodynamic parameters in any of the experimental groups. Furthermore, icatibant did not affect the stimulation frequency-response curves in the control animals and did not modify the vascular sympathoinhibitory effects exerted by perindopril and by losartan. 5 Taken together, these results demonstrate that endogenous bradykinin does not, through B2 receptor activation, contribute to the vascular sympathoinhibitory effects of ACEIs in SHRs.     

Hepatotoxicity associated with angiotensin-converting enzyme inhibitors

OBJECTIVE: To review published reports of hepatotoxicity associated with angiotensin-converting enzyme (ACE) inhibitors and to explore possible mechanisms of injury. DATA SOURCES: Published reports of hepatotoxicity associated with use of ACE inhibitors and investigations that suggest potential mechanisms of injury. DATA SYNTHESIS: Nineteen cases of ACE-inhibitor-associated hepatotoxicity are presented. Early theories regarding mechanisms are reviewed. Laboratory investigations of hepatic effects of eicosanoids on hepatic function are reviewed and a novel mechanism by which ACE inhibitors may cause hepatic injury is postulated. CONCLUSIONS: Hepatotoxicity, usually cholestatic in nature, has been reported with captopril, enalapril, and lisinopril use. Apparent cross-reactivity has been reported twice. Potential mechanisms of injury include idiopathic hypersensitivity and modulation of eicosanoid metabolism by inhibition of kininase II and subsequent increased hepatic bradykinin activity. Mediation via altered eicosanoid metabolism provides a plausible explanation for cross-reactivity among ACE inhibitors. Hepatotoxicity resolves if ACE inhibitors are stopped but may progress to liver failure if treatment is continued.     

Antenatal glucocorticoid therapy suppresses angiotensin-converting enzyme activity in rats with nitrofen-induced congenital diaphragmatic hernia

BACKGROUND: Carcinoma of the true vocal cord represents the earliest clinically recognizable invasive malignancy in the head and neck region and provides a unique model for studying possible prognostic genetic markers. The aim of this study was to determine whether p53 overexpression correlated with tumor recurrence in a homogenous population of patients with early stage glottic carcinoma treated with radiotherapy alone. METHODS: One hundred and fourteen patients with T1N0M0 squamous cell carcinoma of the glottis were treated with curative radiotherapy between 1976 and 1990. With a median follow-up of 6 years, actuarial local control was 80% with 23 local recurrences. Laryngeal biopsy specimens obtained prior to radiation therapy were analyzed retrospectively in 22 patients. Forty-five patients with local control were used as a control group. p53 overexpression indicating a mutated p53 gene was analyzed by immunohistochemistry using the mouse monoclonal antibody D0-7. RESULTS: Approximately 82% of carcinomas that recurred locally expressed p53 compared with only 29% of those with local control (P < 0.001). No significant relation was noted between p53 expression and histologic grade. Intensity of staining did not predict tumor recurrence. CONCLUSIONS: The authors believe that this case-controlled study demonstrated the role of p53 as an independent prognostic factor in patients with early stage glottic carcinoma.     

Angiotensin converting enzyme inhibitors for hypertension

The review paper presents modern opinions upon angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension. It describes their hypotensive properties and therapeutic efficacy. The review discusses also using of ACE inhibitors for disorders often coexisting with hypertension, likewise it presents ACE inhibitors in combination with other hypotensive drugs. The paper discusses also side effects of ACE inhibitors as well as diseases, in which ACE inhibitors are contraindicated.