Effects Of Prolonged Oral Administration Research Articles

The Effect of Orally Administered Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Obesity Parameters in Mice.

Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.

Acute Toxicity and Effect of Prolonged Oral administration of Zingiber officinale ethanol extract on Liver and Kidney Histology in Rats

The study aimed to evaluate the effect of 28-day repeated administration of Zingiber officinale on the histology of the liver and kidney in Wistar rats. An acute toxicity test was carried out using 12 rats. In phase one, nine rats were allotted into three groups and received Zingiber officinale ethanol extract at 10mg/kg, 100mg/kg, and 1000mg/kg respectively. In phase two, three rats received Zingiber officinale ethanol extract at 1600mg/kg, 2900mg/kg, and 5000mg/kg respectively. Twenty-five rats were distributed into five groups. The groups received distilled water and ethanol extract of Zingiber officinale at 25 mg/kg, 50 mg/kg, 75 mg/kg, and 150 mg/kg respectively for 28 days. On the 29th day, all the rats were euthanized. The oral LD50 of Zingiber officinale ethanol extract was calculated to be 3800 mg/kg in rats. The rats that received Zingiber officinale ethanol extract up to 1600 mg/kg showed no signs of toxicity and mortality. The liver of rats that received Zingiber officinale at 150 mg/kg showed distorted hepatocytes and pyknosis. The kidney of 75 mg/kg and 150 mg/kg Zingiber officinale treated rats showed normal glomerulus and normal Bowman’s capsule with severe renal tubular distortion. In conclusion, Zingiber officinale is less toxic. However, long term administration might lead to liver and kidney damage and eventual death.

Toxicity Studies on Aqueous Stem Bark of Khaya senegalensis Extract of Kidneys and Its Biochemical Parameters in Wistar Rats

Introduction: Khaya senegalensis is a genus of seven species of trees in the mahogany family Meliaceae, native to tropical Africa and Madagascar. Mahogany in English, Aganwo in Yoruba, Madachi in Hausa and Ono in Igbo. All species become big trees 30–35m tall, rarely 45m, with a trunk over 1 m trunk diameter, often buttressed at the base. The leaves are pinnate, with 4-6 pairs of leaflets, the terminal leaflet absent; each leaflet is 10–15 cm long abruptly rounded toward the apex but often with an acuminate tip.
 Aim: The aim of the study was to determine the Toxic effect of prolonged oral administration of the aqueous stem bark of Khaya senegalensis extract on the histology of Kidneys and its biochemical parameters in wistar rats.
 Methods: This work is an experimental research. A total of 20 wistar rats were randomly divided in to 5 groups each of which consist of 4 rats. Group 1 received distilled water to serve as control while group 2, 3, 4, and 5 received 500 mg/kg bw, 1000 mg/kg bw 2000 mg/kg bw and 4000 mg/kg bw of the aqueous extract respectively for 60 days after which they were sacrificed, processed in Automatic Tissue Processor machine, Sectioned and stained with H &E.
 Results: There was statistical significant increase in urea and potassium in all the test groups but is not dose dependent. The creatinine was significantly increased in groups 2, 4 and 5. While other parameters such as sodium, chloride and bicarbonate no significant difference when compared to the control group. The kidney sections showed normal structure in group 1 when compared with the test groups. However, there was significant infiltration of inflammatory cell across all the groups which were suggestive of kidney damage or injury. Similarly phenomenon was noticed in group 5 with additional congestion in the glomerulus and more polymorphs seen.
 Conclusion: The LD50 was found to be greater than 5000 mg/kg bw, therefore, 400 mg/kgbw was used as higher dose in the experimental wistar rats. There were statistical significant increases in some parameters groups while some groups not significant. The kidney section showed significant infiltration of polymorphs across all the groups more marked in group 5 with distension and damaging of the glomerulus indicating renal injury.

Effects of Aqueous Leaf Extract of Acalypha wilkesiana on some Serum ‎Biochemical Profiles of Mice in Sub-Acute Toxicity Studies

Acalypha wilkesiana has been used for various medicinal purposes such as in the treatment of hypertension, fungal and bacterial infections. In this study, the effects of prolonged oral administration of the aqueous leaf extract on some biochemical profiles of mice were evaluated. A total of 80 mice were allocated to 4 groups (A, B, C and D) comprising of 20 mice each. Mice in group A (control) were given (1 mL) of distilled water orally while 1 mL of the extract was given to the mice in groups B, C and D daily at the concentrations of 800, 1000 and 1200 mg/kg, respectively. This was continued for three weeks and at the end of each week, 4 mice from each group were humanely sacrificed and sera from blood samples collected were used for determination of activities of biochemical parameters. The results showed that administration of the extract resulted in significantly (p < 0.05) lower concentrations of total protein and cholesterol in the treatment groups at the 3rd week of treatment when compared to control values. Glucose level was significantly (p > 0.05) higher in the extract-treated groups by the 3rd week of treatment, while activities of AST, ALT and ALP were not significantly (p > 0.05) altered by the extract. There were no significant (p > 0.05) differences between the levels of calcium, total and conjugated bilirubin in treatment and control groups, while sodium concentration was significantly (p < 0.05) higher at day 14 after withdrawal of treatment, compared to the control. This study suggests that the extract of Acalypha wilkesiana has a hyperglycaemic effect.

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The effect of prolonged oral administration of gold nanoparticles of various sizes on the structure of the liver, spleen and lymph nodes of mature laboratory rats and their offspring was studied. The morphometric study was performed using the system of digital image analysis of medical Mikrovizor µVizo-103. The detection of conglomerates of gold nanoparticles in tissues was carried out using the dark field microscopy method. It was found that gold nanoparticles of sizes 2 and 50 nm cause the most pronounced morphological changes in the organs, which indicates the size-dependent character of their effects. In the liver of the group with 50 nm gold nanoparticles administration the expressed dystrophy of hepatocytes and activation of monocytic-macrophage system were observed. In the spleen and lymph nodes, the processes of proliferation and differentiation of immunocompetent cells and macrophages were activated. Oral administration of gold nanoparticles during pregnancy in females was accompanied by an increase in the number of hepatocytes with necrobiotic changes and an increase in the number of non-parenchymatous elements in the liver of the offspring, most pronounced in the groups with the administration of 2 and 50 nm gold nanoparticles.

English

This study was designed to determine the effects of prolonged oral administration of aqueous leaf extract of Leptadenia hastata Pers (Decne) on sperm concentration, sperm motility and testicular histology in Wistar rats. Rats were given graded doses (200, 400, 600 and 800 mg kg-1) of aqueous leaf extract of L. hastata orally for 28 days. Weekly changes in sperm concentration and motility as well as testicular weight and histology were monitored. Sperm concentration, motility and testicular weights did not show significant change (p>0.05) among the groups, but a significant difference (p<0.05) exist between control group and the group that had the highest dose (800 mg/kg) of L. hastata. Histopathological studies revealed marked depletion of spermatozoa in the testes and epididymis of rats that received 800 mg/kg of L. hastata. Prolonged administration of aqueous leaf extract of L. hastata at 800 mg/kg caused a reduction in total sperm concentration, sperm motility and a reduction in testicular weight in rats. Key words: Fertility, Leptadenia hastata, spermiogram, rats, testis.

Adverse effects of long-term administration of fluvoxamine on haematology, blood biochemistry and fertility in male albino rats: a possible effect of cessation.

Fluvoxamine is recommended as first-line treatment for a number of obsessive-compulsive disorders, anxiety disorders, social phobia, and post-traumatic stress disorder and panic disorder. The adverse effects of prolonged oral administration of fluvoxamine on haematology, biochemical parameters and fertility in male rats were evaluated in this study. Sixty adult male rats were allocated into 5 equal groups and orally treated with fluvoxamine 9mgkg-1 b.wt. (low therapeutic dose, LTD) and 27mgkg-1 b.wt. (high therapeutic dose, HTD), while the control rats received 0.5ml distilled water for a period of 8weeks. The 4th and 5th groups were gavaged with LTD and HTD of fluvoxamine for 8weeks and then left untreated for another 8weeks (recovery groups). HTD of fluvoxamine induced leukocytosis, lymphocytosis and monocytosis. LTD and HTD of fluvoxamine evoked hepatic, renal and cardiac dysfunction. Moreover, fluvoxamine treatment might lead to the risk of male infertility, which is indicated by its deleterious impacts on spermiogram and steroidogenesis hormones. They also induced oxidative stress, apoptosis in testicular tissue. Fortunately, the previous alterations were mostly reversed during the recovery period.

Effects of prolonged oral administration of dicyandiamide to dairy heifers on excretion in urine and efficacy in soil

Oral administration of the nitrification inhibitor dicyandiamide (DCD) to grazing ruminants for excretion in urine represents a targeted mitigation strategy to reduce nitrogen (N) losses from grazed pastures. A field trial and allied laboratory incubation study were conducted to examine the effects of oral administration of DCD to non-lactating Friesian dairy heifers on excretion of DCD in urine and efficacy in soil. Dairy heifers were orally administered DCD daily at three treatment levels (low, medium and high; 12, 24 and 36gDCDheifer−1day−1, respectively) and compared to a nil-DCD control group over a 90-day continuous dosing period. There were no adverse effects of DCD administration on heifer health or growth, as inferred by live-weight gain and measured blood metabolite levels. Prolonged administration of DCD to dairy heifers resulted in the sustained excretion of DCD in the urine over 90 days and inhibition of nitrification of urinary-N in the silty peat soil for up to 56 days (incubated at 20°C; P<0.001). Field soil sampling (0–75mm depth) of individual urine patches for DCD analysis revealed that a 3-fold increase in the rate of DCD administered resulted in a similar increase in the concentration of DCD voided in the urine and subsequently deposited in urine patches (median equivalent DCD application rates of 22, 36 and 59kgha−1 for the low, medium and high DCD treatment levels, respectively; P<0.001). However, large differences (up to 40-fold) existed between individual urine patches in the rate of DCD deposited at each treatment level, which showed a positively skewed distribution. This study highlights the viability of prolonged daily administration of DCD to ruminants for sustained excretion in urine and effective inhibition of nitrification in soil as a practical targeted mitigation technology to reduce urinary-N losses from grazed pastures.

Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice

BackgroundAlzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.MethodsWe have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on 18F-fluoro-deoxyglucose (18FDG) uptake by positron emission tomography (PET).ResultsNovel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased 18FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.ConclusionsIn summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

Effect of Prolonged Oral Administration of Aqueous Ficus sycomorus Stem-bark Extract on Testicular Size of Growing Albino Rat

La decoccion de la corteza del tallo de Ficus sycomorus se usa para tratar la infertilidad relacionada al bajo conteo de espermatozoides, pero es incierto el riesgo reproductivo asociado con su uso. El extracto acuoso de la corteza se administro, en ratas albinas, por via oral, en una dosis de 200-600 mg/kg, durante 30 dias post-crecimiento puberal. Durante el periodo, fueron controlados los siguientes parametros: peso corporal in vivo, diametro escrotal y tamano testicular. El promedio de peso corporal in vivo y diametro escrotal de las ratas control y tratadas, tuvieron un incremento significativo (p 0,05) esos parametros. No hubo variaciones significativas (p> 0,05) en la media de los parametros tamano testicular en las ratas tratadas y control, ni tampoco se produjeron efectos dependientes de la dosis, ni en funcion del tiempo. Las secciones de los testiculos de los animales tratados mostraron una espermatogenesis activa a nivel de los tubulos seminiferos, sin lesiones histologicas aparentes. Se concluye, que el uso del extracto crudo de Ficus sycomorus, dentro de una dosis de 200-600 mg/kg, presenta minimo riesgo en la reproduccion masculina, sin embargo, se hace necsario estudiar su efecto pro-espermatico.

Administration of dexamethasone per os in finishing bulls. I. Effects on productive traits, meat quality and cattle behaviour as indicator of welfare

The study investigated the effects of prolonged oral administration of dexamethasone at a low daily dosage of 0.75 mg/head per day (Dexa) on beef cattle productive traits, behaviour and meat quality. In all, 14 finishing Marchigiana bulls were used in a trial that begun 56 days prior to slaughter, of which six bulls received treatment from day 5 to day 53, whereas the remaining animals were used for Control. The animals treated showed an increased average daily gain (1515 v. 1177 g/head per day; P < 0.05; s.e.d. = 48.54) and improved warm carcass dressing percentage (60.8% v. 59.7%; P < 0.05; s.e.d. = 0.32). Behavioural observation did not permit a clear distinction between treated and Control animals since feeding and social behaviour were similar in both groups. The bulls treated spent less time lying (16.5% v. 34.6%; P < 0.05; s.e.d. = 4.38) and grooming (6.7% v. 11.9%; P < 0.05; s.e.d. = 1.23), and this may indicate poorer welfare. No evidence of treatment was observed in other carcass traits, and redness was the only meat quality parameter slightly affected by corticosteroid administration.

Effects of oral administration of aflatoxin B 1 and fumonisin B 1 in rabbits ( Oryctolagus cuniculus)

The effects of prolonged oral administration (21 days) of fumonisin B 1 (FB 1) and aflatoxin B 1 (AFB 1) were studied in male New Zealand rabbits by clinical, pathological, biochemical and sphingolipid analyses. Twenty-four animals were randomly divided into the following four experimental groups: (A) 0 mg FB 1 + 0 μg AFB 1/(kg body weight (bw) day) (control); (B) 0 mg FB 1 + 30 μg AFB 1/(kg bw day); (C) 1.5 mg FB 1/(kg bw day) + 30 μg AFB 1/(kg bw day); (D) 1.5 mg FB 1/(kg bw day) + 0 μg AFB 1. Animals from group B and principally from group C presented clinical signs of intoxication. Rabbits from group C presented a lower body weight gain than controls. Differences were observed between intoxicated rabbits and controls with respect to absolute and relative liver and kidney weight, hepatic function, serum urea and creatinine levels and Sa/So ratio. The most frequent hepatic and renal injuries were vacuolar degeneration of the liver and kidney as shown by the histopathological and serum biochemical results. Combined administration of AFB 1 and FB 1 resulted in synergistic toxic effects both in the liver and in the kidney, but hepatic injuries were more marked.

Effects of prolonged oral administration of aflatoxin B1 and fumonisin B1 in broiler chickens

The effects of prolonged oral administration of aflatoxin B1 (AFB1) and fumonisin B1 (FB1) mycotoxins were evaluated in broiler chickens from 21 to 42 d of age. A total of 192 birds were housed in experimental batteries and assigned to 32 cages, 6 birds per cage. The following treatments were applied: 1) 0 mycotoxins (control), 2) 10 mg of FB1, 3) 50 microg of AFB1, 4) 50 microg of AFB1 + 10 mg of FB1, 5) 350 microg of AFB1, 6) 350 microg of AFB1 + 10 mg of FB1, 7) 2,450 microg of AFB1, 8) 2,450 microg of AFB1 + 10 mg of FB1/kg of feed. Each treatment consisted of 4 replicates of 6 birds each. At the end of the trial, blood samples from 12 birds per treatment were collected, and the birds were necropsied. Compared with controls, the percentage of heterophils was lower (P < 0.05) in birds from groups receiving 50 microg of AFB1/kg + 10 mg of FB1/ kg and 2450 microg of AFB1/kg alone or in combination with FB1. A higher percentage of lymphocytes (P < 0.05) was observed in birds fed 50 microg of AFB1/kg + 10 mg of FB1/ kg, 350 microg of AFB1/kg, and 2,450 microg of AFB1/kg. A decrease in plasma albumin was observed only in birds fed 2,450 microg of AFB1/kg + 10 mg of FB1/kg. The liver of AFB1-treated birds had focal areas of necrosis and inflammatory infiltrates. In birds fed rations containing only 10 mg of FB1/kg, bile duct hyperplasia with fibrosis and a mononuclear infiltrate accompanied by trabecular derangement were observed. In contrast, in treatments in which FB1 was administered in combination, hepatic vacuolar degeneration was observed, and renal tissue presented corpuscles with increased cellular agglomeration, characterizing glomerulonephritis, and a clearly visible tubular epithelium with areas of degeneration and necrosis. The FB1 residues were detected in liver and in excreta of all FB1-treated groups, at levels that ranged from 0.013 to 0.051 mg/kg and from 1.19 to 2.79 mg/kg, respectively. Results indicated that FB1 and AFB1, singly or in combination at the levels evaluated, do not change markedly the hematological and serological parameters of broiler chickens, but may cause relevant lesions in liver and in kidneys.

Effects of α - naphthoflavone on body growth and gonad development in chickens (Gallus domesticus)

The aim of this study was to investigate the effects of prolonged oral administration of &amp;alpha; -naphthoflavone on somatic and germinal development in male and female chickens (Gallus domesticus). No significant differences were observed at any tested age (6, 8, 10 and 12 wks) between control and treated groups of either sex in total body weight and in the weights of kidney, liver, gizzard, heart, abdominal fat, breast and ovary tissues (P &amp;gt;&amp;nbsp;0.05). Mean testicular weights were similar between groups at 6, 8 and 10 wks but at 12 wks males supplemented with &amp;alpha; -naphthoflavone had significantly heavier testicle weights (P &amp;lt; 0.01) compared to 2 control groups. Histological examination of the seminiferous tubules (ST) revealed a more advanced stage of maturation in the testes of &amp;alpha; -naphthoflavone-treated males, and the presence of testicular spermatozoa was observable as early as at 12 weeks of age. The testes of males from the two control groups were still at an impuberal stage at this age. &amp;nbsp;

Effects of prolonged oral administration of fumonisin B1 and aflatoxin B1 in rats.

The effects of prolonged oral administration (21 days) of fumonisin B1 (FB1) and aflatoxin B1 (AFB1) were evaluated on male Wistar rats. The animals were housed in individual metabolic cages and submitted to the following treatments: 1-0 microg AFB1 + 0 mg FB1/100g bw.; 2-72 microg AFB1+ 0 mg FB1/100 g bw; 3-0 microg AFB1 + 0.5 mg FB1 g bw; 4-0 microg AFB1 + 1.5 mg FB1/100 g bw; 5-72 microg AFB1 + 0.5 mg FB1/100g bw; 6-72 microgAFB1 + 1.5 mg FB1/100g bw. On day 21, the rats were sacrificed for evaluation. The results showed that treated animals presented differences in body weight and absolute/relative weights of liver and kidney as well as altered hepatic function and cholesterol blood levels. Rats fed with the greatest doses of AFB1 and FB1 gained less weight (2.79 g/day) at the end of the experimental period; their blood concentrations of liver enzymes aspartate aminotransferase (AST) and alkaline phosphatase (AP) were above control levels (130.35 micro/l and 471.00 micro/l, respectively). Blood cholesterol increased in the groups treated with the highest dose of FB1 or FB1 associated with AFB1. Histopathology revealed the occurrence of apoptosis in the liver of rats exposed to FB1. The association of aflatoxin B1 with fumonisin B1 at higher dose probably potentiated the effects of the higher dose of fumonisin B1 acting singly.

Inhibition by d-limonene of gastric carcinogenesis induced by N-methyl- N′-nitro- N-nitrosoguanidine in Wistar rats

The effect of prolonged oral administration of d-limonene on gastric carcinogenesis induced by N-methyl- N′-nitro- N-nitrosoguanidine (MNNG) and on the labeling and apoptotic indices of gastric cancers were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were given chow pellets containing 1% or 2% limonene. In week 52, long-term oral administration of 2%, but not 1%, limonene significantly decreased the incidence of gastric cancers. Limonene also significantly decreased the labeling index and significantly increased the apoptotic index of gastric cancers. No K- ras mutations were detected in gastric cancers induced by MNNG in either group. These findings indicate that limonene inhibits the development of gastric cancers through increased apoptosis and decreased DNA synthesis of gastric cancers, but not through ras oncoprotein plasma membrane association.

Effect of prolonged administration of the serotonin4 (5-HT4) receptor agonist cisapride on aldosterone secretion in healthy volunteers

In man, serotonin (5-HT) has been shown to stimulate aldosterone secretion through activation of 5-HT4 receptors, In particular, we have observed that oral administration of a single dose of the 5-HT4 receptor agonist cisapride (10 mg) induces a 5-fold increase in plasma aldosterone levels in healthy volunteers. Surprisingly, the usual disorders associated with hyperaldosteronism, i.e. hypertension and hypokalemia, have never been reported during chronic treatment with cisapride. In the present study, we have investigated the effect of prolonged oral administration of cisapride (10 mg, 3 times/day during 7 days) on aldosterone secretion in 12 healthy volunteers, in a simple blind fashion versus placebo. On day I of the treatment, cisapride induced a significant increase in plasma aldosterone levels (PAL) which returned to the values observed after placebo treatment within 10 hrs. On days 2 and 3, PAL were similar in cisapride- and placebo-treated subjects. Urinary aldosterone, kalemia and reninemia were not influenced by cisapride during the 7 days of the treatment. The present study shows that cisapride only exerts a transient stimulatory effect on aldosterone secretion in healthy volunteers. These data explain why long-term administration of 5-HT4 agonists does not affect blood pressure in man. They also indicate that prolonged stimulation of adrenal 5-HT4 receptors in vivo yields to a rapid desensitization phenomenon, as previously observed in vitro.

Effects of prolonged administration of oxprenolol on severity of ischaemic arrhythmias, enzyme leakage, infarct size, and intracellular cardiac muscle action potentials.

We examined the effects of prolonged oral administration of oxprenolol (twice daily for 6 weeks) to male Sprague-Dawley rats. At two times (1 or 16-18 h) after the last oral dose, the rats were anaesthetised and subjected to acute coronary artery ligation, and the severity of the resulting arrhythmias was assessed. Ischaemic damage was measured histochemically (using frozen section analysis by toluidine blue dye in nitrobluetetrazolium ) and by myocardial enzyme release. Cardiac muscle (atria and papillary muscle) was also removed and the transmembrane action potentials recorded using conventional microelectrode techniques. When coronary artery ligation was performed 1 h after the last oral dose (at which time there was evidence of substantial myocardial beta 1-adrenoceptor blockade), there was significant reduction in the severity of early arrhythmias, but no evidence that the severity of ischaemic damage was reduced or that the intracellular cardiac action potentials were modified. No protection was observed when coronary artery ligation was carried out 16 h after the last oral dose of oxprenolol. These results support our previous studies with acutely administered beta-adrenoceptor blocking drugs that myocardial beta-adrenoceptor blockade is the main factor involved in the protection afforded by such drugs against early ischaemic arrhythmias and that other possible effects, such as membrane stabilisation and action potential prolongation, are relatively unimportant in this model.

The effect of propylthiouracil and methimazole on the peripheral conversion of thyroxine to 3,5,3'-triiodothyronine in athyreotic thyroxine-maintained rats.

The effect of prolonged oral administration of PTU and MMI on the local conversion of T4 to T3 was studied in T4-maintained athyreotic rats. For this purpose the rats were equilibrated with [125I]T4 and [131I]T3 by means of continuous iv infusions. PTU treatment reduced the MCR of both T4 and T3, as well as the T3 levels in plasma, muscle, liver, kidney and cerebellum. In the cerebral cortex the total intracellular T3 concentration was not affected, while in the pituitary it even increased. The amount of T3 derived from local conversion of T4 to T3 (LcT3(T4)) was reduced in the liver. PTU treatment did not influence Lc T3(T4) in the cerebellum, but did cause an increase in the amount of T3 derived from this source in the cerebral cortex and the pituitary gland (both the homogenate and the nuclear fraction). The results indicate that in contrast to that in liver, local T3 production in the brain and pituitary must occur predominantly via a pathway which is not inhibited by PTU. In MMI-treated rats the total T3 concentration in the cerebral cortex and cerebellum was not altered, whereas both the MCR of T3 and the T3 levels in plasma and various other tissues were elevated. The relative contribution of Lc T3(T4) increased in liver and was reduced in the cerebral cortex, cerebellum and pituitary gland. In all experiments in liver the contribution of Lc T3(T4) to nuclear T3 was negligible, whereas this was not the case for the other hepatic subcellular fractions. As in liver, virtually all renal nuclear T3 was derived from plasma. The present findings suggest that the production of T3 in liver and kidney, and its subsequent release into the blood, may provide a mechanism for the regulation of plasma T3 levels but is not a direct source of their nuclear T3. In the pituitary gland and the brain local T4 to T3 conversion functions as a source of T3 for the control of local utilization. In this respect the maintainance of constant T3 levels in the brain might be important. These differences among tissues suggest that different mechanisms are involved in T4 5'-deiodination.

Possible mechanisms of action of oxyfedrine as an antianginal drug [letter

British Journal of Clinical PharmacologyVolume 11, Issue 3 p. 307-308 Free Access Possible mechanisms of action of oxyfedrine as an antianginal drug [letter] JR Parratt, JR ParrattSearch for more papers by this authorJE Mackenzie, JE MackenzieSearch for more papers by this author JR Parratt, JR ParrattSearch for more papers by this authorJE Mackenzie, JE MackenzieSearch for more papers by this author First published: March 1981 https://doi.org/10.1111/j.1365-2125.1981.tb00540.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References MACKENZIE, J.E. & PARRATT, J.R. (1977). Comparative effects of glyceryl trinitrate on venous and arterial smooth muscle in vitro; relevance to antianginal activity. Br. J. Pharmac., 60, 155– 160. MARSHALL, R.J. & PARRATT, J.R. (1974). Drug-induced changes in blood flow in the acutely ischaemic canine myocardium; relationship to subendocardial driving pressure. Clin. exp. Pharmac. Physiol., 1, 99– 112. PARKER, J.O. (1972). Hemodynamic and metabolic changes during myocerdial ischaemia. Arch. int. Med., 129, 790– 798. PARRATT, J.R. (1974). The haemodynamic effects of prolonged oral administration of oxyfedrine, a partial agonist at β-adrenoceptors: comparison with propranolol. Br. J. Pharmac., 51, 5– 13. PARRATT, J.R. (1979). Nitroglycerin—the first hundred years: new facts about an old drug. J. Pharm. Pharmac., 31, 801– 809. PARRATT, J.R. & LEDINGHAM, I. McA. (1972). Experimental infarction in the dog: changes in blood flow and in oxygen extraction induced by oxyfedrine in areas of developing myocardial ischaemia. In Action of oxyfedrine, eds E. Gerlach & K. Moser, pp. 201– 207. Schattauer Verlag: Stuttgart. WHITTINGTON, J. & RAFTERY, E.B. (1980). A controlled comparison of oxyfedrine, isosorbide dinitrate and placebo in the treatment of patients suffering attacks of angina pectoris. Br. J. clin. Pharmac., 10, 211– 216. Citing Literature Volume11, Issue3March 1981Pages 307-308 ReferencesRelatedInformation