Effects Of Long-term Oral Treatment Research Articles

Behavioral aspects and neurobiological properties underlying medical cannabis treatment in Shank3 mouse model of autism spectrum disorder

Autism spectrum disorder (ASD) is a neurodevelopmental disease with a wide spectrum of manifestation. The core symptoms of ASD are persistent deficits in social communication, and restricted and repetitive patterns of behavior, interests, or activities. These are often accompanied by intellectual disabilities. At present, there is no designated effective treatment for the core symptoms and co-morbidities of ASD. Recently, interest is rising in medical cannabis as a treatment for ASD, with promising clinical data. However, there is a notable absence of basic pre-clinical research in this field. In this study, we investigate the behavioral and biochemical effects of long-term oral treatment with CBD-enriched medical cannabis oil in a human mutation-based Shank3 mouse model of ASD. Our findings show that this treatment alleviates anxiety and decreases repetitive grooming behavior by over 70% in treated mutant mice compared to non-treated mutant mice. Furthermore, we were able to uncover the involvement of CB1 receptor (CB1R) signaling in the Avidekel oil mechanism, alongside a mitigation of cerebrospinal fluid (CSF) glutamate concentrations. Subsequently, RNA sequencing (RNA seq) of cerebellar brain samples revealed changes in mRNA expression of several neurotransmission-related genes post-treatment. Finally, our results question the relevancy of CBD enrichment of medical cannabis for treating the core symptoms of ASD, and emphasize the importance of the THC component for alleviating deficits in repetitive and social behaviors in ASD.

Long-term oral administration of a novel estrogen receptor beta agonist enhances memory and alleviates drug-induced vasodilation in young ovariectomized mice

Development of estrogen therapies targeting the β (ERβ) but not α (ERα) estrogen receptor is critically needed for the treatment of negative menopausal symptoms, as ERα activation increases health risks like cancer. Here, we determined the effects of long-term oral treatment with EGX358, a novel highly selective ERβ agonist, on memory, vasodilation, and affect in young ovariectomized mice. Mice were orally gavaged daily for 9 weeks with vehicle, 17β-estradiol (E2), the ERβ agonist diarylpropionitrile (DPN), or EGX358 at doses that enhance memory when delivered acutely. Tail skin temperature was recorded as a proxy for vasodilation following injection of vehicle or senktide, a tachykinin receptor 3 agonist used to model hot flashes. Anxiety-like behavior was assessed in the open field (OF) and elevated plus maze (EPM), and depression-like behavior was measured in the tail suspension (TST) and forced swim tests (FST). Finally, memory was assessed in object recognition (OR) and object placement (OP) tasks. E2, DPN, and EGX358 reduced senktide-mediated increases in tail skin temperature compared to vehicle. All three treatments also enhanced memory in the OR and OP tasks, whereas vehicle did not. Although E2 increased time spent in the center of the OF, no other treatment effects were observed in the OF, EPM, TST, or FST. These data suggest that long-term ERβ activation can reduce hot flash-like symptoms and enhance spatial and object recognition memories in ovariectomized mice. Thus, the highly selective ERβ agonist EGX358 may be a promising avenue for reducing menopause-related hot flashes and memory dysfunction.

Differential Long-Term Effects of Haloperidol and Risperidone on the Acquisition and Performance of Tasks of Spatial Working and Short-Term Memory and Sustained Attention in Rats

A common feature of the neuropsychiatric disorders for which antipsychotic drugs are prescribed is cognitive dysfunction, yet the effects of long-term antipsychotic treatment on cognition are largely unknown. In the current study, we evaluated the effects of long-term oral treatment with the first-generation antipsychotic haloperidol (1.0 and 2.0 mg/kg daily) and the second-generation antipsychotic risperidone (1.25 and 2.5 mg/kg daily) on the acquisition and performance of two radial-arm maze (RAM) tasks and a five-choice serial reaction-time task (5C-SRTT) in rats during days 15-60 and 84-320 days of treatment, respectively. In the RAM, neither antipsychotic significantly affected the acquisition or performance of a spatial win shift or a delayed non-match-to-position task. Conversely, in the rats administered 5C-SRTT, haloperidol was associated with profound deficits in performance, and the subjects were not able to progress through all stages of task acquisition. Depending on the dose, risperidone was associated with a greater number of trials to meet specific performance criteria during task acquisition compared with vehicle-treated controls; however, most subjects were eventually able to achieve all levels of task acquisition. Both haloperidol and risperidone also increased the number of perseverative and time-out responses during certain stages of task acquisition, and the response and reward latencies were slightly higher than controls during several stages of the study. These results in rats suggest that while long-term treatment with haloperidol or risperidone may not significantly affect spatial working or short-term memory, both antipsychotics can (depending on dose) impair sustained attention, decrease psychomotor speed, increase compulsive-type behaviors, and impair cognitive flexibility.

Effect of long-term oral treatment with L-arginine and idebenone on the prevention of stroke-like episodes in an adult MELAS patient

Introduction Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a maternally-inherited multisystem disorder. Mitochondrial angiopathy mediated by nitric oxide, a metabolite of L-arginine, is among the proposed pathophysiologic mechanisms of stroke-like episodes (SLEs) in MELAS. There are very few reports on long-term prevention of SLEs with oral L-arginine and idebenone treatment in MELAS adult patients. Case report A 38-year-old patient with MELAS and SLEs was treated with oral L-arginine and idebenone for 27 months. She remained free of attacks throughout the treatment period except when she stopped her treatment on two occasions during which she had recurrent cerebral metabolic attacks. The patient experienced no side effect of treatment with L-arginine and idebenone. Conclusion Our observation suggests long-term safety and potential benefit of oral L-arginine and idebenone in the prevention of recurrence of SLEs in adult MELAS patients.

Effects of long-term oral treatment with selective vasopressin V2 receptor antagonist (OPC-31260) on adriamycin-induced heart failure in rats

Background In the treatment of heart failure, the effects of therapeutic agents on life prognosis remains unclear. We investigated the effects of long-term oral administration of a nonpeptide, selective, vasopressin V2 receptor antagonist, OPC-31260, on Sprague–Dawley rats that were treated with adriamycin to induce progressive water retention. Methods Intraperitoneal saline was administered to 14 rats as a control (Group 1). A total cumulative dose of 15 mg/kg of adriamycin was administered intraperitoneally in six equal doses over a period of 2 weeks to another 52 rats. Adriamycin-treated rats were further divided into Group 2, which received saline (p.o.), and Group 3, which received 50 mg/kg (p.o.) of V2 antagonist. Oral administration continued every day for 6 weeks. Group 1 rats also received saline (p.o.) for 6 weeks. Results The V2 antagonist decreased urine osmolality and increased diuresis of rats in Group 3. Urinary excretion of electrolytes was not increased by the V2 antagonist in Group 3. Serum osmolality was likewise unchanged by the V2 antagonist in Group 3. Plasma concentrations of vasopressin were significantly higher in Group 3 than in the other groups (Group 1, 4.0 ± 1.1 pg/ml; Group 2, 4.2 ± 1.5 pg/ml; Group 3, 8.5 ± 1.0 pg/ml; p < 0.05). During the experimental period, survival rate was higher in Group 3 than in Group 2 (Group 1, 100%; Group 2, 59%; Group 3, 83%). Conclusion Our data show that administration of orally active V2 antagonist did not reduce the survival of adriamycin-treated rats through continuous aquaretic action, despite elevated plasma levels of vasopressin.

Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice.

Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-kinase inhibitor and a dominant-negative Rho-kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P<0.01, n=9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-kinase (P<0.05, n=4). Among the proinflammatory cytokines examined, those of macrophage migration inhibitory factor, interferon-gamma, and transforming growth factor-beta1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group (P<0.01, n=5). Vascular inflammation in the allografts, as evidenced by accumulation of inflammatory cells (macrophages and T cells), was also significantly inhibited in the fasudil group (P<0.05, n=5 to 10). These results indicate that long-term treatment with fasudil suppresses CAV in mice, suggesting that Rho-kinase is an important therapeutic target for the prevention of CAV.

Renal cortical calcification in syngeneic intact rats and those receiving an infrarenal thoracic aortic graft: possible etiological roles of endothelin, nitrate and minerals, and different preventive effects of long-term oral treatment with magnesium, citrate and alkali-containing preparations.

Renal cortical nephrocalcinosis (C-NC) is a rare disorder of uncertain etiology. Using highly inbred (syngeneic) male Lewis rats, we describe the spontaneous occurrence of histologically detectable C-NC in sham operated control rats (Sham; n=12), its aggravation following grafting of the ascending thoracic aorta from a donor rat to the infrarenal aorta of a recipient (ATx; n=12), and differences in C-NC inhibition after 12 weeks of oral administration of magnesium (Mg), citrate and alkali. C-NC is characterized by Kossa-positive areas located in cells of the proximal tubule close to blood vessels and also, to a lesser extent, within glomeruli. After ATx there was vascular overproduction of endothelin (ET-1) but decreased production of nitrate; in renal cortical tissue there was an excess of calcium over Mg and phosphorus and oxalate over citrate. In plasma there was an increase in calcium and creatinine within the normal range. Calcification of tubular cells was eliminated by a preparation containing potassium, sodium and bases (from citrate degradation and bicarbonate) in addition to Mg. Less effective than the latter was Mg-potassium citrate and least effective, Mg citrate. The former treatment also normalized calcemia and urinary nitrate, but only incompletely suppressed ET-1 and had no significant effect on glomerular calcification or tissue and urinary oxalate. Urinary ET-1 excess appeared directly related to the cortical tissue calcium/Mg ratio, and urinary excretion of Mg, citrate and total protein appeared to be inversely related to the severity of C-NC. It was concluded that (1) the highly inbred rat is prone to precipitation of calcium phosphate in the renal cortex; (2) this type of C-NC occurs in close proximity to and within renal vascular tissue and is associated with an imbalance of vasoconstrictors and vasodilators of endothelial origin; (3) effective inhibition of C-NC can be achieved by an alkalinizing combination of Mg, potassium, sodium and citrate, underscoring its utility in the prophylaxis of pathological calcium phosphate deposition. The significance of these findings for the etiology and treatment of clinical disorders with renal and vascular calcification is uncertain and requires further investigation.

Effects of long-term oral treatment with leflunomide on allergic sensitization, lymphocyte activation, and airway inflammation in a rat model of asthma.

Short-term treatment with leflunomide is effective in suppressing antigen-specific antibody production and allergen-induced bronchoconstriction after sensitization. This agent may thus have a role in future primary prevention strategies in allergic disease. The current study aimed to determine whether long-term oral treatment with leflunomide prevents allergic sensitization permanently. After sensitization with ovalbumin, six groups of rats (n = 31) were treated daily with leflunomide or diluent for up to 30 days. Ovalbumin-specific IgE and IgG were determined weekly for at least 2 weeks after cessation of treatment. T lymphocytes from another 21 animals were stimulated ex vivo with ovalbumin or concanavalin A. Ovalbumin-specific IgE and IgG were lower during treatment with leflunomide compared with controls (P < 0.002) but increased after the cessation of treatment. Antigen-specific T-cell proliferation was decreased in cells obtained from leflunomide treated animals (P < 0.05), but not when stimulated with concanavalin A. Eosinophil (P < 0.0001) and neutrophil (P < 0.02) numbers in bronchoalveolar lavage 24 h after allergen challenge were lower in the leflunomide treated animals. Leflunomide prevents antigen-specific immunoglobulin production after sensitization during treatment, inhibits allergen-induced airway inflammation and diminishes antigen-specific T lymphocyte proliferation.

Metabolic and anti-atherogenic effects of long-term benfluorex in dyslipidemic insulin-resistant sand rats ( Psammomys obesus)

Benfluorex is a clinical lipid-lowering agent with antihyperglycemic properties. The effect of long-term oral treatment (10 mg/kg/day for 7.5 months) on carbohydrate and lipid metabolism and aortic morphology was investigated in 24 insulin-resistant sand rats receiving a standard laboratory diet supplemented with cholesterol (2%). Untreated controls (n = 34) developed impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and elevated plasma LDL- and VLDL-cholesterol, positively correlated with the proportion of the thoracic aorta displaying oil red O-positive atherosclerosis; ultrastructural examination showed intimal lipid deposits, foam cells, polymorph infiltrates and fibrosis. Benfluorex-treated animals showed significant decreases in glucose intolerance, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and plasma LDL- and VLDL-cholesterol, with no evidence of aortic atheroma. The metabolic benefits of benfluorex may protect against the long-term development of atherosclerosis in the insulin-resistant dyslipidemic syndrome.

1013 Primary structure of OCAM, a novel cell adhesion molecule of the immunoglobulin superfamily

Development of estrogen therapies targeting the β (ERβ) but not α (ERα) estrogen receptor is critically needed for the treatment of negative menopausal symptoms, as ERα activation increases health risks like cancer. Here, we determined the effects of long-term oral treatment with EGX358, a novel highly selective ERβ agonist, on memory, vasodilation, and affect in young ovariectomized mice. Mice were orally gavaged daily for 9 weeks with vehicle, 17β-estradiol (E2), the ERβ agonist diarylpropionitrile (DPN), or EGX358 at doses that enhance memory when delivered acutely. Tail skin temperature was recorded as a proxy for vasodilation following injection of vehicle or senktide, a tachykinin receptor 3 agonist used to model hot flashes. Anxiety-like behavior was assessed in the open field (OF) and elevated plus maze (EPM), and depression-like behavior was measured in the tail suspension (TST) and forced swim tests (FST). Finally, memory was assessed in object recognition (OR) and object placement (OP) tasks. E2, DPN, and EGX358 reduced senktide-mediated increases in tail skin temperature compared to vehicle. All three treatments also enhanced memory in the OR and OP tasks, whereas vehicle did not. Although E2 increased time spent in the center of the OF, no other treatment effects were observed in the OF, EPM, TST, or FST. These data suggest that long-term ERβ activation can reduce hot flash-like symptoms and enhance spatial and object recognition memories in ovariectomized mice. Thus, the highly selective ERβ agonist EGX358 may be a promising avenue for reducing menopause-related hot flashes and memory dysfunction.

Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats.

In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.

Differential Modulation of Baroreceptor Sensitivity by Long-term Antihypertensive Treatment

We investigated the effects of long-term oral treatment with four different classes of antihypertensive drugs (a thiazide diuretic [trichlormethiazide, 10 mg/kg per day]; a beta-blocker [atenolol, 90 mg/kg per day]; a calcium channel antagonist [nicardipine, 150 mg/kg per day]; and an angiotensin-converting enzyme inhibitor [enalapril maleate, 10 mg/kg per day]) on aortic baroreceptor activity in spontaneously hypertensive rats with chronic hypertension (36 weeks of age). Treatment with each of the four drugs, given from 10 to 36 weeks of age, similarly decreased arterial pressure (171 +/- 2 to 144 +/- 1 mm Hg, P < .01) and similarly decreased the threshold pressure for baroreceptors (116 +/- 3 to 103 +/- 1 mm Hg, P < .05). The four antihypertensive drugs also potentiated the maximal gain of the pressure-activity relation in these rats (untreated, 1.08 +/- 0.05% maximum/mm Hg); however, nicardipine and enalapril (1.77 +/- 0.04% and 1.70 +/- 0.06% maximum/mm Hg, respectively) augmented the maximal gain to a greater extent (P < .05 to .01) than did trichlormethiazide or atenolol (1.49 +/- 0.05% and 1.42 +/- 0.02% maximum/mm Hg, respectively). When the initiation of treatment was delayed to 28 weeks of age, no differences were found in the effects on either threshold pressure (104 +/- 1 mm Hg) or maximal gain (1.36 +/- 0.03% maximum/mm Hg) for all four drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of long term caffeine treatment on A1 and A2 adenosine receptor binding and on mRNA levels in rat brain.

The effect of long-term oral treatment with caffeine on A1 and A2 receptors in the rat brain was studied. Caffeine was added to the drinking water and the animals were sacrificed after a 12 day treatment period. The plasma caffeine concentration was close to 100 microM. A1 receptors were studied using quantitative autoradiography with [3H]cyclohexyladenosine (CHA). Caffeine treatment increased the number of A1 receptors in the CA3 subfield of the hippocampus from 337 to 393 fmol/mg with no change in KD (0.692 vs. 0.675 nM). A1 mRNA was measured using Northern blots and quantitative in situ hybridization. There was no increase in A1 mRNA. A2a receptors, located in dopamine rich regions of the rat brain, were studied with quantitative autoradiography using [3H]CGS 21680 as the ligand, and the A2a mRNA was determined using quantitative in situ hybridization. Caffeine treatment produced no significant change in either receptor number or mRNA, even though the apparent Bmax tended to increase from 322 +/- 8 to 352 +/- 8 fmol/mg. The results show that treatment with caffeine in a dose that causes tolerance to several effects of caffeine and increases some effects of adenosine analogues increases the number of A1 receptors without any change in A1 mRNA, suggesting that the adaptive changes are at a post-translational level. There were no significant changes in A2 receptors indicating that the two types are regulated differently and/or that the amount of endogenous agonist is sufficient to regulate A1, but not A2 receptors.

A one year double blind follow-up of blood gas tensions and haemodynamics in almitrine bismesylate therapy

Almitrine bismesylate, a chemoreceptor agonist, improves blood gases in chronic obstructive lung disease (COLD). Some authors have observed an increase in pulmonary artery pressure (Ppa) after single doses of almitrine bismesylate (A). This led to the present one year double blind placebo (P) controlled study to assess haemodynamic effects of long-term oral treatment in COLD (1.5 mg/kg/day for one year), together with clinical benefit and blood gas improvement. Twenty moderately severe patients entered the study, fifteen of whom completed it (eight in group (A), seven in group (P]. Blood gas values, minute ventilation (VE), mean pulmonary artery pressure (Ppa) and cardiac output (Qc) were periodically measured. Ppa and Qc remained unchanged in both groups throughout the study. We observed relevant clinical improvement without side effects and no significant increase in VE in group (A). Arterial oxygen tension (PaO2) showed a 1.2 kPa (9 mmHg) mean increase in group (A) and remained unchanged in group (P). These data and those from the literature seem to indicate that almitrine induces a vascular effect, especially after a single dose. However, as long as PaO2 improves simultaneously no long-term haemodynamic consequence is apparent. The discrepancy between immediate and long-term vascular effects of almitrine might be explained by the improvement in gas exchange which could reduce and/or counter-balance the vasoactive response. In conclusion, after one year of therapy almitrine bismesylate results in considerable clinical and blood gas improvements without significant haemodynamic change.

Clinical and hemodynamic effects of combined propranolol and nifedipine therapy versus propranolol alone in patients with angina pectoris

To determine the comparative effectiveness and hemodynamic effects of long-term oral treatment with propranolol alone and combined with nifedipine in patients with stable angina pectoris, 20 patients with coronary disease were studied by equilibrium radionuclide ventriculography. Measurements were performed at rest and during supine bicycle exercise before treatment, after 4 weeks on propranolol, 1 hour after institution of combined propranolol and nifedipine treatment, and after 4 weeks on the combined treatment. The reduction in exercise rate-pressure product induced by the combination (17.2 ± 2.6 × 10 3) was significantly greater ( p < 0.001) than that attained by propranolol alone (19.3 ± 2.8 × 10 3). In patients at rest, neither propranolol nor the combined therapy altered global left ventricular (LV) ejection fraction (EF). Without drugs and on propranolol, exercise EF decreased significantly. On the combined therapy there was a significant improvement in exercise EF compared both with rest values ( p < 0.01) and with exercise EF on propranolol ( p < 0.001). Exercise tolerance, expressed as total work load, significantly increased on propranolol and further increased on combined therapy. Thus the combined propranolol/nifedipine therapy in patients with stable angina proved to be hemodynamically superior to therapy with propranolol alone and safe even in patients with moderately depressed LV function.

The effect of long-term oral treatment of rats with contraceptive steroids on tissue MAO

The chronic oral administration of ethynyl oestradiol plus norgestrel to female rats for 1 or 2 months decreased monoamine oxidase activity in liver and brain. The changes were less marked after 2 months of treatment. This could be due to the development of some degree of physiological adaptation.