IRANIAN JOURNAL OF PHARMACOLOGY AND THERAPEUTICS (IJPT)
Year:2006 | Volume:5 | Issue:2|Papers Count:16

Heart failure is associated with high morbidity and mortality and is proving to be an economic burden in developing countries. A number of therapeutic agents are presently employed in heart failure; but they are not sufficient to control symptoms of heart failure. Moreover, the prevalence of chronic heart failure is progressively increasing and thus there is a continuing need to develop effective therapies for the management of this disease. The present review has discussed various potential therapeutic agents which may open new vistas for the management of heart failure.

As men get older, there is a decline in functioning of many biological systems; the endocrine systems share such changes in hormone levels. Ageing in men is accompanied by progressive, but individually variable decline in serum testosterone production in healthy men especially in men over 60 years of age. Androgens determine the differentiation of male internal and external genitalia as well as the development and maintain ace of male secondary sex characteristics and male reproductive function. They have important metabolic effects on protein, carbohydrate and fat metabolism and contribute to the determination of muscle mass and strength and also affect behavior and cognition. In ageing men, the serum androgen levels are affected due to several factors such as , circadian rhythmicity, heredity, body mass, diet, stress, life style, smoking, alcohol, and exercise. The decreased levels androgen may lead to senile osteroporo-sis, hypogonadism, decreased libido and brain functions. The incidence of cognitive disorders such as dementia and Alzheimer’s disease is also high in testosterone deficient adults. The relationship between endogenous plasma testosterone levels, visual-spatial orientation, depression and brain function plays a vital role while treating aged males with cognitive disorders associated with decline in testosterone levels. The present paper highlights various aspects of ageing associated decline in androgen levels, cognitive function and usefulness and risk of androgen replacement therapy in aged males.

The genotoxic effect of endosulfan and the modulatory effect of vitamin C in growing albino rats were stu-died by bone marrow micronucleus assay. Seven days old male Wistar rats were treated with 3, 6, 9, 12 mg/kg Endosulfan orally (10 pups/group), for up to 60 days, at intervals of 24h. For 2 more groups (n=10/group), Endosulfan 9 mg/kg and 12 mg/kg was administered along with vitamin C (20 mg/kg). One more group of rats was treated with cyclophosphamide as positive control. The genotoxic effect was studied by bone marrow micronuclei assay. There was an increase in micronuclei in polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) and a decrease in PCE and P/N ratio in endosulfan treated rats. The effect was similar to the standard mutagen cyclophosphamide. In rats treated with vitamin C and endosulfan, there was an increase in PCE and P/N ratio and decrease in micronuclei in PCE and NCE. This could be due to the antimutagenic effect of vita-min C.

There is an increasing tendency for traditional medicine in the world. Many people prefer to take herbal products instead of chemical medicines. However, over consumption of herbal medicines has led to many unpredictable side effects.One of these traditional medicines is Citrullus colocynthis, which is used by diabetic patients as an hypoglycemic agent, but it has been reported to cause gastrointestinal disorders after consumption in some patients.50 rats were randomly divided into five groups (4 experimental and 1 controls). In the experimental groups a single daily dose of alcoholic extract of Citrullus colocynthis (50, 100, 200, 400 g/kg) was administered intraperitonally. Normal saline was administered in control group. After two weeks, the rats were killed and the livers were removed and fixed with formalin (10%). Specimens were then processed and stained with H&E and Reticuline. The results indicated that there is a morphological change in liver cells including karyrrhexis, chromatolysis, and granulation of the cytoplasm. Additionally, collagen and reticular fibers were evident in liver parenchyma in high doses. Citrullus colocynthis can have toxic effects on liver cells which may induce hepatocyte necrosis and liver fibrosis. These effects were dose dependent. Further studies are necessary to clarify the issue.

Gastrointestinal (GI) complications during diabetes mellitus (DM) are common. Attempts to ascribe changes in the glycemic state to the altered GI (gastrointestinal) motility in experimental models yielded varied results. In the present study the possible cause-effect relationship between the changes in the gly-cemic, insulinemic states and small intestinal transit (SIT) in normal mice was examined. Hypoglycemia was induced by either short or long periods of food deprivation. Short periods was attempted in five groups of animals by depriving food for 0, 6, 12, 18 and 24 h duration. Blood glucose (BG) levels were recorded 10 min before the commencement of various periods and just few min before sacrificing the an-imals for SIT measurement. Charcoal meal was administered intragastrically after termination of periods for SIT measurement. Long periods of food deprivation was attempted in four groups for 30, 36, 42 or 48 h. Acute hyperglycemia was attempted in four groups by i.v or i.p administration of dextrose (0.4, 1 and 4 g/kg). Charcoal meal was administered 10 min after dextrose administration. Thirteen groups were treated similarly without SIT measurement but one mL of blood was collected for determination of serum insulin levels. A fall in BG levels was associated with attenuation of SIT in 5 short period groups. The dif-ference in association was minimum in 12 and 6 h groups and maximum in 30 and 48 h groups. Whereas an association between fall in insulin levels and attenuation of SIT was observed in 4 long period groups. The difference between their association was minimum in 48h group and maximum in 30 h group. An ac-celeration of SIT was associated with fall in BG levels in the groups of 24 and 42 h. The difference in rela-tionship was minimum in 42 h and maximum in 24 h group. A similar relationship existed between accele-ration of SIT and fall in insulin levels in 24 and 42 h groups. However in 6 h group a mild elevation of insu-lin level was associated with attenuation of SIT. No association between BG, insulin levels and SIT was observed in 36 group. At a lower doses of dextrose administration (0.4 and 1 g/kg) no association of BG with SIT was seen, but, when the dose was increased by 4 g/kg an inverse relationship observed with SIT. Similarly with the lower doses of dextrose no association between insulinemic state and SIT was ob-served. But, when the dose of dextrose increased to 4 g/kg an inverse relationship between serum insulin levels and SIT was observed. It can be concluded from this study that a fall in BG levels or serum insulin levels favours attenuation of SIT from 6-30 h of food deprivation. Normal to moderate glycemic or insuli-nemic states have no influence on SIT.

Pharmacokinetics of cefepime was studied after single dose intravenous administration at the dose rate of 5 mg/kg body weight in calves. Blood samples were collected from the jugular vein at predetermined time intervals before and after drug administration. Serum was harvested and analyzed for cefepime concentration by reverse-phase high performance liquid chromatography. Following intravenous administra-tion, the mean serum cefepime level of 44.93 ± 5.47 mg/mL was observed at 0.033 h (2 minutes). The therapeutically effective concentration of cefepime ( ³ 1.00  mg/mL) was maintained in serum up to 12 h. The distribution half-life (t1/2a) and elimination half-life (t1/2b) were 0.09 ± 0.01 h and 3.70 ± 0.16 h, respectively. The mean values of apparent volume of distribution [Vd(area)] and volume of distribution of drug at steady-state (Vd(ss)) were calculated to be 0.57 ± 0.03 and 0.43 ± 0.03 L/kg, respectively. The mean value of total body clearance (ClB) was 1.81 ± 0.16 mL/min/kg. The average values for area under serum drug concentration-time curve (AUC) and area under first moment of curve (AUMC) were 47.73 ± 4.05 ±g h/mL and 190.3 ± 19.9 ±mg h2/mL. The average value of mean residence time (MRT) was 3.95 ± 0.11 h. A satisfactory intravenous dosage regimen would be 4.20 mg/kg body weight as priming dose followed by 3.78 mg/kg repeated at 12 h intervals.

The most important role in postoperative pain management is still played by opioid administration through various modes. For the last few years, there has been an intensive search for alternative mode of opioid administration in pain management. The intranasal modes of opioid administration seems to be an attrac-tive alternative. Sixty boys (aged 0.5-6 yr); ASA (American Society of Anesthesiologists) physical status I, who were candidates for lower abdominal surgery, were included in this prospective randomized, con-trolled study. Five minutes before extubation, patients were randomized to two groups and allocated to receive intranasal sufentanil (0.7 μg/kg) or normal saline, using a double-blinded study design. Satisfacto-ry analgesia was achieved with intranasal sufentanil. It was effective after 10 minutes with the least pain scores (pain score 2.3±0.4 vs. 4.1±0.5) (p = 0.001). Pain scores in 15, 20 and 25 minutes were similar in sufentanil group. None of patients had bradycardia, hypotension or SpO2 (arterial O2 saturation) <95%. High bioavailability of sufentanil after intranasal administration due to direct entrance of the drug into the systemic circulation and avoidance of the hepatic first- pass effect makes sufentanil an opioid with rapid onset and limited duration. As it has minimal side effects, sufentanil is one of the best choices for post-operative pain control in children. We used 0.7 μg/kg of intranasal sufentanil and found satisfactory anal-gesia accompanied with least side effects.

Diabetic nephropathy (DN) is one of the major causes of end stage renal disease. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) are preferred for delaying progression of DN. This study compared the preventive renal effects of telmisartan (10 mg/kg, p.o.), an ARB, that completely blocks angiotensin action, and benazepril (5 mg/kg, p.o.), an ACE inhibitor, which is a partial blocker of angiotensin II production, in an animal model of diabetic nephropathy. DN was induced by streptozotocin (50 mg/kg, i.p.) single injection in male albino rats. Biochemical parameters (creatinine clearance, urinary protein and blood urea) were significantly (p<0.01) altered in diabetic rats after 4 weeks. Telmisartan (10 mg/kg, p.o.) and benazepril (5 mg/kg, p.o.) treatment significantly (p<0.01) re-duced elevated levels of blood urea and urinary protein in diabetic rats. After 8 weeks of diabetes there was significant difference in reduction of blood urea in between telmisartan and benazeril group. Differ-ence between telmisartan and benazepril for reduction in proteinuria was not singnificant. Difference be-tween telmisartan and benazepril for creatinine clearance improvement was also not significant (p>0.05). Histology revealed beneficial effects produced by both drugs. This study demonstrates telmisartan is equally renoprotective as benazepril.

The aim of this study was to evaluate the antiarthritic activity of ethanolic extract of the leaves of Crotalaria juncea (CJE) in Complete Freund’s Adjuvant (CFA) induced arthritis model in rats, and also to evaluate antiulcerogenic activity of CJE. Arthritis was induced in male albino Wistar rats by injection of CFA (0.1 mL) into the left foot pad of the animals. Treatment with CJE at 200 and 400 mg/kg and standard indomethacin (0.3 mg/kg) was started on the same day and continued up to day 12. The paw volume was measured on day 1, 5, 12 and 21 for both the paws and antiarthritic activity was evaluated. Anti-ulcerogenic potential of CJE was also evaluated. For possible mechanism of anti-ulcerogenic potential, appetite suppressant activity was recorded. The drug CJE produced reduction in the inflammation of the paw produced due to CFA. The antiarthritic action started on the day 5 and continued till day 12 and the activity was comparable to that of the standard on both days. In indomethacin treated animals ulcer was observed, where as CJE was found to protect the animals from ulcer formation which may be due to ap-petite suppressant activity. CJE significantly inhibited adjuvant induced arthritis and has significant anti-inflammatory effect (p<0.001). It has anti-ulcerogenic property compared to indomethacin, which may be due to appetite suppressant activity.

The present study was carried out to investigate the effect of benazepril on corneal permeation in goat cornea and its effect on experimentally induced acute and chronic glaucoma in rabbits. Acute glaucoma was produced by i.v. infusion of 5% glucose (15 mL/kg) in rabbits, whereas chronic glaucoma was induced by injection of alpha-chymotrypsin into posterior chamber of rabbit eye. We studied the interaction of benazepril on isolated rat ileum pre-administered with acetylcholine, the enzyme cholinesterase bio-chemically and on ACE levels in aqueous humor after topical application. A significant increase in intra ocular pressure (IOP) in rabbits was observed which reached to the peak of 41±0.85 after 90 min. Injection of alphachymotrypsin produced sustained elevation of Intraocular Pressure which lasted for almost 3 months. Benazepril produced significant fall in Intraocular Pressure in normotensive as well as glucose or alpha-chymotrypsin treated rabbit eyes. It was been observed that the benazepril produced significant potentiation of responses to acetylcholine in isolated rat ileum preparation and inhibition of cholinesterase enzyme. The corneal permeation of benazepril from 0.1% solution was maximum at 15 min after which there is a decline in rate of permeation was observed. The results observed in the present study indicate that the potential ocular hypotensive activity of benazepril which may be due to inhibition of ACE (Kini-nase-II) and cholinesterase.

Previous studies indicate that organ fibroblasts play an important role in wound healing, collagen production, remodeling processes and pathogenesis of progressive heart, lung, renal and hepatic fibrotic diseases. Several studies suggest a possible inhibitory role for adenosine in the regulation of fibroblast proliferation. The effect of adenosine A2 agonists on proliferation and differentiation of chick embryo skin/muscle fibroblasts was studied in collagen-based 3-dimensional tissue constructs and also in plated monolayer cells. Materials and Methods: Chick embryo primary fibroblasts were plated in separate groups and were synchronized by growth arrest before stimulation by different doses of adenosine, and A2 receptor agonists, CV1808, NECA and an A2 receptor antagonist, CGS15943, and control, in the presence of serum or serum free medium. The cell counts for each treatment of monolayer fibroblasts were compared to determine fibroblast proliferation. Western blot analysis, immunostaining and myofibroblast size measurements were conducted to measure the effect of adenosine on the fibroblast differentiation into myofibroblasts. Cell proliferation was also gauged with DNA assays in the 3-D constructs. Results: Adenosine agonists at low doses significantly reduced fibroblast proliferation in monolayer and 3-D cell culture in the presence of 5% Fetal Calf Serum (FCS) demonstrating a potential antifibrotic activity possibly by activation of the A2B receptor. Western blot analysis and immunostaining of cells revealed no significant inhibition of the expression of  a-smooth muscle actin on a per cell basis by adenosine agonists. Cell size measurements indicated increased numbers of smaller fibroblasts suggesting that adenosine may inhibit the conversion of fibroblasts to myofibroblasts. Conclusion: This study suggests that agents that increase tissue cAMP levels may be of beneficial therapeutic value in organ tissue fibrosis.

In developing a drug delivery strategy, issues of absorption, distribution, metabolism, and elimination must be considered. The eye presents unique opportunities and challenges when it comes to the delivery of pharmaceuticals. While absorption by this route is bungling, there are few side effects with convention-al ocular dosage forms. Hence, ocular inserts were prepared with prolonged release of drug and mini-mum swelling within cul-de-sac using ofloxacin as a model drug; and hydroxypropyl methyl cellulose, methyl cellulose, poly vinyl pyrrolidone and poly vinyl alcohol as polymers. PEG-400 was incorporated as plasticizer. The main purpose of the study was to deliver the drug in zero order kinetics. Solvent casting technique was followed to prepare ofloxacin ocular films. Eight formulations were formulated and sub-jected to various physicochemical evaluations. Ocular inserts prepared were smooth and passed all the evaluation tests performed. Formulation OF2 shows a maximum cumulative percentage drug release of 91.27 % at the end of 24 hours. Ocuserts formulated also passed the test for sterility. They showed zero-order release of the drug in the in vitro and in vivo release studies. The drug in the films was found to be active against selected microorganisms as was proved by microbial efficacy studies. A high correlation coefficient was found between in vitro and in vivo release rate studies. Shelf-life of the product was found to be more than one year. The results of in vitro, in vivo, kinetic treatment (zero order and Korsemeyer’s regression values) and rate constant ‘k’ value suggest that OF2 was the best formulation among the formulations studied for formulating ofloxacin ocular insert.

Alfa-cypermethrin (a-CP) a synthetic pyrethroid (type-II) insecticide, dissolved in dimethyl sulfoxide (DMSO-1 mL) was given consecutive daily orally for 60 days at 1/10 LD50 (14.5 mg/kg). The animals were sacrificed on day 61st. Biochemicals, cytochrome P450, b5 contents in liver along with antioxidant status, tissue residual concentration, and brain GABA level were studied. It increased the serum aminotransami-nase (AST, ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) activities and blood glucose level significantly (p<0.05). It significantly (p<0.05) decreased and increases cytochrome P450 content and b5 content in liver respectively. It increased the malondialdehyde (MDA) level, and decreased the activities of catalase (CAT) and superoxide dismutase (SOD) and glycogen in liver significantly. The py-rethroid was considerable in amount in tissues. The GABA levels in cerebellum and in whole brain without cerebellums were decreased significantly (p<0.05). Therefore repeated daily oral dose toxicity of a-CP at 1/10 LD50 altered biochemical parameters, decreased cytochrome P450 content, antioxidant status, and decreased brain GABA level.

The Suffof-e-Suzak Qawi is an unani polyherbomineral formulation and is being used in the alternative system of medicine for its anti-gonorrheal and diuretic activity. It is an official monograph in national for-mulary of unani medicine (NFUM) and reported as anti-gonorrheal and diuretic. The aqueous suspension of the formulation was studied for its possible diuretic activity and its effect on urinary sodium and potas-sium excretion. The results were compared with animal groups treated with vehicle and standard drug furosemide. When tested in healthy adult rats the formulation at a dose of 500, 750 and 1000 mg/kg has shown increase in the urinary output and urinary sodium excretion but not any increase in the urinary po-tassium excretion at all dose levels. The present study showed that, the aqueous suspension of Suffof-e-Suzak Qawi has diuretic activity comparable with the standard drug furosemide in producing urinary out-put and urinary sodium excretion and has no effect on urinary potassium excretion.

The ethanolic extract of the flowering tops of Rosa damascena (Rosaceae) was assessed for effect on the central nervous system (CNS) using a number of neuropharmacological experimental models in mice. The extract produced a dose-dependent reduction of the onset and duration of pentobarbitone-induced hypnosis, reduction of locomotor and exploratory activities in the open field, hole cross tests. At the same dose levels, the extract dose-dependently inhibited acetic acid-induced writhing in mice. These results suggest that the extract possess CNS depressant activity.

In the present study, the analgesic and anti-inflammatory activities of a new alkaloid (5′-Hydroxymethyl-1′- (1,2,3,9-tetrahydro-pyrrolo [2,1-b] quinazolin-1-yl)-heptan-1-one) (compound 1), isolated from Sida cordi- folia Linn. was investigated in animal models. The analgesic activity was investigated in the acetic acid induced writhing and the radiant heat tail flick model in mice and the carrageen an induced rat paw edema  model was used for anti-inflammatory study. The compound produced significant (p<0.01) analgesic activity in both models. The compound also exhibited significant (p<0.01) inhibition of rat paw edema induced by carrageen an. These results indicated that compound 1 possessed analgesic and anti-inflammatory activities.