Journal of Pharmacy and Pharmacology 

About: Journal of Pharmacy and Pharmacology is an academic journal. The journal publishes majorly in the area(s): Pharmacokinetics & Dopamine. It has an ISSN identifier of 0022-3573. Over the lifetime, 16789 publications have been published receiving 330900 citations.

Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems

Abstract: Objectives The frontline drug doxorubicin has been used for treating cancer for over 30 years. While providing a cure in select cases, doxorubicin causes toxicity to most major organs, especially life-threatening cardiotoxicity, which forces the treatment to become dose-limiting. Key findings Doxorubicin is known to bind to DNA-associated enzymes, intercalate with DNA base pairs, and target multiple molecular targets to produce a range of cytotoxic effects. For instance, it causes the activation of various molecular signals from AMPK (AMP-activated protein kinase inducing apoptosis) to influence the Bcl-2/Bax apoptosis pathway. By altering the Bcl-2/Bax ratio, downstream activation of different caspases can occur resulting in apoptosis. Doxorubicin also induces apoptosis and necrosis in healthy tissue causing toxicity in the brain, liver, kidney and heart. Over the years, many studies have been conducted to devise a drug delivery system that would eliminate these adverse affects including liposomes, hydrogel and nanoparticulate systems, and we highlight the pros and cons of these drug delivery systems. Summary Overall the future for the continued use of doxorubicin clinically against cancer looks set to be prolonged, provided certain enhancements as listed above are made to its chemistry, delivery and toxicity. Increased efficacy depends on these three aims being met satisfactorily as discussed in turn in this review.

Nitric Oxide Scavenging by Curcuminoids

Abstract: Because curcumin, a compound with anti-inflammatory and anticancer activity, inhibits induction of nitric oxide synthase in activated macrophages and has been shown to be a potent scavenger of free radicals we have investigated whether it can scavenge nitric oxide directly. Curcumin reduced the amount of nitrite formed by the reaction between oxygen and nitric oxide generated from sodium nitroprusside. Other related compounds, e.g. demethoxycurcumin, bisdemethoxycurcumin and diacetylcurcumin were as active as curcumin, indicating that the methoxy and the phenolic groups are not essential for the scavenging activity. The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free-radical scavenging properties, including those toward nitric oxide.

The concept of dissolution efficiency.

Abstract: The recent interest in drug availability has resulted in a proliferation of in vitro dissolution testing, now standard for many dosage forms. The usual method of evaluation is the comparison of the time taken for given proportions of the active drug to be released into solution and figures such as the t20, t50 and t90 % times are often quoted. Alternatively the fraction of drug in solution after a given time is used for comparison, i.e. 60% release in 30 min. A further parameter suitable for the evaluation of in vitro dissolution has been suggested by Khan & Rhodes (1972), who introduced the idea of Dissolution Efficiency. This is defined as the area under the dissolution curve up to a certain time, t, expressed as a percentage of the area of the rectangle described by 100% dissolutionin the sametime. The simplest case, shown in Fig. 1 where, dissolution of a tableted drug, is

Evidence for dopamine receptor stimulation by apomorphine

Abstract: Sm,-Recently, Ernst (1967) has reported that the apomorphine-induced compulsive gnawing in rats is not mediated via the release of catecholamines, since it is not reduced by the catecholamine synthesis inhibitors a-methyl-3,4dihydroxyphenylalanine and a-methyltyrosine. On the other hand, the gnawing seen after treatment with (+)-amphetamine is blocked by these synthesis inhibitors. Since the apomorphine-induced gnawing requires an intact corpus striatum and gnawing can also be produced by the catecholamine precursor dihydroxyphenylalanine, Ernst (1967) suggested that apomorphine acts on the dopamine receptors whereas amphetamine acts by releasing dopamine. In the present paper supporting evidence for this view is given by further functional, biochemical and histochemical studies. The functional influence of apomorphine on dopamine neurotransmission in the corpus striatum was examined after unilateral removal of the corpus striatum of adult hooded rats weighing about 200 g (And& Dahlstrom & others, 1966a). A possible action of apomorphine on the noradrenaline receptors of the spinal cord was tested in acutely spinalized adult hooded rats by evaluating the changes in the flexor reflex evoked by pinching the hind limbs. The effect of apomorphine on the dopamine and noradrenaline levels of the brain and spinal cord was determined biochemically (Bertler, Carlsson & Rosengren, 1958; Carlsson & Waldeck, 1958) and histochemically (Falck, Hillarp & others, 1962; Dahlstrom & Fuxe, 1964; Hamberger, Malmfors & Sachs, 1965). Function. These studies were made mainly on rats which had been pretreated with reserpine (10 mg/kg i.p., 3 hr) plus a-methyltyrosine methylester (H 44/68, 500mg/kg, i.p., 2 hr) after removal of the left corpus striatum by suction. After this treatment all the operated animals turned towards the unoperated side (cf. And6n & others, 1966a). After injection of apomorphine (1-25 mg/kg s.c.) these rats changed their position and turned or rotated towards the operated side. This effect began about 5 min after the injection and was evident for about 45-60 min. If apomorphine was given to operated rats not pretreated with reserpineH 44/68 combination, this action of apomorphine, like the gnawing, seemed to be less pronounced. If haloperidol (5 mg/kg i.p.) was given 15-20 min after apomorphine all the rats turned from the operated towards the unoperated side in about 15 min and the gnawing ceased. (+)-Amphetamine (0.5-25 mg/kg s.c.), like apomorphine, made the rats turn or rotate towards the operated side. In contrast to apomorphine, however, this action of amphetamine was not seen after pretreatment with reserpine plus H 44/68 (cf. Weissman, Koe & Tenen, 1966; Hanson, 1967; Ernst, 1967). Apomorphine (25 mg/kg s.c.), in contrast to (+)-amphetamine (05-25 mg/kg s.c.) and ~-3,4-dihydroxyphenylalanine (50-75 mg/kg i.v. 2 hr after nialamide 50 mg/kg i.p.), did not cause a definite increase of the flexor reflex in spinalized rats. Chemistry. The biochemical results obtained in unoperated adult hooded rats are presented in Table 1. Apomorphine caused a retardation of the depletion in brain dopamine produced by H 44/68. The difference between the dopamine levels in the apomorphine-H 44/68 group and in the H 44/68 group is statistically significant (P < 0.001, Student’s r-test). This action of apomorphine on the brain dopamine was blocked by haloperidol. The disappearance of noradrenaline from the brain and the spinal cord after H 44/68 did not seem to be influenced by apomorphine. (+)-Amphetamine did not cause any significant retardation of the dopamine and noradrenaline loss after H 44/68.

Nanoparticle uptake by the rat gastrointestinal mucosa : quantitation and particle size dependency

Abstract: Polystyrene microspheres in the size range 50 nm to 3 microns were fed by gavage to female Sprague Dawley rats daily for 10 days at a dose of 1.25 mg/kg-1. Previous histological evidence of the uptake of these particles and their absorption across the gastrointestinal tract and passage via the mesentery lymph supply and lymph nodes to the liver and spleen was confirmed by analysis of tissues for the presence of polystyrene by gel permeation chromatography. Measurement of radioactivity of tissues following administration of 100 nm and 1 micron I125-labelled polystyrene latex particles for 8 days was corroborative although less secure because of the potential lability of the labelled particles. The extent of absorption of 50 nm particles under the conditions of these experiments was 34% and of the 100 nm particles 26% (as measured by determination of polystyrene content), of which total, about 7% (50 nm) and 4% (100 nm), was in the liver, spleen, blood and bone marrow. Particles larger than 100 nm did not reach the bone marrow, and those larger than 300 nm were absent from blood. No particles were detected in heart or lung tissue.