ISRN Pharmacology最新文献

The present study was undertaken to test the chemopreventive effects of one herbal medicinal plant, Indigofera aspalathoides, on chemically induced carcinogenesis in rats. A well-known polyaromatic hydrocarbon, namely, 20-methylcholanthrene, which is a known carcinogenic substance, was used to induce fibrosarcoma in Wistar strain of male albino rats. Fibrosarcoma rats were treated with aqueous extracts of Indigofera aspalathoides. The rats were divided into four groups, each consisting of six animals. Group I served as normal control, Group II served as fibrosarcoma-induced animals, Group III were fibrosarcoma-bearing animals treated with aqueous extracts of Indigofera aspalathoides, and Group IV animals, which were normal healthy animals treated with Indigofera aspalathoides aqueous extract, served as drug control set. Group III and Group IV animals were treated with aqueous extract of Indigofera aspalathoides intraperitoneally at a dose of 250 mg/kg. b.w. for 30 days. The fibrosarcoma was proved by pathological examinations. The activity levels of nucleic acids such as total DNA and RNA and hexose, hexosamine, and sialic acid in liver and kidney of treated rats were used to monitor the chemopreventive role of the plant extract. The observed increase in the levels of DNA, RNA, hexose, hexosamine, and sialic acid in liver and kidney tissues of fibrosarcoma-bearing animals reached near normal state after the treatment with aqueous extracts of Indigofera aspalathoides, suggesting that Indigofera aspalathoides does have a chemotherapeutic role.

Immunocompetent mice, Fc receptor γ-chain deficient mice (Fcer1g(-/-)), and molecular tools as F(ab')(2) bivalent fragments appear as the most suitable biological models to study the mechanisms of the action of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs). In vivo experiments contrasting antitumor effects of whole Abs and their bivalent fragments commonly involve a previous comparative pharmacokinetics study. In this paper, pharmacokinetics and biodistribution of an anti-mouse EGFR Ab were assessed using immunocompetent mice. (125)I-labeled 7A7 mAb holds an elimination half-life (t(1/2)β) of 23.1 h in C57BL/6 mice. Accumulation of mAb was found in liver, spleen, kidneys, and mostly in lungs. We used an ELISA method to determine the t(1/2)β of a 7A7 mAb using the same experimental setting. Results from this new analysis revealed a t(1/2)β of 23.9 h, supporting this method as a safer and easier system to evaluate pharmacokinetics parameters of mAbs targeting mouse EGFR. Using this system we also studied pharmacokinetics of 7A7 F(ab')(2) fragment. A tenfold difference between the mAb and fragment t(1/2)β was found. These data support the use of the 7A7 F(ab')(2) fragment in in vivo studies to explore the contribution of the EGFR signaling blockade and the Fc region to the antitumor effect of 7A7 mAb in this autologous scenario.

Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01 mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper.

The anticancer drugs screening program is a long and expensive process. It is estimated that only 5% of drugs entering clinical trials are approved by the FDA. Moreover, many of the drugs that enter clinical trials are often of limited use in clinical practice, and most cancers remain untreatable. Brain tumors are particularly difficult to treat due to the presence of the blood brain barrier that limits the penetration of anticancer drugs. Additionally the isolation from most brain tumors of putative cancer stem cells and novel models of cancer stem cell biology suggest that anticancer drugs should be delivered for prolonged time and at higher concentrations to deplete any potential tumorigenic cell. In this paper, current concepts of cancer stem cell biology and novel concepts of anticancer drugs screening are integrated to develop a seven-steps algorithm as a guideline for the preclinical evaluation of active compounds for the treatment of brain tumors. The flexibility of the algorithm allows the inclusion of alternative studies to exhaustively investigate anticancer drugs and creates multiple opportunities where decisions to engage or not in early clinical trials can be made providing a useful tool for translational research in neurooncology.

The dopamine hypothesis of schizophrenia remains the primary theoretical framework for the pharmacological treatment of the disorder. Despite various lines of evidence of dopaminergic abnormalities and reasonable efficacy of current antipsychotic medication, a significant proportion of patients show suboptimal treatment responses, poor tolerability, and a subsequent lack of treatment concordance. In recent decades, intriguing evidence for the critical involvement of other neurotransmitter systems in the pathophysiology of schizophrenia has emerged, most notably of dysfunctions within the glutamate pathways. Consequently, the glutamate synapse has arisen as a promising target for urgently needed novel antipsychotic compounds-particularly in regards to debilitating negative and cognitive symptoms poorly controlled by currently available drugs. In this paper, recent findings integrating glutamatergic and dopaminergic abnormalities in schizophrenia and their implications for novel pharmacological targets are discussed. An overview of compounds in various stages of development is given: drugs enhancing NMDA receptor function as well as metabotropic glutamate receptor (mGluR) agonist and positive allosteric modulators (PAMs) are emphasised. Together with other agents more indirectly affecting glutamatergic neurotransmission, their potential future role in the pharmacotherapy of schizophrenia is critically evaluated.

Introduction. Adherence to antiretroviral therapy (ART) in low-income countries is mainly assessed by self-reported adherence (S-RA) without drug level determination. Nonadherence is an important factor in the emergence of resistance to ART, presenting a need for drug level determination. Objective. We set out to establish the relationship between plasma stavudine levels and S-RA and validate S-RA against the actual plasma drug concentrations. Methods. A cross-sectional investigation involving 234 patients in Uganda. Stavudine plasma levels were determined using high-performance liquid chromatography. We compared categories of plasma levels of stavudine with S-RA using multivariable logistic regression models. Results. Overall, 194/234 patients had S-RA ≥ 95% (good adherence) and 166/234 had stavudine plasma concentrations ≥ 36 nmol/L (therapeuticconcentration). Patients with good S-RA were eight times more likely to have stavudine levels within therapeutic concentration (Adjusted Odds Ratio: 7.7, 95% Confidence Interval: 3.5-7.0). However, of the 194 patients with good S-RA, 21.7% had below therapeutic concentrations. S-RA had high sensitivity for adherence (91.6%), but limited specificity for intrinsic poor adherence (38.2%). Conclusions. S-RA is a good tool for assessing adherence, but has low specificity in detecting nonadherence, which has implications for emergence of resistance.

Glutamate dehydrogenase (GDH, E.C. 1.4.1.3.) is a key enzyme for the biosynthesis and modulation of glutamate (GLU) metabolism and an indirect γ-aminobutyric acid (GABA) source, here we studied the effect of anticonvulsants such as pyridoxal phosphate (PPAL), aminooxyacetic acid (AAOA), and hydroxylamine (OHAMINE) on GDH activity in mouse brain. Moreover, since GLU is a glucogenic molecule and anoxia is a primary cause of convulsions, we explore the effect of these drugs on oxygen consumption. Experiments were performed in vitro as well as in vivo for both oxidative deamination of GLU and reductive amination of α-ketoglutarate (αK). Results in vitro showed that PPAL decreased oxidative deamination of GLU and oxygen consumption, whereas AAOA and OHAMINE inhibited GDH activity competitively and also inhibited oxygen consumption when αK reductive amination was carried out. In contrast, results showed that in vivo, all anticonvulsants enhanced GLU utilization by GDH and also decreased oxygen consumption. Together, results suggest that GDH activity has repercussions on oxygen consumption, which may indicate that the enzyme activity is highly regulated by energy requirements for metabolic activity. Besides, GDH may participate in regulation of GLU and, indirectly GABA levels, hence in neuronal excitability, becoming a key enzyme in seizures mechanism.

The residents of Lower Dir and Malakand agency, Khyber Pakhtunkhwa, Pakistan, use the dry powder of whole plant of Pentanema vestitum for the treatment of asthma and diabetes. No documented reports are available about the therapeutic action of Pentanema vestitum. The present study was aimed to explore the antihyperglycemic effect of 70% methanol extract of Pentanema vestitum whole plant in glucose-induced nondiabetic hyperglycemic and alloxan-induced diabetic rabbits. During this study, the effects of plant extract on the serum lipid profile, GPT, ALP, bilirubin and creatinine of diabetic rabbits were also studied. The extract of Pentanema vestitum whole plant exhibited significant (P < 0.05) antihyperglycemic activity in glucose-induced hyperglycemic rabbits. Treatment of alloxan-induced diabetic rabbits with extract significantly (P < 0.05) reduced the elevated levels of serum glucose, GPT, ALP, bilirubin and creatinine. During the study of lipid profile, the extract proved to be antihyperlipidemic and HDL boosting in diabetic rabbit models. From the finding of the present research, it was concluded that the 70% methanol extract of Pentanema vestitum whole plant has beneficial effects on serum levels of glucose, lipid profile, GPT, ALP, bilirubin, and creatinine of diabetic rabbits.

The present study examined the effect of nicotine, alone and in combination with various drugs that act on the CNS, on ambulatory activity, a behavioral index for locomotion, in ICR (CD-1) strain mice. Nicotine at 0.25-2 mg/kg acutely reduced ambulatory activity of ICR mice. The effect of nicotine was similar to that of haloperidol and fluphenazine but distinct from that of bupropion and methylphenidate. ICR mice developed tolerance against the inhibitory effect of nicotine on ambulatory activity when nicotine was repeatedly administered. This effect was also distinct from bupropion and methylphenidate as they produced augmentation of their ambulation-stimulating effects in ICR mice. Nicotine reduced the ambulation-stimulating effects of bupropion and methylphenidate as well as haloperidol and fluphenazine. Taken together, nicotine exhibited unusual effects as a psychostimulant on ambulatory activity in ICR mice.

Curcumin is an important nutraceutical that has enormous potential for a variety of diseases, but the medicinal properties of curcumin cannot be utilized due to its low in vivo bioavailability. Therefore, in view of the foregoing, there is an extensive need for combinatorial extract "curcumin with piperine and quercetin" which may enhance bioavailability of oral curcumin by inhibiting the enzymes responsible for the metabolism of curcumin. Thus, the present study investigated the effect of combinatorial extract of curcumin on obesity, glucose intolerance, and oxidative stress in high fat diet and low-dose streptozotocin-induced rats. Oral administration of combinatorial extract for 28 days significantly (P < 0.05) reduced PGL (64.84%), PTG (88.94%), LDL (26.38%) and PTC (50.23%) levels, respectively and improved glucose tolerance (P < 0.05) significantly to exogenously administered glucose (2 g/kg) at 60, 90, and 120 min interval on OGTT. The results for antioxidant potential indicate that at 100 mg/kg dose of combinatorial extract of curcumin significantly prevented the high-fat diet and low-dose streptozotocin-induced changes in the oxidative stress parameters (P < 0.01) which supports popular medicinal uses of this combinatorial extract as antihyperglycemic and hypolipidemic and is likely to bring this promising natural product to the forefront of therapeutic agents in the in the treatment of "metabolic syndrome".