Showing papers by "Central Drug Research Institute published in 2001"

Inhalable microparticles containing drug combinations to target alveolar macrophages for treatment of pulmonary tuberculosis.

Abstract: Purpose: Drug therapy of tuberculosis (TB) requires long-term oral administration of multiple drugs for curing as well as preventing and/or combating multi-drug resistance. Persistent, high blood levels of antitubercular drugs resulting from prolonged oral administration of anti-TB drugs may be neither necessary nor sufficient to kill mycobacteria residing in macrophages (Mφ). Inhalable biodegradable microparticles containing two of the first-line anti-TB drugs, isoniazid (H), and rifampicin (R), were prepared and tested for (i) phagocytosis by mouse Mφ, (ii) administration as a dry powder inhalation to rats, and (iii) targeting alveolar Mφ with high drug doses when administered to rats.

Antioxidant status in delayed healing type of wounds.

Abstract: This investigation studied the contribution of antioxidants in delaying healing in excision cutaneous wounds (8 mm) in diabetic, aged and immunocompromised animals. Skin levels of catalase, glutathione (GSH), ascorbic acid (AA) and vitamin E in streptozotocin-induced diabetic rat were lower as compared to nondiabetics. The 7-d wound tissue of diabetic rats showed an increased vitamin E level along with depleted GSH content. In aged rats (18 months old), higher levels of skin superoxide dismutase (SOD), glutathione peroxidase (Gpx) and thiobarbituric acid reactive substances (TBARS) and lower levels of catalase and GSH were found as compared to their values in young rats (3-4 months old). The levels of SOD, GPx, catalase, AA, GSH and vitamin E in 7-d wound tissue of aged rats were significantly lower in comparison to those in young rats. However, TBARS were elevated in these wound tissues. The non-wounded skin of immunocompromised (athymic) mice showed lower levels of SOD, catalase, and TBARS and higher GSH and GPx levels in comparison to those present in normal mouse skin. Surprisingly, the analysis of 7-d wound tissue showed higher levels of SOD, catalase, GPx, and GSH and lower TBARS level in athymic mice compared to the wound tissue of normal mice. Thus low levels of antioxidants accompanied by raised levels of markers of free radical damage play a significant role in delaying wound healing in aged rats. In diabetic rats reduced glutathione levels may have a contributory role in delaying the healing process. However, in immunocompromised mice the antioxidant status following injury showed an adapted response.

Present trends and future strategy in chemotherapy of malaria.

Abstract: This review starts from a brief introduction followed by the list of commercial antimalarial drug. According to the nature of chemical entities, these drugs have been divided into the following categories--Quinolines, pyrimidines, amidinies, guanidines, sulfonamides, sulfones, acridines, antibiotics and sesquiterpene lactones. The site of action and status of the antimalarial drugs have been described against each category. A brief description of reasons behind the search of a new antimalarial drug have been discussed. Finally, the review deals the well known biochemical target sites such as folate metabolism, pyrimidine metabolism and polyamines for the designing of antimalarial drugs. The detail description of the newly discovered biochemical target sites, alpha-tublin and DNA topoisomerases, have been highlighted. In the conclusion section, we have discussed the future strategies for the chemotherapy of malaria.

Long term effect of aflatoxin B1 on lipid peroxidation in rat liver and kidney: effect of picroliv and silymarin

Abstract: Aflatoxin B(1) (AFB(1)) is a potent hepatotoxic and hepatocarcinogenic mycotoxin. The mechanism of cellular damage caused by AFB(1) has not been fully elucidated. Lipid peroxidation is one of the main manifestations of oxidative damage and has been found to play an important role in the toxicity and carcinogenesis of many carcinogens. The present investigation aims at assessing the comparative antioxidant effect of picroliv, a standardized iridoid glycoside fraction of Picrorhiza kurroa and silymarin, a well known standard hepatoprotective, on aflatoxin B(1) induced lipid-peroxidation in rat liver and kidney. Marked increases in lipid peroxide levels and a concomitant decrease in enzymic antioxidant levels were observed in aflatoxin B(1) (2 mg/kg, i.p) -toxicated rats, while drug (picroliv and silymarin both) treatment reversed the condition to near normal levels. The effects of picroliv and silymarin were comparable.

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone-related clinical disorders.

Abstract: DL-Centchroman (67/20; INN: Ormeloxifene) synthesized at the Central Drug Research Institute, Lucknow, is a nonsteroidal once-a-week oral contraceptive. It was introduced in Delhi in July, 1991, marketed in India in 1992 as Saheli and Choice-7 (Hindustan Latex Ltd., Thiruvananthapuram) and Centron (Torrent Pharmaceuticals India Ltd., Ahmedabad), and included in the National Family Welfare Programme in 1995.5 According to post-marketing surveillance, approximately 100,000 women were using this pill and approximately 1100,000 menstrual cycles were covered until 1996. It is a unique need-oriented contraceptive being effective when taken immediately after coitus or routinely as a weekly pill and has the advantage of less frequent administration. Its contraceptive action is quickly reversible. It has long terminal serum halflife of 168 hr in women and exhibits duration of anti-implantation/estrogen antagonistic action of 120 hr, despite a short (24.1 hr) serum halflife, in the rat. In lactating women, it is excreted in milk in quantities considered unlikely to cause any deleterious effect on suckling babies. In phase II and III multicentric trials as a contraceptive, children born of method-and-user failure pregnancies showed normal milestones, without any congenital anomaly. Reports of its promising action in the management of certain hormone-related clinical disorders are available. It has an excellent therapeutic index and is considered safe for chronic administration.

Monovalent cation-induced conformational change in glucose oxidase leading to stabilization of the enzyme

Abstract: Glucose oxidase (GOD) from Aspergillus niger is an acidic dimeric enzyme having a high degree of localization of negative charges on the enzyme surface and dimer interface. We have studied the effect of monovalent cations on the structure and stability of GOD using various optical spectroscopic techniques, limited proteolysis, size exclusion chromatography, differential scanning calorimetry, and enzymic activity measurements. The monovalent cations were found to influence the enzymic activity and tertiary structure of GOD, but no effect on the secondary structure of the enzyme was observed. The monovalent cation-stabilized GOD was found to have a more compact dimeric structure but lower enzymic activity than the native enzyme. The enzyme's Km for d-glucose was found to be slightly enhanced for the monovalent cation-stabilized enzyme (maximum enhancement of about 35% for LiCl) as compared to native GOD. Comparative denaturation studies on the native and monovalent cation-stabilized enzyme demonstrated a si...

Nitrite content and antioxidant enzyme levels in the blood of schizophrenia patients.

Abstract: Rationale: Recent studies have suggested augmentation in the inflammatory response as well as involvement of nitric oxide (NO) in mood disorders. Polymorphonuclear leukocytes (PMN), NO and free radicals have been associated with inflammatory response; however, the status of NO in the PMN has not been investigated so far in schizophrenia patients. Objectives: The present study was undertaken to investigate levels of nitrite (a metabolite of NO), malonaldehyde (MDA, lipid peroxidation product) and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (Gpx) in the PMN of schizophrenia patients. Methods: Patients with schizophrenia (n=62) were diagnosed according to DSM-IV and were free of anti-psychotic medications/ECT for at least 3 months. Mean age of the patients was 29.06±1.17 years, with a male to female ratio of 4:1, and mean duration of illness was 3.7±0.6 years. The control group consisted of 82 healthy subjects with a mean age of 37.0±1.26 and a male to female ratio of 5:1. PMN were isolated from the blood. Nitrite, MDA and antioxidant enzymes were estimated by standard biochemical techniques in the PMN of normal healthy controls and schizophrenia patients. Platelet and plasma nitrite levels were also estimated in controls and schizophrenia patients. Results: Nitrite content in the PMN was reduced to 68%, while plasma and platelet nitrite content in schizophrenia patients was not significantly changed in comparison to controls. Malonaldehyde (MDA) content in PMN was significantly augmented in schizophrenia patients but activity of SOD, catalase and Gpx remain unaltered. Conclusion: Results obtained indicate a significant decrease in NO synthesis and an increase in MDA in the PMN of schizophrenia patients, while antioxidant enzyme activities were not altered in the PMN of schizophrenia patients. This suggests that the decrease in PMN NO synthesis by PMN might lead to oxidative stress in schizophrenia patients.

Herbal preparations as a source of hepatoprotective agents.

Abstract: Mono- and polyherbal preparations with potent antihepatotoxic activity in various liver disorders, made from traditionally used herbs with proven efficacy, have been described. More than 700 mono- and polyherbal preparations in the form of decoction, tincture, tablets and capsules from more than 100 plants are in clinical use. Some of the herbs--such as Silybum marianum, Picrorhiza kurroa, Andrographis paniculata and Glycyrrhizae radix--are very common in most of the polyherbal preparations. This review covers the preparations of widely used herbs such as S. marianum, Schisandra chinensis, Phyllanthus amarus, P. kurroa, A. paniculata, G. radix, Lycium chinense and Cochlospermum tinctorium as hepatoprotectants and includes the mode of action of these preparations. Some polyherbal preparations such as Livex, HD-03, Hepatomed and Hepatoguard with proven efficacy are also described in this review.

Biochemical changes induced in liver and serum of aflatoxin B1-treated male wistar rats: preventive effect of picroliv.

Abstract: Administration of aflatoxin B 1 to rats (2 mg/kg intraperitoneally) caused significant increase in the activities of γ-glutamyl transpeptidase 5'-nucleotidase, acid phosphatase, acid ribonuclease as well as content of lipid peroxides in liver after six weeks. However, the activities of succinate dehydrogenase, glucose-6-phosphatase, catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase and glutathione reductase in liver were decreased. The levels of glycogen and reduced glutathione were also decreased. There were significant elevations in the levels of serum transaminases, phosphatases (acid and alkaline), dehydrogenases (sorbitol, lactate and glutamate) and bilirubin following aflatoxin B 1 administration. Picroliv (25 mg/kg/day orally for six weeks), an iridoid glycoside isolated from the roots and rhizomes of Picrorhiza kurroa, significantly prevented the biochemical changes induced by aflatoxin B 1 .

Role of nitric oxide in a progressive neurodegeneration model of Parkinson's disease in the rat.

Abstract: This study was undertaken to investigate the nitric oxide synthase (NOS) activity in the striatum following 6-hydroxydopamine (6-OHDA) induced neurodegeneration in rats. Constitutive NOS (cNOS) activity remained unaltered at 3, 7 and 14 days after lesion, while a 43% and 45% decrease was observed at 30 and 50 days, respectively. Inducible NOS (iNOS) activity was detected only on the 3rd day after lesion and not in subsequent days or the control striatum. N(G)-nitro-L-arginine methyl ester (L-NAME) pretreatment blocked the amphetamine-induced rotations and inhibited the iNOS activity at the 3rd day after the 6-OHDA injection. L-NAME pretreatment also significantly restored the striatal dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in 6-OHDA treated rats. Thus a possible role of nitric oxide in 6-OHDA induced neurodegeneration is suggested.

Natural products of plant origin as anticancer agents.

Abstract: Natural products have been used as effective remedies for the treatment of various ailments. Numerous plant products in the form of decoction, tincture, tablets and capsules have been clinically used for the treatment of different kinds of cancer. This review covers some of the important plants with clinically proven anticancer activity, including Catharanthus roseus, Podophyllum peltatum, Taxus brevifolia, Camptothecin acuminata, Cephalotaxus harringtonia, Viscum album, Onchrosia elliptica, Annona bullata, Asmina triloba and Rhizoma zedoariae. Synthetic analogues in some cases have also been prepared to improve the efficacy and decrease the side effects of parent compounds. The modes of action of clinically used drugs are also delineated.

Carbanion-Induced Base-Catalyzed Synthesis of 1H-Isothiochromenes, Benzo[c]thiochromenes, Benzo[c]chromenes, and 1-Benzothiophenes through Ring-Transformation Reactions of 6-Aryl-2H-pyran-2-ones†

Abstract: An innovative approach to the one-pot synthesis of highly functionalized 3,4-dihydro-1H-isothiochromenes (3), 6H-benzo[c]thiochromenes (5, 6), 6H-benzo[c]chromenes (8), and 2,3-dihydro-1-benzothiop...

Identification of inhibitors of DNA topoisomerase II from a synthetic library of glycoconjugates.

Abstract: A library of 24 glycoconjugates related to glycosylated b-amino acid derivative (I) was been prepared and screened against DNA topoisomerase-II of the filarial parasite S. cervi. Among these, compound 6 was found to be a potent inhibitor of DNA topoisomerase-II with 95percent inhibition at 1.0?mM. Furthermore, compound 6 was at least three times more potent than the lead compound, glycosylated b-amino acid derivative I.

Blood Nitrite Levels in Patients With Migraine During Headache‐Free Period

Abstract: Objective.—To investigate blood nitrite levels after migraine attacks and to assess whether or not the change in nitric oxide levels observed during acute migraine persist after the attacks. Background.—Involvement of nitric oxide has been suggested in the initiation of acute migraine. Recent studies have shown alteration in the platelet response and platelet nitrite levels during migraine attacks. Methods.—Patients with migraine with aura and patients without aura were included in the study. The study was conducted on 50 patients with migraine and 90 healthy controls. Blood from the patients was collected at least 7 ± 0.8 days after the last attack of migraine. Nitrite levels in the polymorphonuclear leukocytes, platelets, and plasma were estimated. Platelet aggregation response in some of these patients was also studied. Results.—No significant change in the polymorphonuclear leukocyte, platelet, and plasma nitrite levels in patients with migraine compared to controls was observed. Patients with migraine with aura had significantly lower polymorphonuclear leukocyte nitrite levels compared to those without aura (P<.05). In addition, no significant difference in the adenosine diphosphate–induced platelet aggregation was observed in the migraineurs compared to the healthy controls. Conclusions.—Results obtained indicate that the platelet aggregation response and the blood nitrite levels were not altered significantly after an attack in the patients with migraine.

Use of Liposomes as an Immunopotentiating Delivery System: in Perspective of Vaccine Development

Abstract: Liposomes have been widely used to deliver antigens to the antigen-presenting cells (APCs) and also to modify their immunological behaviour in model animals. We recently demonstrated the potential of yeast lipid liposomes to undergo membrane–membrane fusion with cytoplasmic membrane of the target cells. Interestingly, studies in the present report revealed that antigen encapsulated in yeast lipid liposomes could be successfully delivered simultaneously into the cytosolic as well as endosomal processing pathways of APCs, leading to the generation of both CD4+ T helper and CD8+ cytotoxic T cells. In contrast, encapsulation of same antigen in egg phosphatidyl-choline (PC) liposomes, just like its free form, has inefficient access to the cytosolic pathway of major histocompatibility complex (MHC) I dependent antigen presentation and failed to generate antigen specific CD8+ cytotoxic T-cell response. However, both egg PC as well as yeast lipid liposomes have elicited strong antigen specific antibody responses in immunized animals. These results imply usage of liposome encapsulated antigen as potential candidate vaccine capable of eliciting both cell mediated as well as humoral immune responses.

Centchroman,a Selective Estrogen Receptor Modulator, as a Contraceptive and for the Management of Hormone-Related Clinical Disorders

Abstract: DL-Centchroman (67/20; INN: Ormeloxifene) synthesized at the Central Drug Research Institute, Lucknow, is a nonsteroidal once-a-week oral contraceptive. It was introduced in Delhi in July, 1991, marketed in India in 1992 as Saheli and Choice-7 (Hindustan Latex Ltd., Thiruvananthapuram) and Centron (Torrent Pharmaceuticals India Ltd., Ahmedabad), and included in the National Family Welfare Programme in 1995.5 According to post-marketing surveillance, approximately 100,000 women were using this pill and approximately 1100,000 menstrual cycles were covered until 1996. It is a unique need-oriented contraceptive being effective when taken immediately after coitus or routinely as a weekly pill and has the advantage of less frequent administration. Its contraceptive action is quickly reversible. It has long terminal serum halflife of 168 hr in women and exhibits duration of anti-implantation/estrogen antagonistic action of 120 hr, despite a short (24.1 hr) serum halflife, in the rat. In lactating women, it is excreted in milk in quantities considered unlikely to cause any deleterious effect on suckling babies. In phase II and III multicentric trials as a contraceptive, children born of method-and-user failure pregnancies showed normal milestones, without any congenital anomaly. Reports of its promising action in the management of certain hormone-related clinical disorders are available. It has an excellent therapeutic index and is considered safe for chronic administration.