Compulsory licensing of patents.

Compulsory licensing (CL) is a mechanism made by the government to provide balance between the monopoly right holders and the third person with public interest by ensuring the ease availability of the patented products at reasonable rate. This paper discusses the background criteria for getting CL in India as per the Indian Patent Act, 1970 starting from the concepts outlined in the Trade-Related Aspects of Intellectual Property Rights agreement. We reviewed the case studies for the accepted and rejected CL in India. We also discuss important CL cases that were permitted internationally, including the present COVID pandemic CL. Finally, we provide our analytical perspectives regarding the pros and cons of CL.

Prevalence and correlates of community re-entry challenges faced by HIV-infected male prisoners in Malaysia.

HIV-infected prisoners face an inordinate number of community re-entry challenges. In 2007, 102 HIV-infected prisoners in Malaysia were surveyed anonymously within six months prior to release to assess the prevalence and correlates of community re-entry challenges. Staying out of prison (60.8%), remaining off drugs (39.2%), finding employment (35.3%) and obtaining HIV care (32.4%) were the re-entry challenges reported most frequently. Global stigma, negative self-image and public attitudes-related stigma were independently associated with challenges to obtaining HIV care. In multivariate analyses, those with previous incarcerations (adjusted odds ratio [AOR], 3.2; 95% confidence interval [CI], 1.4-7.6), higher HIV-related symptoms (AOR, 2.0; 95% CI, 1.0-4.1) and higher public attitudes-related stigma (AOR, 2.5; 95% CI, 1.2-5.1) had a significantly higher likelihood of identifying more re-entry challenges. Targeted interventions, such as effective drug treatment, HIV care and public awareness campaigns, are crucial for stemming the HIV epidemic and improving health outcomes among HIV-infected prisoners in Malaysia.

Lipid lowering activity of Eclipta prostrata in experimental hyperlipidemia.

The plant Eclipta prostrata is used in the traditional medical practices of India to treat hepatic diseases and hyperlipidemia. The total alcoholic extract of the plant when tested for antihyperlipidemic potential, exhibited a dose-dependent activity in albino rats when compared to standard drugs. The activity was assessed by studying the lipid profiles of serum, liver and heart of the control and drug-treated animals. The results lend support to the traditional use of Eclipta prostrata in the treatment of hyperlipidemia.

Antioxidant activity of Cassia fistula (Linn.) flowers in alloxan induced diabetic rats.

Aqueous extract of Cassia fistula (Linn.) flowers (ACF) was screened for its antioxidant effect in alloxan induced diabetic rats. An appreciable decrease in peroxidation products viz thiobarbituric acid reactive substances, conjugated dienes, hydroperoxides was observed in heart tissues of ACF treated diabetic rats. The decreased activities of key antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione in diabetic rats were brought back to near normal range upon ACF treatment. These results suggest that ACF has got promising antioxidative activity in alloxan diabetic rats.

Protective role of Bacopa monniera on morphine-induced brain mitochondrial enzyme activity in rats.

Alcoholic extract of Bacopa monniera was tested for its protective role on morphine-induced brain mitochondrial enzyme status in rats. The level of the brain mitochondrial enzymes was significantly lower in the morphine-treated group when compared with control animals. These enzymes were maintained at normal level when Bacopa extract was administered orally at a dose of 40 mg/kg, 2 h before the administration of morphine.

Protective role of Bacopa monniera on morphine induced hepatotoxicity in rats.

The protective effect of Bacopa monniera on morphine induced liver antioxidant levels was studied in rats. Oral administration of alcohol extracts of Bacopa monniera induced a significant hepatoprotective effect. In the morphine treated group, a significant increase of lipid peroxidation and a significant decrease in liver antioxidant enzyme levels were observed. Simultaneous administration of morphine and Bacopa extract prevented these alterations. The results of this study showed that Bacopa monniera alcohol extract exerted a hepatoprotective effect against morphine induced liver toxicity.

Biochemical studies on hypoglycemic effect of Aavirai kudineer: a herbal formulation in alloxan diabetic rats.

Aavirai Kudineer (AK) is an herbal decoction of seven botanical drugs, cited in the Gunapadam; a Tamil Siddha medical text. The anti-diabetic efficacy of this formulation was evaluated using alloxan-induced diabetic and normal rats. Glucose tolerance was observed within 1 hr in AK-treated rats (10 ml/kg body ) as compared to control. A significant decrease in the severe hyperglycemia characteristic of alloxan diabetes was noted after 15 days of AK treatment. Further AK treatment reversed the elevated urea, creatinine, cholesterol and decreased protein values to near normal levels. Assay of glycogen content and chief carbohydrate-metabolizing enzymes, viz. hexokinase, glucose-6-phosphatase and fructose 1,6 diphosphatase in the liver of diabetic and AK-treated diabetic rats clearly ascertains the hypoglycemic efficacy of this formulation. The mode of action of this herbal formulation remains to be elucidated.

Role of nitric oxide on GABA, glutamic acid, activities of GABA-T and GAD in rat brain cerebral cortex.

The results of the present study clearly shows that a correlation exists between nitric oxide (NO) and gamma-aminobutyric acid transaminase (GABAT-T) activity as well as gamma-aminobutyric acid (GABA), glutamic acid and the activity of glutamic acid decarboxylase (GAD). Supporting of this 10 min after the administration of L-Arginine (L-Arg) increased GABA concentration and diminished the activity of GABA-T. There was no change in GAD activity and glutamic acid level. Administration of convulsion inducing agent Picrotoxin (PCT) decreased the NO concentration in the brain and enhanced the activity of GABA-T, and the fact that the NOS inhibitor (N(G)-nitro-L-Arg methyl ester (L-NAME) diminished the activity of NOS and increased the activity of GABA-T provide another support for the involvement of NO on GABA-T activity. The present study clearly showed that high concentrations of NO in the brain suppresses the activity of GABA-T.

Biochemical evaluation of antitumor effect of muthu marunthu (a herbal formulation) on experimental fibrosarcoma in rats.

Natural products from plants are rich sources used for treating a number of diseases. Many of the pharmacological principles of the currently used anticancer agents have been initially isolated from plants. Most of the herbal drugs are a mixture of a number of plant ingredients. Their cumulative effect increases the efficacy of the drug in curing the diseases. Muthu Marunthu is a herbal formulation comprising of eight various plant ingredients, and has been claimed to possess antitumor effect. Therefore, attention has been focused on studying the various plant ingredients in the drug as a whole for its antitumor effects. It was observed that the growth rate in rats was normal and there was no change in blood parameters such as glucose, urea, proteins, cholesterol and also in the activities of pathophysiological enzymes such as lactate dehydrogenase (LDH), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), alkaline and acid phosphatase after Muthu Marunthu administration. The tumor weight was found to be reduced in methylcholanthrene induced fibrosarcoma rats after Muthu Marunthu treatment. Elevated levels of glycocomponents of glycoproteins such as hexose, hexosamine, sialic acid and fucose in plasma of fibrosarcoma rats decreased significantly after Muthu Marunthu treatment. The DNA and RNA levels of liver and kidney, which were increased in fibrosarcoma rats, returned to near normal levels after Muthu Marunthu treatment. The vitamins such as A, C and E in plasma were decreased in fibrosarcoma rats but increased significantly after Muthu Marunthu treatment. The altered levels of copper, zinc and selenium in plasma have also been corrected after Muthu Marunthu treatment. These observations clearly suggested the antitumor potency of Muthu Marunthu in experimentally induced fibrosarcoma in rats.

Chemopreventive effect of Ocimum sanctum on DMBA-induced hamster buccal pouch carcinogenesis.

Ocimum sanctum L., a plant having multi-medicinal properties, has been investigated for its chemopreventive activity against 7,12-dimethylbenz (a) anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. O. sanctum, in the form of fresh leaf paste, aqueous extract and ethanolic extract were topically applied and the extracts were orally administered to buccal pouch mucosa of animals exposed to 0.5% of DMBA. Incidence of papillomas and squamous cell carcinomas were significantly reduced, and increased the survival rate in the topically applied leaf paste and orally administered extracts to animals. Among them, the orally administered aqueous extract showed profound effect than the other two forms. Histopathological observations made on the mucosa confirmed these findings. Further fluorescent spectral studies at 405 nm excitation on the mucosa of control, DMBA and extracts orally administered experimental animals showed a prominent maxima at 430 nm for control, 628 nm for DMBA induced carcinomas while aqueous and ethanolic extracts administered animals showed at 486 nm and 488 nm, respectively. The fluorescent intensity at 630 nm (FI630 nm) was significantly reduced and the ratio of fluorescent intensities at 520 nm and 630 nm (FI520 nm/630 nm) were significantly increased in orally administered extracts compared to DMBA treated animals. These observations suggest that the orally administered extract of O. sanctum may have the ability to prevent the early events of carcinogenesis.

Spectrofluorimetric detection of DMBA-induced mouse skin carcinoma.

An attempt has been made to evaluate the normal and cancer blood samples of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mouse skin carcinoma by spectrofluorimetric method. Analysis of acetone extracts of plasma, erythrocyte and erythrocyte membrane showed an alteration around 630 nm when excited at 400 nm by cancer samples, compared to normal samples. The ratio of fluorescent intensity at 530 nm/630 nm was found to be decreased in erythrocyte and plasma and increased in erythrocyte membrane. These changes are not detectable in both hemolysates. It has been suggested that erythrocytes may be the carriers of fluorophors that accumulate in cancer tissue and may be useful in the diagnosis and treatment of malignancies.

Modulation of the impaired drug metabolism in sarcoma-180-bearing mice by echitamine chloride.

Echitamine chloride (EC), an indole alkaloid, extracted from the bark of Alstonia scholaris has got highly promising anticancer effect. The effect of this drug on the microsomal drug detoxifying system was studied in sarcoma-180 induced mice. When given sub-cutaneously at a dosage of 5 mg/kg body weight, it was able to alter the impaired drug detoxifying system which was observed in the Sarcoma-180 bearing mice. The levels of microsomal protein, Cyt-P450, Cyt-b5, NADH-Cyt-C-reductase, NADPH-Cyt-C-reductase, and glu-6 phosphatase were determined. The levels of these drug metabolizing enzymes were decreased in S-180 bearing mice. EC treatment corrected to near normal levels of these enzymes and microsomal hemeproteins. In order to understand the mechanism responsible for the decreased protein level and its normalization after treatment with EC, 3H-Phenylalanine incorporation study was carried out. From the results, it is observed that the synthesis of apoproteins is also altered in tumor-bearing animals. All these changes which were observed in tumor-bearing animals were corrected to near normal levels after treatment with EC.

Inhibition of glycolysis and respiration of sarcoma-180 cells by echitamine chloride.

Malignant tumors are known to exhibit high rates of glycolytic activity leading to high production of lactic acid. Hence, neoplastic cells have elevated activity of enzymes responsible for glycolysis. Echitamine chloride, an indole alkaloid extracted from the bark of Alstonia scholaris, has been reported to have a highly promising anticancer activity against fibrosarcoma in rats. In the present study, the effect of echitamine chloride on energy metabolism of S-180 cells is investigated to have a better understanding on the mode of action of echitamine chloride. The effect of echitamine chloride on the mitochondrial and cellular respiration of S-180 cells was studied. Also, the effects on glucose utilization, pyruvate utilization and lactate formation were studied on whole S-180 cells and S-180 cell-free homogenate. The levels of glycolytic enzymes such as hexokinase and lactate dehydrogenase were estimated in which particular emphasis has been laid on hexokinase which occurs both in cytosolic and particulate forms in neoplastic cells. Hence the differential effect of echitamine chloride on the levels of total, cytosolic and particulate hexokinase has been investigated. In conclusion, echitamine chloride affects both cellular and mitochondrial respiration, leading to reduction of the cellular energy pool and thereby resulting in the loss of viability of S-180 cells.

Effect of radiotherapy and chemoradiotherapy on circulating antioxidant system of human uterine cervical carcinoma.

Circulating lipid peroxide, antioxidant components and the activities of defense enzymes were estimated in uterine cervical carcinoma patients (before and after radiotherapy and radiotherapy combined chemotherapy) and compared with controls. Some of the antioxidant components such as glutathione, vitamin E and selenium are reduced in cervical cancer. The reduced levels of vitamin E and glutathione were normalized after treatment. Erythrocyte lipid peroxide (E-LPx) and erythrocyte membrane lipid peroxide (EM-LPx) levels were found to be increased in all the stages of uterine cervical carcinoma. The important antioxidant enzymes such as erythrocyte superoxide dismutase (E-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PDH) were found to be decreased in uterine cervical carcinoma. These altered biochemical parameters were reversed to normal, of course with varied degree after different mode of therapy. Significant normalization was observed in Type II chemoradiotherapy.

Inhibitory effect of dietary flavonol quercetin on 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.

The inhibitory effect of dietary supplementation with flavonol quercetin on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis was investigated. Dietary quercetin inhibited the incidence of both papillomas and tumors induced by DMBA. The fluorescence spectra of papillomas and tumors showed different prominent maxima and a characteristic peak around 620-630 nm, which could be attributed to the accumulation of porphyrin compounds. Further, the fluorescence intensities at 630 nm (FI630nm) were elevated, whereas the ratio FI530nm/FI630nm was decreased in DMBA-induced lesions. Quercetin treatment significantly decreased FI630nm and increased the ratio FI520nm/FI630nm when compared with DMBA-induced lesions. It is therefore evident that quercetin has an inhibitory effect on DMBA-induced carcinogenesis and further studies will throw more light on its use as a chemopreventive agent against oral cancer.

Studies of the activities of lysosomal enzymes in serum and buccal pouch tissue of hamsters during 7,12-dimethylbenz[a]anthracene-induced carcinogenesis.

Alterations in the activities of certain lysosomal enzymes such as beta-D-galactosidase, beta-D-glucosidase, beta-D-glucuronidase, alpha-L-fucosidase, N-acetyl-beta-D-glucosaminidase, cathepsins B and D were studied in serum and tissue homogenates of buccal mucosa of hamsters treated with 0.5%, 7,12-dimethylbenz[a]anthracene (DMBA) in liquid paraffin. Among the enzymes studied, the activities of beta-D-galactosidase and N-acetyl-beta-D-glucosaminidase showed significant elevation both in serum and tissue homogenates fro papilloma onwards and the elevations were progressive with the development of carcinomas. The elevations in the activities of alpha-D-fucosidase and cathepsin D were found to be significant from papillomatous tissue onwards whereas in serum they showed higher activities only in carcinoma stages. The activities of beta-D-glucosidase, beta-D-glucuronidase and cathepsin B in both serum and in tissue homogenate were elevated markedly only in carcinoma stages. It is suggested that beta-D-galactosidase and N-acetyl-beta-D-glucosaminidase may be used as diagnostic markers for premalignant and malignant lesions of oral mucosa.

Purification and characterization of hexosaminidase from human uterine cervical carcinoma.

Normal human uterine cervical tissue and uterine cervical carcinoma tissue were collected and subjected to fractionation of hexosaminidase isoenzymes Hex A, Hex B, and Hex I using DEAE-cellulose anion-exchange chromatography. Hex A was found to be the major isoenzyme in control tissues, whereas Hex B was the major isoenzyme in carcinoma tissues. These two major isoenzyme fractions were first purified using heparin-Sepharose 4B affinity chromatography and then subjected to further purification on epsilon-ACMA-Sepharose 4B. The purified isoenzymes were found to be homogeneous by polyacrylamide gel electrophoresis. The Hex A and Hex B isoenzymes obtained from control and carcinoma patients were characterized. Hex A from control and carcinoma patients exhibited more or less similar properties. However, the Hex B isoenzyme from carcinoma patients exhibited some characteristic variations in pH, temperature, substrate concentration optima, and isoelectric point compared with the control. From these observations it may be inferred that altered properties of the Hex B isoenzyme fraction from carcinoma patients may be the reason for the elevated activity of hexosaminidase in carcinoma of the uterine cervix.

Fluorescence spectroscopic identification of 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.

An attempt was made to study whether light-induced fluorescence spectroscopy could be exploited to discriminate premalignant and malignant tissues of hamster buccal pouch carcinogenesis from normal tissues during a 16 week regimen of tri-weekly topical application of 7,12-dimethylbenz[a]anthracene (DMBA) in liquid paraffin. Histologically, the DMBA-treated buccal mucosa showed hyperplastic changes at 4-6 weeks, papillomas at 8-10 weeks, early invasive carcinomas at 11-13 weeks and finally well-differentiated squamous cell carcinomas at 14-16 weeks of treatment. Acetone extracts of these different staged tissues with age matched control tissues were excited at 405 and 420 nm and the emissions were scanned from 430 and 440 to 700 nm respectively. The spectral profiles of control and transformed tissues were found to be different, each displaying their own characteristic prominent maxima and other spectral marks. The spectra of transformed tissues showed characteristic peaks around 620-630 nm which did not appear in control tissues and the fluorescent intensities at 630 nm [FI(630)nm] were significantly increased from early stages onwards when compared to controls. The spectra of DMBA carcinomas developed at the 18th week after withdrawal of DMBA application at the 10th week and carcinoma extract spiked with DMBA confirmed the peak around 620-630 could be attributed only to porphyrin compounds accumulated in transformed tissues. Furthermore, the ratios of FI(520)nm/FI(630)nm of transformed tissues were also significantly decreased when compared to control tissues. This diagnostic test had a very close resemblance with respect to histological studies. These results suggest that this technique using conventional light-induced fluorescence spectroscopy may be useful for early diagnosis of premalignant and malignant lesions of oral cavity.

Extracellular matrix components and proteolytic enzymes in uterine cervical carcinoma.

The important components of mucopolysaccharides and collagen have been analyzed in tissues of control and carcinoma of uterine cervix. Among these components hyaluronic acid and chondroitin sulphate levels were found to be increased, whereas decreased level of collagen was observed in uterine cervical carcinoma. Serum cathepsin B, D and acid and alkaline phosphatases have also been analyzed in controls and carcinoma patients before and after treatments. The activities of these enzymes have been found to increase prominently in advanced stages. Among these enzymes cathepsin B and alkaline phosphatase have exhibited remarkable increase in activity in uterine cervical carcinoma. Different modes of treatment exerted reversion of the elevated activities of these enzymes. However, combined therapy type II (radiation combined with cisplatin and cyclophosphomide) seems to be more effective in reverting the activities of these enzymes to normal levels.

Effect of radiation on serum glycoproteins and glycosidases in patients with cervical carcinoma.

OBJECTIVE: The serum glycan moieties of glycoproteins and the activities of glycosidases were analyzed in order to elucidate the metabolism of glycoprotein in uterine cervical cancer. METHODS: Serum was collected from patients at different stages of cervical cancer before and after treatment. The results were analyzed using Student's t-test. RESULTS: The glycan moieties such as sialic acid and fucose were significantly elevated even in the early stages of carcinoma, whereas a significant elevation in hexose and hexosamine levels was observed only in the advanced stages. Among the investigated lysosomal glycohydrolases, beta-D-galactosidase, N-acetyl-beta-D-glucosaminidase and alpha-L-fucosidase activities were elevated significantly at all stages except for stage I. The altered levels of glycoproteins and glycosidases were reduced to near-normal levels after radiotherapy. CONCLUSION: The levels of glycan moieties and the activities of glycosidases can be used as diagnostic markers to assess the stage of cancer and can be used as prognostic markers during therapy.