Linagliptin: a novel methylxanthin based approved dipeptidyl peptidase-4 inhibitor.

Chemically, methylxanthine nucleus based Linagliptin (BI-1356, BI-1356-BS) is a dipeptidyl peptidase-IV inhibitor, which has been developed by Boehringer Ingelheim in association with Lilly for the treatment of Type-II Diabetes. Linagliptin was marketed by Lilly under the trade name Tradjenta and Trajenta. Linagliptin was approved as the once-daily dose by USFDA on 2 May 2011, for the treatment of Type-II Diabetes. Linagliptin 5mg once daily dose was approved based on a clinical trial program, which was conducted on approximately 4,000 adults with Type-II Diabetes. Linagliptin demonstrated statistically significant mean difference in HbA1c from placebo of up to 0.72 percent, when it was used monotherapically. In patients, who were not adequately controlled on metformin or metformin plus sulphonylurea, the addition of Linagliptin resulted in a statistically significant mean difference in HbA1c from placebo of -0.6 percent. Linagliptin was observed to produce significant reduction in fasting plasma glucose (FPG) compared to placebo, when used as a monotherapy in combination with metformin, sulfonylurea and/or pioglitazone. Linagliptin demonstrated significant reduction post-prandial glucose (PPG) levels in two hours as compared with placebo in monotherapy as well as in combination with metformin. In vitro assays also anticipated that Linagliptin is a potent DPPIV inhibitor as well as it exhibits good selectivity for DPP-IV as compared with other DPPs. The in-vivo studies also demonstrated same anticipation with respect to Linagliptin. Consequently, increasing the GLP-1 levels so far improved glucose tolerance in both healthy animals. X-ray crystallography anticipates that Linagliptin complexes with human DPPIV enzyme, e.g. butynyl substituent occupies the S1 hydrophobic pocket of the enzyme; the aminopiperidine substituent in the xanthine scaffold occupies the S2 subsite and its primary amine interacts with the key amino acid residues, which involves in the recognition of peptide substrates. In the present review, we have tried to cover comparative study of DPPIV inhibitors, chemistry, physical properties, commercial synthesis, patent portfolio, crystalline polymorphic forms of Linagliptin and its receptor interaction, Pharmacophore rational, mechanism, clinical studies, preclinical, adverse effect, available formulations, dose regimen, co-therapy of Linagliptin, giving emphasis on the medicinal chemistry aspects.

Balaglitazone: a second generation peroxisome proliferator-activated receptor (PPAR) gamma (γ) agonist.

Balaglitazone (DRF-2593) is a novel partial agonist of PPAR-gamma (γ), which is developed by Dr. Reddy's laboratories India. Balaglitazone is a second generation peroxisome proliferator-activated receptor (PPAR) gamma agonist with only partial agonistic properties. Balaglitazone is currently being evaluated in phase III clinical trial in United States and Europe. Selective PPAR-γ modulators bind in distinct manners to the ligand-binding pocket of PPAR-γ, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved novel antidiabetic agents are in current development. Clinical studies conducted with 409 subjects of randomized, double blind, parallel-group placebo and active comparator-controlled subject groups to determine the efficacy and safety of Balaglitazone. The study showed that the trial met its primary endpoint. Balaglitazone treated groups shown significantly reduce of HbA1c (%), FSG (mmol/L), postprandial glucose as comparison to pioglitazone. Phase III clinical studies data clearly shows that Balaglitazone provides robust glycemic control as an add-on to insulin therapy. Balaglitazone 10 mg and 20 mg show the similar magnitudes of the effects which comparable to the effects seen in the pioglitazone 45 mg group. The incidence of fluid retention and fat accumulation fewer than those observed with pioglitazone 45 mg. Hence, Balaglitazone is prominent candidate of new glitazone which requires fewer doses as comparison pioglitazone and shows better safety profile less incidence of special adverse effect like heart failure, peripheral oedema, and myocardial infarction. Unlike other marketed PPAR gamma agonists, Balaglitazone shows less fluid retention, less heart enlargement and no reduction of bone formation than full PPAR gamma agonists in preclinical studies. In present review, we have tried to cover classification PPARs various ligands, chemistry, physical properties, commercial synthesis, current patent status, polymorphic information, receptor interaction, pharmacophore rational, mechanism, adverse effect and clinical status of Balaglitazone, giving emphasis on medicinal chemistry aspect.

Apixaban: a new player in the anticoagulant class.

Apixaban (BMS-562247-01) is a compound being investigated as an anticoagulant. Apixaban molecule is developed in a joint venture by Pfizer and Bristol-Myers Squibb. Apixaban, a coagulation factor Xa inhibitor, approved in the E.U. in 2011 for the prevention of venous thromboembolic events in adult patients, who have undergone elective hip or knee replacement. The Apixaban based drug will be marketed under the brand name Eliquis® and is expected to rack up annual sales of over $2.5 billion. Apixaban is expected to provide stiff competition to warfarin, a popular blood thinner used in Europe. Warfarin is known to cause some serious side effects in patients. Apixaban, as compared with aspirin, reduced the risk of stroke or systemic embolism in patients experiencing atrial fibrillation by more than 50% (from 3.7% per annum with aspirin to 1.6% per annum with apixaban). Apixaban exhibits superiority to enoxaparin in preventing thrombosis in patients undergoing elective hip replacement surgery with similar bleeding rates. Apixaban is a highly selective and potent Factor Xa Inhibitor with Ki=0 8nM to both free as well as prothrombinase bound FXa. In X-ray crystal structure studies indicate that the pyrazole N-2 nitrogen atom interacts with backbone of Gln192 and the carbonyl oxygen of carboxamide interacts with NH of Gly216. The orientation of phenyllactum in the S4 region indiacates an edge to face interaction with Trp215, which is positioned between the Tyr99 and Phe174. In the present review, we have tried to cover comparative study of various FXa-inhibitors and point out apixaban in the various aspect including molecular chemistry, physical properties, commercial synthesis, current patent status, crystalline polymorphic forms, molecular receptor interaction, pharmacophore rational, mechanism of action, clinical studies, preclinical, adverse effect, available formulation, dose regimen and co-therapy, thus giving emphasis on medicinal chemistry aspects.

Accommodation: its relation to refractive errors, amblyopia and biometric parameters.

AIM: To study accommodation in relation to different refractive errors, amblyopia and to measure the anatomical changes in the accommodating eye MATERIALS AND METHODS: We studied the amplitude of accommodation (AA) in 150 patients in the age group 11 ± 30 years which included emmetropes, myopes, hypermetropes and hypermetropic amblyopes using the Royal Air Force (RAF) rule. The anterior chamber depth (ACD), axial length (AxL) and lens thickness (LT) changes during accommodation were measured using an A-scan. Myopes and hypermetropes were further divided based on the amount of refractive error : less than 2D, 2 -4D and greater than 4D. RESULTS: Corrected low myopes had the highest accommodation amplitude (p less than 0.05) followed by emmetropes. Corrected hypermetropes were found to have the lowest amplitude of accommodation (p less than 0.05). The amblyopic eye had a significantly low AA compared to the non-amblyopic eye (p less than 0.05). ACD decreased (p less than 0.05) and LT increased (p less than 0.05) during accommodation. The AxL increase was maximum in myopes (p less than 0.05) followed by hypermetropes but the change was not significant in hypermetropes (p greater than 0.05). CONCLUSION: The amblyopic eye has low amplitudes of accommodation proving the benefit of near adds in amblyopic patients. Prolonged near work might induce myopia in susceptible eyes by increasing the axial length.

Fresh look at the Doppler changes in pregnancies with placental-based complications.

Placental-based complications of pregnancy can be classified as acute and chronic. An example of acute placental complication is abruptio placenta. The chronic placental complications include pregnancy induced hypertension (PIH) and idiopathic Intrauterine growth restriction (IUGR). The fetus is at risk for perinatal complications in both acute and chronic conditions. Here we take a look at the natural history of the Doppler parameters in chronic conditions. The techniques used for assessing the fetal well-being include, clinical methods, biophysical tests, conventional ultrasonography, and fetal Doppler studies. Arterial Doppler studies are used to assess the well-being of the fetus and to determine the timing of delivery. However, arterial Dopplers predict only the subset of fetuses at risk of having perinatal complications. Venous Dopplers have been used to improve upon the prognostication. However, by the time the commonly used venous Doppler signs, that is, 'A' wave reversal in ductus venosus (DV) is present, the fetus is likely to be already compromised. The fetus tries to adapt to the environment of deprivation by making a series of changes in the umbilical artery circulation, cerebral circulation, and hepatic circulation. As a result of these adaptations, the fetus overcomes the state of chronic hypoxia. This article takes a look at these changes and also the effect of these adaptations. It is suggested that serial comparisons of the venous flow characteristics of the DV and inferior vena cava (IVC) can provide an early indication of the impending decompensation and can be used to predict the time the delivery.

Task-specific deactivation patterns in functional magnetic resonance imaging.

In general, image analysis of cognitive experiments using functional magnetic resonance imaging techniques has emphasized those regions of the brain where increases in signal intensity, with regard to the reference state, are associated with activation. Nevertheless, a number of recent papers have shown that there are areas of deactivation as well. In this study, we have used a univariate analysis and echo-planar functional magnetic resonance imaging to address the relationship of the reference state to the deactivations. We employed two dichotomous covert tasks, orthographic lexical retrieval and pure visual retrieval, to contrast with the reference state (baseline) of silent counting. Our analysis yielded extensive, task-specific landscapes of regional incremental and decremental responses. We have specifically demonstrated that the decremental responses are not due to activation in the reference state. We have also demonstrated that they are not an artifact of a specific part of the image analysis, and propose that they represent a physiological, task specific signal that should be considered an integral component of neural networks representing brain function.

Exchange transfusion in neonatal hyperbilirubinemia.

Four hundred and thirty three exchange transfusions (ET) for neonatal hyperbilirubinemia in 225 full term (Group I) and 110 premature/low birth weight (Group II) babies were analyzed. A total of 78.5% cases required one, 15.22% two, 4.8% three and 1.5% four ET. In Group I ABO HDN (35.94%), Rh HDN (10.7%), septicemia (8.9%), and G-6-PD deficiency (6.2%) were the major causes. Nearly 20% had multiple factors and in 9.3% no cause was identified. In multifactorial cases 13.3% had septicemia, 17.3% ABO HDN and 6.2% Rh HDN in various combinations. Common causes in Group II babies were septicemia (20.9%), ABO HDN (19.07%), Rh HDN (6.4%) and G-6-PD deficiency (5.4%). Nearly 8% had multifactorial etiology while 30.9% were idiopathic. Complications occurred in 20.4% Group I and 41.8% in Group II babies during ET. Procedure related mortality was 3.2/100 ET which declined to 0.9/100 ET when high risk babies were excluded. Overall mortality in babies subjected to ET was 10.6/100 ET. Cardiorespiratory arrest during procedure (30.4%), septicemia (26.1%) and kernicterus (19.6%) were the leading causes of death. Anemia (23.5% Group I and 50.9% Group II babies) and clinical septicemia (14.2% Group I and 16.4% Group II babies) were major delayed complications.

Short-term effect of ovral and norgestrel on the vitamin B6 and B1 status of women.

PIP: An attempt was made to determine the effect of steroidal contraceptives on the utilization of Vitamins-B1 and B6. Subjects, aged 22-38 years, were not taking any external source of vitamins. A 24-hour urine sample was collected and a fasting blood sample drawn for the estimation of erythrocyte amino-transferases and transketolase. Then each subject was given 2 gm of L-tryptophan. Another 24-hour urine specimen was then collected. Xanthurenic acid values in urine specimens were compared. Ovral or norgestrel was then given for 3 cycles. After these 3 cycles, blood collections and tryptophan load tests were repeated. Erythrocyte alanine aminotransferase (EAIT) and aspartates aminotransferases (EAsT) were measured. Also, erythrocyte transketolase (ETK) was estimated and the "TPP" effect determined by adding 75 mcg of thiamine pyrophosphate. of 11 women taking Ovral, 7 showed an abnormal response to the tryptophan load as shown by the xanthurenic acid excretion. Responses of all 11 women on norgestrel to tryptophan loads were normal. EAIT and EAsT tests were normal with both drugs (p more than .05). Erythrocyte transketolase activity was not significantly changed by either preparation (p more than .05). The increased xanthurenic acid excretion with Ovral after tryptophan load is thought to indicate Vitamin-B6 deficiency. Basal levels of ETK decreased in 7 of 10 women on Ovral but increased in 5 of 8 women on norgestrel therapy. Also, in vitro stimulation with TPP was observed in 4 of these women. The relation of this finding to Vitamin-B1 is not clear. Urinary thiamine, blood pyruvic acid, and alpha-ketoglutaric acid and transketolase activity require study to assess the Vitamin-B1 status under contraceptive therapy.^ieng