Harish S. Parihar

Magnetic nanoparticle drug delivery systems for targeting tumor

Tumor hypoxia, or low oxygen concentration, is a result of disordered vasculature that lead to distinctive hypoxic microenvironments not found in normal tissues. Many traditional anti-cancer agents are not able to penetrate into these hypoxic zones, whereas, conventional cancer therapies that work by blocking cell division are not effective to treat tumors within hypoxic zones. Under these circumstances the use of magnetic nanoparticles as a drug delivering agent system under the influence of external magnetic field has received much attention, based on their simplicity, ease of preparation, and ability to tailor their properties for specific biological applications. Hence in this review article we have reviewed current magnetic drug delivery systems, along with their application and clinical status in the field of magnetic drug delivery.

Functional group interactions of a 5-HT3R antagonist

BackgroundLerisetron, a competitive serotonin type 3 receptor (5-HT3R) antagonist, contains five functional groups capable of interacting with amino acids in the 5-HT3R binding site. Site directed mutagenesis studies of the 5-HT3AR have revealed several amino acids that are thought to form part of the binding domain of this receptor. The specific functional groups on the ligand that interact with these amino acids are, however, unknown. Using synthetic analogs of lerisetron as molecular probes in combination with site directed mutagenesis, we have identified some of these interactions and have proposed a model of the lerisetron binding site.ResultsTwo analogs of lerisetron were synthesized to probe 5-HT3R functional group interactions with this compound. Analog 1 lacks the N1 benzyl group of lerisetron and analog 2 contains oxygen in place of the distal piperazine nitrogen. Both analogs show significantly decreased binding affinity to wildtype 5-HT3ASRs. Mutations at W89, R91, Y142 and Y152 produced significant decreases in binding compared to wildtype receptors. Binding affinities of analogs 1 and 2 were altered only by mutations at W89, and Y152.ConclusionsBased on the data obtained for lerisetron and analogs 1 and 2, we have proposed a tentative model of the lerisetron binding pocket of the 5-HT3ASR. According to this model, The N-benzyl group interacts in a weak interaction with R91 while the benzimidazole group interacts with W89. Our data support an interaction of the distal amino nitrogen with Y142 and Y152.

5-HT3R Binding of lerisetron: an interdisciplinary approach to drug–Receptor interactions

The design, synthesis, and use of lerisetron-based molecular probes to investigate the 5-HT(3)R binding site are described. A SAR study, which involved distance and electronic parameter modifications of lerisetrons N-benzyl group, resulted in the discovery of a partial agonist.

A clinical review of statin-associated myopathy

Objective: To review the epidemiology, clinical features, proposed mechanisms, risk factors, and management of statin-associated myopathy. Data Sources: Literature searches were conducted in PubMed (1948 to April 2013), TOXLINE, International Pharmaceutical Abstracts (1970 to April 2013), and Google Scholar using the terms statin, hydroxymethylglutaryl-coenzyme A reductase inhibitors, myopathy, myalgia, safety, and rhabdomyolysis. Results were limited to English publications. Study Selection and Data Extraction: All relevant original studies, guidelines, meta-analyses, and reviews of statin-associated myopathy and safety of statins were assessed for inclusion. References from selected articles were reviewed to identify additional citations. Data Synthesis: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors remain one of the most effective medications for reducing low-density-lipoprotein cholesterol. Statins are well tolerated by most patients; however, it is estimated that 10% to 15% of patients develop statin-related muscle adverse effects known as statin-associated myopathy. Although clinicians may be aware of statin-associated myopathy, they may not be aware of its clinical presentation. Providers should assess individual patient risk factors before choosing the appropriate statin. A variety of skeletal muscle aches that may not present as a danger to the patient, may affect patient adherence and quality of life. There are several steps that providers can take to properly treat and manage patients with myalgia complaints. Conclusions: Statin-associated myopathy is a clinical problem that contributes to statin therapy discontinuation. Patients who are statin intolerant may be treated with alternative treatment options such as low-dose statins, switching statins, using alternative dosing strategies in statins with longer half-lives, non-statin lipid-lowering agents, and complementary therapies.

Metformin in Gestational Diabetes Mellitus

As currently diagnosed, gestational diabetes mellitus (GDM) affects 5–9% of all pregnancies in the United States and is growing in prevalence.1 It is defined as carbohydrate intolerance of variable severity that is first recognized during pregnancy. Although GDM has been recognized for decades, the potential significance of the condition, as well as criteria for screening and diagnosis, remain debatable.1 Historically, GDM has been treated with lifestyle modifications and insulin, and oral antihyperglycemic agents have been used infrequently because of concerns regarding neonatal hypoglycemia and teratogenicity. Most recent studies suggest that oral hypoglycemic agents, specifically metformin, are safe to use during pregnancy (Table 1).2–13 Risk for developing GDM has been noted in women who are overweight before pregnancy, have had GDM in a previous pregnancy, or have a family history of diabetes. Poorer outcomes have been seen in both pregnant women and their developing fetuses, including induction of labor and caesarean delivery in women and death, shoulder dystocia, bone fracture, and nerve palsy in fetuses.1 Moreover, recent studies show that diagnosis and management of this disorder will have beneficial effects on both maternal and neonatal outcomes.14,15 According to the American College of Obstetrics and Gynecology, comprehensive screening techniques have been implemented by > 90% of practices in the United States.16 Reasons for the implementation of screening programs were developed from the evidence obtained in the Hyperglycemia and Adverse Pregnancy Outcomes study.17 This large, prospective, observational study found possible adverse effects associated with even mild maternal hyperglycemia. It included a cohort of women with glucose levels at the upper end of the normal range, as well as women with mild GDM. The investigators found a linear correlation between higher levels of maternal glucose and adverse outcomes, including increased birth weight, …

Retrospective Review of Maternal and Fetal Outcomes in Patients With Gestational Diabetes Mellitus in an Indigent Prenatal Clinic

Gestational diabetes mellitus (GDM) is diabetes that is diagnosed during the second or third trimester of pregnancy and is not clearly overt diabetes (1). Diagnosis is defined by severity of carbohydrate intolerance. The upper end of the GDM diagnostic glucose range is the same as would be indicative of diabetes outside of pregnancy, whereas the lower end of the GDM range is only slightly above normal and asymptomatic but still associated with increased risk of fetal morbidity (1,2). Diabetes during pregnancy is diagnosed by either a one-step approach involving a 75-g oral glucose tolerance test (OGTT) or a two-step approach starting with a 50-g (nonfasting) screen followed by a 100-g OGTT for those who initially screen positive (1). Glycemic goals for patients with a GDM diagnosis are as follows: preprandial ≤95 mg/dL and either 1-hour postprandial ≤140 mg/dL or 2-hour postprandial ≤120 mg/dL. Hyperglycemia throughout pregnancy carries increased risk for adverse fetal and maternal outcomes (3–8). Treatment of diabetes during pregnancy is aimed at decreasing the risk of perinatal outcomes such as macrosomia, birth trauma, neonatal metabolic abnormalities, and cesarean section (4,9–12). Lifestyle modification is first-line treatment and includes medical nutrition therapy (MNT), exercise, and glucose monitoring (13). Pharmacological therapy generally consists of insulin, glyburide, or metformin, and agents may be used adjunctly to MNT depending on presence and severity of hyperglycemia (13). Insulin is the preferred pharmacological treatment for management of diabetes in pregnancy if lifestyle modification is insufficient in achieving euglycemia (13). The setting of this review is the diabetes clinic located within the Hall County Health Department (HCHD) prenatal clinic in Gainesville, Ga. The population of Gainesville is ∼187,000 and includes a large percentage of Latino immigrants (14). The proportion of Latinos in the diabetes clinic has grown …

Is depression an independent risk factor for the onset of Type 2 diabetes mellitus

Depression is one of the most common mental illnesses characterized by loss of pleasure, whereas diabetes is a metabolic disorder which leads to high serum glucose levels. Current literature supports the development of depressive symptoms in patients with chronic illnesses including diabetes. However, depression as a potential risk factor for diabetes has attracted a lot of attention for clinicians and researchers. It has been hypothesized that both diabetes and depression may be bidirectional in nature, and each may exacerbate the symptoms or play an important role in the development of the other. The most common association between them is the diagnosis of depression in Type 1 or Type 2 diabetes. As the matter of fact, diabetes has been reported to double the risk of depression. In this review article, we have summarized various scientific studies to evaluate the potential of depression as a risk factor for diabetes. MEDLINE search identified various articles assessing this hypothesis. Our review of literature indicate some support for depression as a risk factor for Type 2 diabetes however more clinical studies need to be performed to clarify the contribution of depression as an independent risk factor for diabetes and to check the diabetes epidemic from escalating at a higher rate.

Good Clinical Practice (GCP)

This article is a revision of the previous edition article by Sharmilee P. Sawant and Harihara M. Mehendale, volume 2, pp 457–460,