Radiolabeling and evaluation of alginate blend-isoniazid microspheres by 99mTc for the treatment of tuberculosis in rabbit model

Isoniazid (INH) is the first line anti-tubercular drug that is widely used in the treatment of tuberculosis. ^99mTc-alginate-INH microsphere scintigraphy has been demonstrated to be a useful noninvasive imaging technique for microsphere deposits located in different organs of the rabbits. The aim of this study was to develop an improved formulation, to validate the formulation for long-time retention, as well as to assess radiotracer stability by novel quality control methods. Our study reports the labeling and evaluation of alginate blends-INH microspheres. The incorporation efficiency of optimized formulation was 89% w/w. The in vitro release study was carried out in simulated intestinal fluid at pH 7.4, and it was found that the formulation delivered the drug for 36 h. The labeling efficiency of ^99mTc-alginate blends-INH microspheres was seen at various pH (i.e. pH ranging from 5 to 7.5) and different concentration of stannous chloride dehydrate (i.e. 25–200 μg) and it was concluded that 96% labeling efficiency was achieved in case of pH 7.5 and 60 μg stannous chloride. The stability study was carried out in saline and serum and it was found that the complex was highly stable in vitro and in vivo. The blood clearance in rabbits showed bi-exponential pattern depicting that 50% of activity washed out at 2 h with t_1/2(Fast) was 2.1 h and t_1/2(Slow) was 12.5 h. Bio-distribution was normal and the experimental mice showed major accumulation of the radiolabeled formulation in liver, intestine, lungs and kidneys, indicating hepatobiliary and renal route of excretion. The distribution of the drugs to the lung was showing its efficiency in the treatment of tuberculosis.     

Relationship of whole-blood FK506 concentrations to rejection and toxicity in liver and kidney transplants

FK506 (tacrolimus) has been shown to be a safe and effective immunosuppressant for the prevention of organ rejection after liver and kidney transplantation. Like cyclosporine,

the use of FK506 has been associated with some adverse effects such as toxicity and organ rejection. Therapeutic monitoring of the whole-blood FK506 drug concentrations has been used in an effort to determine how the concentration of FK506 in the blood is related to the development of toxicity or the risk for organ rejection. Cox regression analysis of two recent clinical trials of FK506 in patients receiving kidney and liver transplants shows a significant correlation between the whole-blood FK506 concentrations and the incidence of both toxicity and organ rejection. Because of these relationships and the pharmacokinetics of FK506, therapeutic monitoring of the whole-blood FK506 levels is expected to be helpful for minimizing the risks of both toxicity and rejection in liver and kidney transplants.     

Microvesicles from patients with acute coronary syndrome enhance platelet aggregation

Abstract

Microvesicles (MVs) released from leukocytes, platelets and endothelial cells are elevated in patients with acute coronary syndrome (ACS). In the present study, we assessed the potential pro-aggregatory properties of MVs obtained from ACS patients. Thus, we divided the patients into two groups based on clopidogrel-responsiveness, i.e. high on-treatment platelet reactivity (HPR; n?=?16), and low or normal on-treatment platelet reactivity (non-HPR; n?=?14), respectively. MVs from patients were obtained by high-speed centrifugation, and the pro-aggregatory effect of MVs added to fresh isolated platelets from healthy subjects were analyzed by 96-well microplate aggregometry. MVs from HPR patients significantly enhanced spontaneous platelet aggregation around two times more than MVs from non-HPR patients. The pro-aggregatory effect of three out of four MV phenotypes correlated to MV-concentrations as determined by flow cytometry. Furthermore, MVs from patients with diabetes mellitus (n?=?9) had a stronger pro-aggregatory effect compared to MVs from those without diabetes (n?=?21; p?=?.025 between groups). In conclusion, MVs from ACS patients with clopidogrel non-responsiveness enhance platelet aggregation, as do MVs from ACS patients with diabetes. Thus, MVs from patients with hyperreactive platelets boost platelet aggregation. Blocking MV-formation may reduce platelet hyperreactivity.     

Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain

Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV-V of the dorsal horn in diabetes. These diabetes-induced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.     

Clinical,Angiographic Characteristics and In-Hospital Outcomes of Smoker and Nonsmoker Patients After Primary Percutaneous Coronary Intervention

BackgroundSmoking is a well-established cardiac risk factor there is dearth of Local data regarding clinical and angiographic characteristics of smoker patients.ObjectivesThis study was planned to assess the differences in the clinical characteristics, angiographic characteristics, and in-hospital outcomes of smokers and nonsmokers after primary percutaneous coronary intervention at a tertiary care hospital in Karachi, Pakistan.MethodsWe included patients between 40 and 80 years of age diagnosed with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention from July 1, 2017, to March 31, 2018. Clinical and angiographic characteristics and in-hospital outcomes were obtained from the cases submitted to the National Cardiovascular Data Registry's CathPCI (Catheterization–Percutaneous Coronary Intervention) Registry from our site.ResultsA total of 3,255 patients were included in this study. Smokers consist of 25.1% (817) of the total sample. A high majority of smokers were male, 98.8% (807), and smokers were relatively younger as compared to nonsmokers with a mean age of 52.89 ± 10.59 versus 55.98 ± 11.24 years; p < 0.001. Smokers had higher post-procedure TIMI (Thrombolysis In Myocardial Infarction) flow grade III: 97.8% (794) versus 95.53% (2,329); p = 0.037, and they had a relatively low mortality rate: 2.69% (22) versus 3.16% (77); p = 0.502.ConclusionsSmokers were predominantly male and around 3 years younger than nonsmokers. Diabetes mellitus and hypertension were less common among smokers and single-vessel disease was the more common angiographic finding for smokers as compared to 3-vessel disease for nonsmokers. No statistically significant differences in in-hospital outcomes were observed. ST-segment elevation myocardial infarction in smokers despite younger age and the low atherosclerotic risk profile, in our region, emphasize the need for nicotine addiction management and smoking cessation campaigns at large and for pre-discharge counseling.     

Antiprotozoal activity of diterpenoids isolated from Zhumeria majdae- absolute configuration by circular dichroism

PurposeZhumeria majdae, a unique species of the Zhumeria genus, is an endemic Iranian plant in the Lamiaceae family. Phytochemical investigation and biological activity of this plant are rarely reported. The current study aimed to find new antiprotozoal compounds from the roots of Z. majdae and to determine the absolute configuration of isolated compounds by circular dichroism.MethodsThe extraction process from roots and aerial parts of Z. majdae was carried out by hexane, ethyl acetate and methanol followed by testing their antiprotozoal effects against Leishmania donovani, Trypanosoma brucei rhodesiense, T. cruzi, and Plasmodium falciparum, respectively. Structure elucidation was done using 1D and 2D NMR spectroscopy and HREIMS spectrometry. In addition, experimental and theoretical circular dichroism spectroscopy was used to establish absolute configuration.ResultsIn comparison with aerial parts, the hexane extract from roots showed superior activity against T. b. rhodesiense, L. donovani and P. falciparum with IC₅₀ values of 5.4, 1.6 and 2.1 μg/ml, respectively. From eight abietane-type diterpenoids identified in roots, six were reported for the first time in the genus Zhumeria. 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) exhibited a promising biological activity against P. falciparum (IC₅₀ 8.65 μM), with a selectivity index (SI) of 4.6, and lanugon Q (8) showed an IC₅₀ value of 0.13 μM and SI of 15.4 against T. b. rhodesiense.ConclusionAltogether, according to the results, of 8 isolated compounds, dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) exhibited a promising activity against T. b. rhodesiense and P. falciparum. In conclusion, these compounds could be potential candidates for further analysis and may serve as lead compounds for the synthesis of antiprotozoal agents. Open in a separate windowGraphical abstractElectronic supplementary materialThe online version of this article (10.1007/s40199-020-00345-w) contains supplementary material, which is available to authorized users.