Toxicity studies of highly bioavailable isoniazid loaded solid lipid nanoparticles as per Organisation for Economic Co-operation and Development (OECD) guidelines.

Solid lipid nanoparticles (SLNs) are presently being promoted to improve bioavailability of encapsulated drugs. These are well tolerated in living systems, as they are made from biocompatible material. Despite finding extensive applicability, these systems have not been sufficiently investigated for the toxicity so far. We have reported use of SLNs to improve plasma bioavailability of isoniazid (INH), a hepatotoxic, antitubercular drug. Presently we evaluate acute and repeated (28-day) oral dose toxicity, with satellite group, of developed INH loaded COMBI-SLN. In addition to high bioavailability, the COMBI-SLN exhibited 3 times higher LD50 (2000 mg/kg BW) versus 650 mg/kg BW for free INH. Results were complemented with histopathological evidence in brain, sciatic nerve and liver tissue all of which indicated enhanced safety of INH upon incorporation into SLNs. In the repeated dose study at doses selected as per Organisation for Economic Co-operation and Development (OECD) guidelines, a series of behavioural and haematological tests, clinical biochemistry (kidney and liver function, lipid profile) and histopathological studies were performed to evaluate the effect of low (250 mg/kg BW), medium (500 mg/kg BW) and high oral dose (1000 mg/kg BW). Absence of adverse effects like hepatotoxicity and peripheral neuropathy observed in rats at an oral intake level of 500 and 1000 mg/kg BW of COMBI-SLN, that is 20-40 folds above the anticipated human intake levels (after normalizing the surface area correction for rats), supports the conclusion that SLN are an intrinsically safe nanocarrier system that improves both the efficacy and the safety of INH.

Histone Deacetylase Inhibitors Prevented the Development of Morphine Tolerance by Decreasing IL6 Production and Upregulating µ-Opioid Receptors.

BACKGROUND: Morphine tolerance on long-term usage leads to chronic pain conditions. Preclinical studies demonstrated that the upregulation of HDACs is associated with a decrease in the sensitivity of µ-opioid receptors, which results in morphine tolerance. OBJECTIVE: The present study was designed to assess the influence of the selected known HDAC inhibitors (NMJ2 and NMJ3) on the pain tolerance induced by chronic administration of morphine in Balb/c mice. METHODS: In the present study, morphine was administered in incremental doses 1, 2, 3.6, 6.5, 11.2, 21, and 21 mg/kg daily for seven days to develop morphine tolerance. The nociceptive thresholds, analgesia, and tolerance were assessed 30 min after morphine administration alternatively from 1st day to 7th day using the hot plate and mechanical allodynia methods. RESULTS: The morphine control group showed a reduction in the Paw Withdrawal Threshold (PWT) and the percentage Maximum Possible Effects (MPEs). In contrast, the combination of SAHA and test drugs with morphine increased the PWT and MPEs as compared to the morphine alone group. Administration of morphine alone also showed an increase in the production of the pro-inflammatory mediator, IL-6, and down-regulation of the µ-opioid receptor in the brain tissues. Treatment with HDAC inhibitors, SAHA, and test drugs showed a reversal in these changes. CONCLUSION: Results indicated that HDAC inhibitors were involved in the prevention of morphine tolerance in normal mice by inhibiting pro-inflammatory marker production and by increasing the sensitivity of neurons towards morphine in producing an analgesic effect in morphine tolerated mice.

Prosthetic rehabilitation of severe Siebert's Class III defect with modified Andrews bridge system.

Prosthetic dentistry involves the replacement of missing and contiguous tissues with artificial substitutes to restore and maintain the oral functions, appearance, and health of the patient. The treatment of edentulous areas with ridge defects poses a challenging task for the dentist. Management of such cases involves a wide range of treatment options comprising mainly of surgical interventions and non surgical techniques such as use of removable, fixed or fixed- removable partial dentures. But each treatment plan undertaken should be customized according to patient needs. A variety of factors such as quality and quantity of existing contiguous hard and soft tissues, systemic condition and economic status of the patient play an important role in treatment planning, clinical outcome and prognosis. This case report presents the restoration of a Seibert's Class III ridge defect by an economical modification of Andrews Bridge in a 32 Year old patient.

Nano-formulation of rifampicin with enhanced bioavailability: development, characterization and in-vivo safety.

Rifampicin (RIF) was encapsulated into solid lipid nanoparticles (SLNs) to overcome its poor and unreliable oral bioavailability. Novel microemulsification method with high drug loading (50%) and entrapment efficiency (∼67%) was developed (Indian Patent Application 3356/DEL/2013). RIF-SLNs were characterized using TEM, AFM, DSC and XRD. Near neutral SLNs (zeta -3.5 ± 0.8), with average particle size of 130.0 ± 22.6 nm showed 70.12% release in phosphate buffer pH 6.8 in 9 days. Single oral dose (50mg/kg) pharmacokinetic studies in Wistar rats indicated 8.14 times higher (in comparison to free RIF) plasma bioavailability with sustained levels for 5 days. Pharmacodynamic parameters viz. TMIC (120 h; time for which plasma levels were above MIC of 0.2 µg/ml), AUC0-∞/MIC (1868.9h) and Cmax/MIC (75.6) for RIF-SLNs were greater than free RIF by 2.5, 8.2 and 6.6 times, respectively. Similar LD50 (1570 mg/kg) and absence (or reversal in satellite group) of adverse events in repeat dose (three doses; highest dose was up to 50 times the human therapeutic dose) toxicity studies confirmed safety of RIF-SLNs. Improved pharmacokinetic profile of RIF-SLNs can be translated to a reduced dose and dosage frequency of RIF, thus resulting in lower or no hepatotoxicity commonly associated with its use.

Comparative evaluation of the reinforcing effect of different post systems in the restoration of endodontically treated human anterior teeth at two different lengths of post space preparation- an in vitro study.

OBJECTIVES: Comparative evaluation of the reinforcing effect of different post systems in the restoration of endodontically treated human anterior teeth at two different lengths of post space preparation- an in vitro study. MATERIALS AND METHODS: 135 extracted human incisors were endodontically treated, out of which 120 teeth were decoronated 2mm above the cementoenamel junction and divided into four experimental groups based on the post system to be used: Glass fiber post (GFP) and stainless steel post (SSP), titanium post (TTP), cast metal post (CMP). Each group was divided into two sub-groups according to the length of post space preparation: 5mm and 10mm. All the samples were restored with metal crowns. The fracture resistance was measured by applying loads at an angle of 135º to the long axis of teeth in an instron universal testing machine. Fracture mode was analyzed for all the samples. Results from the four test groups were compared and analysed using one-way ANOVA test and the Post-hoc Bonferroni test to demonstrate differences between pairs of groups. RESULTS: The results revealed that SSP group at 10mm post space length showed the significantly ("P-value< 0.05") highest fracture resistance (793.7787 N). Decrease in post length resulted in the decrease in fracture resistance in all the groups reduced to values even lesser than the control (437.8733N). CONCLUSION: The different post systems used in the study were able to reinforce endodontically treated teeth only at 10mm post space length.

In vitro evaluation of the effect of post system and length on the fracture resistance of endodontically treated human anterior teeth.

OBJECTIVES: The aim of this study was to evaluate the effect of post system and length on the fracture resistance of endodontically treated human anterior teeth. MATERIAL AND METHOD: Seventy-five extracted human incisors were endodontically treated, out of which 60 were decoronated 2 mm above the cementoenamel junction and divided into two experimental groups based on the type of post system to be used: glass fiber post (GFP) and Ribbond fiber post groups (RFP). Endodontically treated human anterior teeth in which no post was placed served as control group. Each group was divided into two subgroups according to the length of post space: 5 and 10 mm and all the samples were restored with metal crowns. The fracture resistance was measured by applying loads at an angle of 130° to the long axis of teeth in an Instron universal testing machine. RESULTS: The results revealed that GFP group at 10-mm post space length showed the significantly highest fracture resistance (740.2133 N) among all groups and subgroups. Decrease in post length resulted in the decrease in fracture resistance in GFP group (425.1867 N), whereas in group RFP 5-mm subgroup (299.6200 N) showed significantly higher fracture resistance than 10-mm subgroup (216.9300 N) but lesser than the control (437.8733 N) in both the subgroups. CONCLUSION: Glass fiber posts efficiently increase the fracture resistance of an endodontically treated tooth but the determination of optimal post length is also essential. CLINICAL RELEVANCE: The present investigation highlights the significance of using glass fiber posts in the restoration of endodontically treated teeth. Endodontically treated teeth restored with glass fiber posts showed increased fracture strength and favorable mode of fracture, and are therefore highly recommended to achieve better clinical outcomes.