Metastatic adenocarcinoma in testis presenting as a testicular mass--a case report and review of literature

Testicular metastasis presenting as a testicular mass is an extremely rare condition. There are only nine previously reported cases where testicular mass was the first clinical manifestation of underlying malignancy. Here we report a case of metastatic mucin secreting adenocarcinoma in testis presenting as a testicular mass with unknown primary. We have given a brief review of literature about the spread of tumor to testes.     

Cannabinoids: is there a potential treatment role in epilepsy?

Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system’s regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy.     

Tribocatalytic behaviour of a TiO2 atmospheric plasma spray (APS) coating in the presence of the friction modifier MoDTC: a parametric study

Recent engine design and emission trends have led to the commercial use of Atmospheric Plasma Spray (APS) coatings for cylinder liner applications like the TiO₂ APS coating. It was shown in our previous work that this type of coating showed better friction results compared to steel lubricated with MoDTC. To further investigate this feature, a parametric study was carried out involving the effect of MoDTC concentration, test temperature, Hertzian contact pressure and the change of counterpart materials from steel balls to ceramic balls (Al₂O₃ and ZrO₂). Ball-on-flat tribotests were carried out on a reciprocating (ball-on-flat) tribometer lubricated with base oil containing MoDTC. Results show that for all the test conditions used including the concentration of MoDTC, test temperature and the contact pressure, lower friction and wear is observed for the TiO₂ APS coating compared to reference steel. To explain the low friction behavior, tribofilm compositions were investigated and it was observed that MoS₂ is always formed in the case of TiO₂ APS with no oxysulphide species. For the reference steel, MoO_xS_y species are mainly detected in the tribofilms. XPS analyses performed on TiO₂ APS flats when the counterpart material was changed from steel balls to ceramic balls suggested the formation of MoS₂ (Mo in +iv oxidation state) and Mo–C (Mo in +iv or +ii oxidation state) species with a negligible amount of MoO₃ (Mo in +vi oxidation state). It was also shown that a significant amount of molybdenum atoms inside the tribofilm, originating from MoDTC (Mo in +v oxidation state) were reduced in the tribological contact. A mechanism for the decomposition of MoDTC on the basis of tribocatalytic behaviour hypothesized in our previous work was proposed and discussed.

Tribocatalytic behaviour of TiO₂ APS coatings in presence of MoDTC additive under boundary lubrication conditions – decomposition mechanism     

Choroidal thickness profile in healthy Indian children

Purpose:

The purpose was to study choroidal thickness and its profile based on location in healthy Indian children using enhanced depth spectral-domain-optical coherence tomography (SD-OCT).

Methods:

In this cross-sectional observational study 255 eyes of 136 children with no retinal or choroidal disease were consecutively scanned using enhanced depth SD-OCT. Eyes with any ocular disease or axial length (AXL) >25 mm or < 20 mm were excluded. A single observer measured choroidal thickness from the posterior edge of the retinal pigment epithelium to the choroid/sclera junction at 500-microns intervals up to 2500 microns temporal and nasal to the fovea. Generalized estimating equations were used to evaluate the correlation between choroidal thickness at various locations and age, AXL, gender and spherical equivalent (SEq).

Results:

Mean age of the subjects was 11.9 ± 3.4 years (range: 5–18 years). There were 62 Females and 74 males. The mean AXL was 23.55 ± 0.74 mm. Mean subfoveal choroidal thickness was 312.1 ± 45.40 μm. Choroid was found to be thickest subfoveally, then temporally. Age, AXL and SEq showed a significant correlation with choroidal thickness, whereas gender did not affect choroidal thickness.

Conclusion:

Our study provides a valid normative database of choroidal thickness in healthy Indian children. This database could be useful for further studies evaluating choroidal changes in various chorioretinal disorders. Age and AXL are critical factors, which negatively correlated with choroidal thickness.     

Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems

Components:In order to formulate a successful SMEDDS for maximum therapeutic effect, due consideration must be given to various factors such as physicochemical properties of the active moiety as well as excipients, potential for drug excipient interaction (in vitro and in vivo) and physiological factors that promote or inhibit the bioavailability. Further, other important factors such as regulatory status, solubilization capacity, miscibility, physical state of the excipients at room temperature, digestibility and compatibility with capsule shell, chemical stability and cost of the materials should also be considered during the formulation[15]. Such a rationale approach not only helps in reducing the time involved in the formulation development but also reduces the cost of its development[11].

Oil/lipid phase:

The function of oil phase in self-microemulsifying system is to solubilize the hydrophobic/lipophilic active moiety in order to improve both drug loading and bioavailability of the hydrophobic active moiety. Selection of oil plays a vital role in the formulation as it determines the amount of drug that can be solubilized in the system[16]. A lipid molecule with a large hydrophobic portion compared to hydrophilic portion is desirable as it maximizes the amount of drug that can be solubilized. Open in a separate windowLIST OF OILS USED IN FORMULATION OF SMEDDS

Long chain triglycerides:

Lipids that have fatty acid chains of 14-20 carbons are categorized as LCTs[17]. Fixed oils i.e., vegetable oils contain a mixture of glyceride esters of unsaturated long chain fatty acids. These are considered safe as they are commonly present in daily food and are easily digestible[15]. Large hydrophobic portion of triglycerides is responsible for their high solvent capacity for lipophilic moieties. Though it is difficult to microemulsify, some marketed formulations such as Neoral^® (composed of olive oil which, has shown superior oral bioavailability) and Topicaine^® gel (composed of Jojoba oil for transdermal application) have been successfully practicing the microemulsification of LCTs[18].

Medium chain triglycerides and related esters:

Lipids that have fatty acid chains of 6-12 carbons are categorized as MCTs[17]. MCTs are the most common choice of oil for SMEDDS as they are resistant to oxidation and possess high solvent capacity compared to LCT because of their high effective concentration of ester group. MCTs produced from the distillation of coconut oil are known as glyceryl tricaprylate and comprises of saturated C8 and C10 fatty acids in the liquid state[15]. Labrafac CM 10, a MCT, has shown superior solubility for fenofibrate and produced wider microemulsion region at all surfactant/co-surfactant combinations than Maisine 35, which, is a LCT[19]. Drug substance should possess minimum solubility of 50 mg/ml in LCTs for lymphatic absorption[20]. Upon digestion, products of short and medium chain triglycerides are directed towards portal vein whereas chylomicrons formed from LCTs triggers the lymphatic transport. Further, highly hydrophobic drug substances are easily soluble in vegetable oils and can easily be formulated as simple oil solutions which are readily emulsified in the gut. However, most conventional hydrophobic drug substances do not exhibit superior solubility in LCT such as vegetable oil[21,22].Moderately hydrophobic drug substances, on the other hand, cannot be formulated into simple oil solutions as their solubility is limited. In such cases, SMEDDS are promising alternative where the drug solubility in the oil will be enhanced due to microemulsification of oil by surfactants. It is well accepted that oils with long hydrocarbon chains (high molecular volume) such as soybean oil, castor oil are difficult to microemulsify compared to MCT (low molecular volume) such as capmul MCM and Miglyol. However, solubilizing capacity of oil for lipophilic moiety increases with chain length (hydrophobic portion) of the oil. Hence the selection of oil is a compromise between the solubilizing potential and ability to facilitate the formation of microemulsion[23]. Malcolmson et al. studied the solubility of testosterone propionate in various oils for the formulation of O/W microemulsion and concluded that oils with larger molecular volume such as triglycerides show superior solubility than the corresponding micellar solution containing only surfactants without oil[24,25]. Enhancement of drug solubility in SMEDDS not only relies on the solubility of the drug in the oil but also on the surfactant(s). For instance, ethyl butyrate, small molecular volume oil, has shown higher solubility for testosterone propionate but its ME formulation has only improved the solubility slightly than the corresponding micellar solution. On the contrary, Miglyol 812 which is a larger molecular volume oil has shown improved solubilization in the ME formulation though the solubility of testosterone propionate is less in the individual components compared to ethyl butyrate[24].

Drug solubility in lipid:

Oil component alters the solubility of the drug in SMEDDS by penetrating into the hydrophobic portion of the surfactant monolayer. Extent of oil penetration varies and depends on the molecular volume, polarity, size and shape of the oil molecule. Overall drug solubility in SMEDDS is always higher than the solubility of drug in individual excipients that combine to form SMEDDS. However, such higher solubility considerably depends on the solubility of drug in oil phase, interfacial locus of the drug and drug-surfactant interactions at the interface[26]. In light scattering experiments, it was observed that oils with small molecular volume act like co-surfactants and penetrate into the surfactant monolayer. This forms thinner polyoxyethylene chains near the hydrophobic core of the micelle disrupting the main locus of the drug solubilization due to which, a higher solubility of drug is not observed. Large molecular volume oils, however, forms a distinct core and do not penetrate effectively into the surfactant monolayer. The locus of drug solubilization was found to be effected by the microstructure and solubility of the drug in the excipients. The locus of drug solubilization was found to be at the interface of micelle for phytosterols whereas the same for cholesterol was found to be between the hydrophobic head groups of surfactant molecules. This is attributed to altered side chain flexibility of phytosterol due to the additional substitution of alkyl side chain compared to cholesterol[27].In addition to molecular volume and polarity of the oil, drug solubility in oil is affected by physicochemical properties of drug molecule itself. Consideration of BCS classification and Lipinski''s rule of 5 for the selection of drug is only useful during initial screening stages. As per BCS classification, some of the acidic drugs are listed in Class II despite having good absorption and disposition as they do not satisfy the requirement of higher solubility at low pH values. Lipinski''s rule of 5, on the other hand, holds good only when the drug is not a substrate for the active transporter[4]. This suggests that aqueous solubility and log P alone are not sufficient to predict the solubility of drug in the oil. This further indicates that the solubility of any two drugs with similar log P would not be the same due to their different physicochemical properties.To demonstrate this, a study was conducted in our laboratory with two antihypertensive drugs having close partition coefficient (log P) values, different aqueous solubility and varying physicochemical properties. Candesartan cilexetil is hydrophobic and has log P value of 7.3, molecular weight 610.66 g/mol with a polar surface area 135.77 whereas, valsartan is slightly soluble in aqueous phase with log P value of 5.3, molecular weight 434.53 g/mol with a polar surface area 103.48 (clogP and polar surface area were calculated using chembiodraw ultra 11.0). Unlike candesartan cilexetil, valsartan exhibits pH dependent solubility[28].If only log P and aqueous solubility of these two drugs are considered, it is only natural to assume that candesartan cilexetil would be highly soluble in lipid phase whereas valsartan would be less soluble. A specific and sensitive HPLC-UV method was developed and validated to measure the super saturation solubility of these two drugs in various oils and the results showed a completely different solubility profiles. Solubility profile of these two drugs in different oil phase is given in fig. 2.Open in a separate windowFig. 2Solubility of active ingredients in various oils. Valsartan, candesartan cilexetil.Although log P and polar surface area of valsartan and candesartan cilexetil are closer, their solubility with triacetin, castor oil and capmul MCM C8 differs significantly. This may be attributed to the hydrogen bonding capacity and electrostatic interaction of both the scaffold with the oils. Nevertheless, valsartan is having aliphatic carboxylic group which is expected to be involved in hydrogen bond interaction with the hydrogen acceptor functionality of the triacetin as well as castor oil. We assume that the branched chain aliphatic ester moiety of triacetin, capmul MCM C8 and castor oil gets involved in the electrostatic repulsion with cilexetil part of candesartan. In case of valsartan, such electrostatic interactions are not possible. Furthermore, aliphatic ester chain of triacetin and castor oil may solvate the lipophilic chain of valsartan more favorably than candesartan in the absence of any electrostatic repulsion (proposed interaction is shown in fig. 3). However, significant difference was not observed with other oils such as olive oil, peanut oil, corn oil, miglyol 810, sunflower oil and soybean oil (data not shown).Open in a separate windowFig. 3Proposed interactions of valsartan and candesartan cilexetil with triacetin.     

Alcohol-induced increases in insulin-like growth factor binding protein-1 are partially mediated by TNF

BACKGROUND: Alcohol (EtOH) alters the plasma and tissue content of insulin-like growth factor (IGF)-I, an important anabolic hormone. However, the bioavailability and bioactivity of IGF-I can also be modulated by changes in soluble proteins that bind IGF-I (IGFBPs). The purpose of the present study was to determine whether EtOH intoxication in rats alters the plasma concentration and tissue mRNA content of various IGFBPs. Based on initial results subsequent studies were performed to assess potential mechanisms by which EtOH increased IGFBP-1. METHODS: Rats were administered EtOH (75 mmol/kg) and blood and tissues collected at various times thereafter. Separate groups of rats were also pretreated with 4-methylpyrazole (4-MP; alcohol dehydrogenase inhibitor), cyanamide (inhibitor of acetaldehyde metabolism), RU486 (glucocorticoid receptor antagonist) or the tumor necrosis factor (TNF) antagonist (TNF(BP)) prior to EtOH administration. RESULTS: Acute EtOH intoxication did not alter the mRNA content of IGFBP-3, -4 or -5 in liver or kidney. However, EtOH increased IGFBP-1 in blood (5-fold), which was associated with an up-regulation of IGFBP-1 mRNA content in liver and kidney (2- to 3-fold). Likewise, the injection of the nonmetabolizable alcohol -butanol also increased IGFBP-1 in plasma, liver, and kidney. The increased IGFBP-1 in blood and tissues was not prevented by inhibiting alcohol metabolism with 4-MP. However, pretreatment with cyanamide markedly accentuated the EtOH-induced increase in IGFBP-1 in blood (20-fold), liver (3.5-fold), and kidney (12-fold), indicating that accumulation of acetaldehyde can enhance IGFBP-1 synthesis. A time course study indicated that EtOH increased plasma IGFBP-1 levels as early as 0.5-1 hr, and that this response was associated with elevated IGFBP-1 mRNA in liver but not kidney. Pretreatment with RU486 did not prevent or attenuate the EtOH-induced increase in IGFBP-1. However, the alcohol-induced increase in IGFBP-1 was attenuated by TNF(BP). CONCLUSIONS: These data suggest that the acute alcohol-induced increase in IGFBP-1 is mediated, at least in part, by TNF and is independent of EtOH metabolism and increases in endogenous glucocorticoids.