Synthesis of Isosteviol analogues as potential protective agents against Doxorubicin-induced cardiomyopathy in zebrafish embryos.

Doxorubicin (DOX) is a powerful anthracycline antibiotic agent which is widely used to treat various types of cancers. Despite efficacy, it displays severe cardiotoxic side effects. Discovery of novel and effective protective agents against DOX-induced cardiotoxicity has been a subject of great interest. Herein, we report the synthesis of two series of analogues of Isosteviol (ISV) 1 with modifications at C-16, C-19 positions as the first series and at C-15, C-16 positions as the other series. Interestingly second series analogues have shown a potential protective effect against DOX-induced cardiotoxicity in zebrafish embryos in vivo. Further, we have demonstrated that the synthesized new analogues of ISV, prevented the morphological distortions caused due to DOX cardiotoxicity in zebrafish heart and the associated cardiac impairments.

Enantioselective resolution of Rac-terbutaline and evaluation of optically pure R-terbutaline hydrochloride as an efficient anti-asthmatic drug.

Terbutaline is a ß2 -adrenoceptor agonist for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Among the two isomers of terbutaline (TBT 2), R-isomer was found to be the potent enantiomer in generating therapeutic effect, while S-isomer has been reported to show side effects. In this study, R-terbutaline hydrochloride (R-TBH 6) was synthesized through chiral resolution from the racemic terbutaline sulfate (rac-TBS 1) with 99.9% enantiomeric excess (ee) in good overall yield (53.6%). Further, R-TBH 6 nebulized solution was prepared in half dosage of Bricanyl®, which is a marketed product of racemic terbutaline and evaluated in vitro aerosol performance and in vivo anti-asthmatic effect on guinea pigs via. pulmonary delivery. From the investigation, it is evident that R-TBH 6 nebulized solution of half dosage performed similar fine aerosol characteristics and anti-asthmatic effect with Bricanyl®.

Passive Cycle Training Promotes Bone Recovery after Spinal Cord Injury without Altering Resting-State Bone Perfusion.

INTRODUCTION: Spinal cord injury (SCI) produces diminished bone perfusion and bone loss in the paralyzed limbs. Activity-based physical therapy (ABPT) modalities that mobilize and/or reload the paralyzed limbs (e.g., bodyweight-supported treadmill training (BWSTT) and passive-isokinetic bicycle training) transiently promote lower-extremity blood flow (BF). However, it remains unknown whether ABPT alter resting-state bone BF or improve skeletal integrity after SCI. METHODS: Four-month-old male Sprague-Dawley rats received T 9 laminectomy alone (SHAM; n = 13) or T 9 laminectomy with severe contusion SCI ( n = 48). On postsurgery day 7, SCI rats were stratified to undergo 3 wk of no ABPT, quadrupedal (q)BWSTT, or passive-isokinetic hindlimb bicycle training. Both ABPT regimens involved two 20-min bouts per day, performed 5 d·wk -1 . We assessed locomotor recovery, bone turnover with serum assays and histomorphometry, distal femur bone microstructure using in vivo microcomputed tomography, and femur and tibia resting-state bone BF after in vivo microsphere infusion. RESULTS: All SCI animals displayed immediate hindlimb paralysis. SCI without ABPT exhibited uncoupled bone turnover and progressive cancellous and cortical bone loss. qBWSTT did not prevent these deficits. In comparison, hindlimb bicycle training suppressed surface-level bone resorption indices without suppressing bone formation indices and produced robust cancellous and cortical bone recovery at the distal femur. No bone BF deficits existed 4 wk after SCI, and neither qBWSTT nor bicycle altered resting-state bone perfusion or locomotor recovery. However, proximal tibia BF correlated with several histomorphometry-derived bone formation and resorption indices at this skeletal site across SCI groups. CONCLUSIONS: These data indicate that passive-isokinetic bicycle training reversed cancellous and cortical bone loss after severe SCI through antiresorptive and/or bone anabolic actions, independent of locomotor recovery or changes in resting-state bone perfusion.

Development and evaluation of a novel topically applied sildenafil citrate hydrogel and its influence on wound healing in dogs.

OBJECTIVE: To develop a topical sildenafil hydrogel and evaluate its effect on wound healing in dogs. ANIMALS: 6 purpose-bred, sexually intact, adult Beagles. PROCEDURES: Hydrogels containing sildenafil citrate, N-methyl-2-pyrrolidone, propylene glycol, and poloxamer 407 were developed. Four excision wounds were created along the dorsum of the dogs. Each wound was treated for 21 days with a nonadherent bandage (C) or with a hydrogel containing 0% (G), 5% (5S), or 10% (10S) sildenafil. Daily bandage changes with wound imaging were performed. Biopsy specimens were collected 5 times. RESULTS: Hydrogels were homogenous at room temperature and released > 90% of the sildenafil within 8 hours in vitro. Time to first granulation tissue was significantly shorter for the sildenafil groups (mean ± SD, 2.8 ± 0.8 days [5S and 10S]), compared with the control groups (5.2 ± 0.4 days [C] and 6.3 ± 1.4 days [G]). The G wounds had a 10% to 14% lower contraction rate, compared with the C, 5S, and 10S wounds. 5S wounds had a total wound area 0.7 ± 0.3 cm2 larger than 10S wounds. No significant differences were present when C wounds were compared with 5S and 10S wounds for total wound area, contraction, or epithelialization. Histologic acute inflammatory scores were higher for 5S and 10S wounds in the early and late stages of wound healing, with higher reparative scores on day 7. Neovascularization was higher for 10S wounds on day 7 and 14. CLINICAL RELEVANCE: The topical sildenafil hydrogel promoted early granulation tissue, which may be beneficial for secondary wound closure in clinical settings.

Bone loss after severe spinal cord injury coincides with reduced bone formation and precedes bone blood flow deficits.

Diminished bone perfusion develops in response to disuse and has been proposed as a mechanism underlying bone loss. Bone blood flow (BF) has not been investigated within the unique context of severe contusion spinal cord injury (SCI), a condition that produces neurogenic bone loss that is precipitated by disuse and other physiological consequences of central nervous system injury. Herein, 4-mo-old male Sprague-Dawley rats received T9 laminectomy (SHAM) or laminectomy with severe contusion SCI (n = 20/group). Time course assessments of hindlimb bone microstructure and bone perfusion were performed in vivo at 1- and 2-wk postsurgery via microcomputed tomography (microCT) and intracardiac microsphere infusion, respectively, and bone turnover indices were determined via histomorphometry. Both groups exhibited cancellous bone loss beginning in the initial postsurgical week, with cancellous and cortical bone deficits progressing only in SCI thereafter. Trabecular bone deterioration coincided with uncoupled bone turnover after SCI, as indicated by signs of ongoing osteoclast-mediated bone resorption and a near-complete absence of osteoblasts and cancellous bone formation. Bone BF was not different between groups at 1 wk, when both groups displayed bone loss. In comparison, femur and tibia perfusion was 30%-40% lower in SCI versus SHAM at 2 wk, with the most pronounced regional BF deficits occurring at the distal femur. Significant associations existed between distal femur BF and cancellous and cortical bone loss indices. Our data provide the first direct evidence indicating that bone BF deficits develop in response to SCI and temporally coincide with suppressed bone formation and with cancellous and cortical bone deterioration.NEW & NOTEWORTHY We provide the first direct evidence indicating femur and tibia blood flow (BF) deficits exist in conscious (awake) rats after severe contusion spinal cord injury (SCI), with the distal femur displaying the largest BF deficits. Reduced bone perfusion temporally coincided with unopposed bone resorption, as indicated by ongoing osteoclast-mediated bone resorption and a near absence of surface-level bone formation indices, which resulted in severe cancellous and cortical microstructural deterioration after SCI.

Correlations among upper and lower tear menisci, noninvasive tear break-up time, and the Schirmer test.

PURPOSE: To determine the relationships among tear meniscus parameters, noninvasive tear break-up time (NITBUT), and the Schirmer test. DESIGN: Experimental study. METHODS: Thirty-six subjects were tested on one randomly selected eye. Real-time corneal optical coherence tomography (OCT) was used to image the upper and lower tear menisci during normal and delayed blinking followed by measurement of NITBUT and the Schirmer test. Digital images of the eye were taken for measuring the lid lengths to estimate tear volume in the menisci. RESULTS: Compared with normal blinking, significant increases of tear menisci occurred during delayed blinking (post hoc, P < .01). NITBUT was weakly but significantly correlated with the height (r = 0.36; P = .03) and area (r = 0.37; P = .03) of the lower tear meniscus during normal blinks. NITBUT was also correlated with the lower tear meniscus volume (r = 0.45; P < .05) and total tear meniscus volume (r = 0.43; P < .05) during normal blinking. The Schirmer test was not significantly related to any parameters of the tear menisci, volumes, or NITBUT; however, it was negatively correlated with the age of the subjects (r = -0.47; P = .004). The age was negatively correlated with the upper tear meniscus (r ranged from 0.36 to 0.37 for the radius, height, and area, P < .05) measured during delayed blinking. CONCLUSIONS: NITBUT appears correlated with the lower tear meniscus during normal blinking, and the Schirmer test appears not correlated with the noninvasively measured tear meniscus.

Effect of blinking on tear dynamics.

PURPOSE: Optical coherence tomography (OCT) was used to study the impact of blinking on tear dynamics. METHODS: One eye of 21 subjects was imaged at the same time of day on two consecutive days. Dimensional information of the tear film and of the upper and lower tear menisci during normal and delayed blinking were obtained from OCT images using custom software. Digital camera images were used to measure eyelid length and ocular surface area for tear volume estimation. RESULTS: No significant changes in any measured variable occurred between the two repeat visits. During normal and delayed blinking sessions, the tear film thickness increased significantly after each blink (P < 0.05) and then decreased (P < 0.05) during the open-eye period. For normal blinks, the tear meniscus did not change significantly during blinking or during the open-eye period. Except for upper tear meniscus curvature, all other parameters of tear menisci during delayed blinks were higher than those measured during normal blinks (P < 0.05). For delayed blinks, the lower tear meniscus height decreased after the blink (P < 0.05). Also for delayed blinks, the height and area of both upper and lower tear menisci significantly increased during the open-eye period. The total estimated tear volume on the ocular surface was greater during the delayed blinks (P < 0.01), and most of the volume was located in the lower tear meniscus (P < 0.01). CONCLUSIONS: OCT is a promising tool for studying the impact of blinking on tear dynamics. Tear distribution is dynamically balanced and consistent during normal blinking, but it becomes altered during delayed blinking.

Effect of blinking on tear volume after instillation of midviscosity artificial tears.

PURPOSE: To determine by optical coherence tomography (OCT) the effect of blinking on ocular surface tear volume after instillation of artificial tears. DESIGN: Experimental study. METHODS: Normal human eyes (n = 21) were imaged to obtain dimensions of the tear film and menisci during blinking. The imaging was carried out immediately and five minutes after the instillation of 35 microl midviscosity artificial tears (1.0% carboxymethylcellulose; Refresh Liquigel; Allergan, Irvine, California, USA). The exposed ocular surface area and the lid lengths were used to calculate the volumes. RESULTS: Immediately after the instillation, total tear volume was increased (P < .001) compared with five minutes after the instillation, with the major increases in the lower tear meniscus volume and tear film volume. After the instillation, blinking caused tear loss in total tear volume because of the decrease of the lower tear meniscus volume (P < .05). In contrast, blinking increased the tear film volume (P < .05). At the end of the eye-opening period, tear film volume decreased and lower tear meniscus volume increased significantly (P < .05), with no significant changes in total tear volume (P > .05). During the blink cycle immediately after the instillation, net loss was evident in tear film volume, lower tear meniscus volume, and total tear volume (P < .05). CONCLUSIONS: Blinking plays a crucial role in distribution and removal of instilled tears. When the tear system is overloaded, the increase in blink output helps restore balance.