Label extension, single-arm, phase III study shows efficacy and safety of stempeucel® in patients with critical limb ischemia due to atherosclerotic peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) of lower extremities comprises a clinical spectrum that extends from asymptomatic patients to critical limb ischemia (CLI) patients. 10% to 40% of the patients are at the risk of primary amputation. This study was planned in "no-option" patients of CLI due to atherosclerotic PAD to assess the efficacy and safety of pooled, allogeneic, adult human bone marrow-derived mesenchymal stromal cells which is already approved for marketing in India for CLI due to Buerger's disease. METHODS: This was a single-arm, multi-centric, phase III study where mesenchymal stromal cells was injected as 2 million cells/kg body weight in the calf muscle and around the ulcer. Twenty-four patients of lower extremity CLI due to PAD with Rutherford III-5 or III-6 and ankle-brachial pressure index ≤ 0.6 and having have at least one ulcer with area between 0.5 and 10 cm2 were included in the study. These patients were evaluated over 12 months from drug administration. RESULTS: Over a period of 12 months, statistical significant reduction of rest pain and ulcer size along with improvement in ankle-brachial pressure index and ankle systolic was observed. The quality of life of patients improved together with increase in total walking distance and major amputation-free survival time. CONCLUSION: Mesenchymal stromal cells may be a feasible option to treat "no-option" patients with atherosclerotic PAD. Trial registration This study is registered prospectively in National Institutes of Health and Clinical Trials Registry-India (CTRI) website: CTRI/2018/06/014436. Registered 6th June 2018. http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=24050&EncHid=&userName=stempeutics .

Phase IV postmarketing surveillance study shows continued efficacy and safety of Stempeucel in patients with critical limb ischemia due to Buerger's disease.

Buerger's disease or thromboangiitis obliterans is a type of obstructive vascular diseases categorized as vasculitis and usually present in 95% of young smoker men. The main pathogenetic mechanism is interplay between immune system and inflammation. Earlier our phase II study has shown that Stempeucel is safe when injected at 2 million cells/kg body weight by virtue of its anti-inflammatory, immunomodulatory, and angiogenetic properties. The present study was conducted to further assess the safety and efficacy of Stempeucel in critical limb ischemia due to Buerger's disease after obtaining approval from Indian FDA based on the data generated in the phase II study. This is an open label, multicenteric phase IV PMS study conducted across India with experienced vascular surgeons. Fifty patients of critical limb ischemia due to Buerger's disease with Rutherford III-5 or III-6 were included in the study and each individual received a dose of 2 million cells/kg body weight of Stempeucel in the calf muscles and around the ulcer. These patients were evaluated over 12 months from drug administration. The present study showed the continued long term efficacy over a period of 12 months follow up in these patients corroborating the result obtained in the previous phase II studies. There was significant improvement in rest pain, ankle systolic pressure, and ankle brachial pressure index with accelerated ulcer healing. In conclusion, the present study shows that the intramuscular administration of Stempeucel continues to be safe, tolerable, and effective alternative treatment in patients with Buerger's disease.

Dilemma of Timing of Administration of Non-Steroidal Anti-inflammatory Agents in Relation to Food in the Prevention of Drug Induced Gastritis: Debusting the Myth.

BACKGROUND & OBJECTIVE: We aimed to identify the signals that indicate the possible benefits of administering Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) at the initiation of meal, compared to immediately after food. METHODS: This was a randomized, controlled, pilot study in 160 patients who received only NSAIDs for various pain conditions. Patients were randomized to Group I (control group) -NSAID After Food (AF), Group II-NSAID Before Food (BF), Group III-NSAID BF for 2 days and then crossed over to AF for next two days (CO-1) and Group IV-NSAID AF for 2 days and then crossed over to BF for next two days (C0-2 group). Group III & Group IV were given a washout period of 48 hours after the initial two days of treatment. All were followed up for the next 2 drug free days. Patients were observed for the development of gastritis (epigastric distress, epigastric pain, nausea, fullness of stomach, repeated reflux) throughout the study. RESULTS: Symptoms of gastritis were seen in 6.45% (2/31) and 36.11% (13/36) patients in group I and II, respectively. There was no statistically significant difference in the development of gastritis in AF group. However, statistically significant difference (P<0.05) was found between BF group and AF intake of NSAIDs [CO-1 (AF), CO-2 (A.F), AF (control group)] in terms of development of gastritis. INTERPRETATION & CONCLUSION: Administering NSAIDs at the initiation of meal is better tolerated as indicated by the lower incidence of gastritis. If proved in larger population, routine concurrent administration of medication for prevention of gastritis can be avoided.

Mass in the Left Iliac Fossa-a Diagnostic Dilemma.

Clinical diagnosis of abdominal masses remains a challenge to this day; in spite of the availability of advanced imaging facilities, we fail to reach a definitive diagnosis in a few cases and have to resort to a laparotomy, which reveals unexpected findings. We present a case of a 70-year-old lady who presented with pain abdomen and loss of appetite for 3 months; clinical examination revealed a fixed intra-abdominal firm to hard mass in the left iliac fossa. CT scan of the abdomen showed a large cystic hypodense lesion in the left iliac, lumbar and hypogastric region with no definite organ of origin. The patient underwent an exploratory laparotomy and in toto excision of the cyst; on opening the cyst wall, we found multiple daughter cysts in a pool of thick, purulent fluid. Microscopic examination confirmed the presence of a hydatid cyst Primary peritoneal hydatid cysts are a rare entity and constitute around 2 % of hydatid cysts found in the human body. Very few cases of primary peritoneal hydatid cyst have been reported from non-endemic areas, and this case report highlights the need to maintain a high index of suspicion while evaluating cystic abdominal swellings.

Estimation of gestational age from gall-bladder length.

Establishing a precise duration of gestation is vital in situations such as infanticide and criminal abortions. The present study attempted to estimate the gestational age of the foetus from gall-bladder length. Foetuses of various gestational age groups were dissected, and the length of the gall bladder was measured. The results were analysed, and a substantial degree of correlation was statistically confirmed. This novel method is helpful when the foetus is fragmented, putrefied or eviscerated, where this method can be used as an additional parameter to improve the accuracy of foetal age estimation.

Melatonin counteracts the stimulatory effects of blinding or exposure to red light on reproduction in the skipper frog Rana cyanophlyctis.

An earlier study reported that blinding or exposure to red light stimulates reproduction in R. cyanophlyctis. The present study investigates whether melatonin counteracted blinding- or red-light-induced ovarian stimulation. The study consisted of two experiments carried out during the prebreeding (March/April) and breeding phase (August/September) of the reproductive cycle of this species. In experiment 1, exposure to red light for 30 days increased (P<0.01) the gonadosomatic index (GSI) and oviductal weights, whereas exposure to continuous darkness for the same duration decreased (P<0.01) the GSI. Data on follicular kinetics revealed an increase in vitellogenic oocytes and decrease in previtellogenic oocyte numbers following exposure to red lights. Exposure to continuous dark on the other hand increased previtellogenic oocyte and decreased vitellogenic oocyte numbers. In experiment 2, the GSI and the number of vitellogenic oocytes increased in blinded and red-light-exposed frogs. However, treatment with melatonin (15 microg sc) for 30 days to both these groups of frogs reduced the GSI, oviductal weights, and the number of vitellogenic oocytes. The results both confirm earlier finding that blinding and exposure to red light stimulate ovarian growth and also demonstrate that melatonin counteracts blinding or red-light-induced stimulation of ovarian activity. This apart, the findings from experiment 1 demonstrate for the first time that exposure to continuous dark inhibits ovarian growth in this species. Ocular melatonin seems to play an important role in regulation of reproduction in this species.

Changes in ovarian follicular kinetics in intact blinded and parietal shielded frogs exposed to different spectra of light.

Ovarian follicular kinetics and gravimetric changes in the ovary and oviduct were studied in intact, blinded (BL), and parietal shielded (PS) skipper frog Rana cyanophlyctis exposed to different light spectra. The gonadosomatic index (GSI) increased (P < 0.01) in intact and PS frogs, held in green, yellow, and red light. The maximum increase was in red light followed by yellow and green. The GSI of BL frogs also increased (P < 0.001) in white, green, yellow, and red light. However, the GSI of blinded and parietal shielded (BLPS) frogs increased (P < 0.001) in white and all the colored lights compared with controls. The percentage changes of oviductal weights were similar to the ovarian weights. Data on follicular kinetics revealed a decrease in previtellogenic oocytes in intact and PS frogs placed in blue, green, yellow, and red lights. The previtellogenic oocytes of BL and BLPS frogs decreased in white light, while their number did not vary significantly in other spectra. The vitellogenic oocytes of intact and PS frogs increased in all the spectra, with a maximum increase in red. The vitellogenic oocyte count increased in both BL and BLPS frogs held in white light. The green, yellow, and red spectra stimulated vitellogenic oocyte count of BL frogs. The response of BPLS frogs was similar except for a slightly decreased oocyte count in red light. The pattern of vitellogenic oocyte counts in general exhibited a negative correlation with previtellogenic oocyte counts in all the frogs. The atretic follicular numbers did vary significantly in all of the groups. Red light stimulated ovarian activity maximally, followed by yellow and green. As the ovary exhibited varied response to the different spectra of light even in BL frogs, it may be concluded that extraretinal perception of colored light occurs in this species.

Effect of exposure to continuous light and melatonin on ovarian follicular kinetics in the skipper frog, Rana cyanophlyctis.

Ovarian follicular kinetics and gravimetric changes in the ovary and oviducts were studied in the skipper frog, Rana cyanophlyctis, following exposure to continuous light and melatonin treatment during the breeding season. Daily late-afternoon injections of melatonin (15 micrograms subcutaneous) for 30 days decreased the gonadosomatic index (GSI), whereas continuously available melatonin from subcutaneous implants did not influence the GSI compared to those of controls. Exposure to continuous light for 30 days stimulated the GSI, and melatonin given as daily injections prevented the continuous-light induced increase in GSI. Oviductal weights decreased only in the melatonin-injected groups. Data on follicular kinetics revealed a decrease in first-growth-phase (FGP) oocytes and an increase in medium-sized second-growth-phase (MSGP) and large-sized second-growth-phase (LSGP) oocytes following continuous-light exposure. Melatonin administered to continuous-light-exposed frogs did not change the FGP oocyte number; however, it reduced both the MSGP and LSGP oocytes. Melatonin administration to frogs held in a light and dark cycle increased FGP oocytes and decreased MSGP and LSGP oocytes. Atretic follicles increased in all melatonin-treated groups. The results suggest that continuous light stimulates and melatonin inhibits reproductive function in this species.

Ovarian follicular kinetics in response to enucleation and parietal shielding in Rana cyanophlyctis.

Ovarian follicular kinetics, gravimetric changes in the ovary and the oviduct, were studied in the skipper frog, Rana cyanophlyctis, following enucleation (ENX) and parietal shielding (PS), during the breeding reason. PS was to prevent extraoptic photoreception by the pineal via the frontal organ. The gonadosomatic index (GSI) was high in ENX and PS frogs (P < 0.01). The highest GSI occurred in frogs that were both ENX and PS (P < 0.01). Percentage of oviductal weight decreased (P < 0.01) in PS frogs and increased (P < 0.01) in those subjected to both ENX and PS. Oviductal weight of ENX frogs was unchanged. Data on follicular kinetics revealed a decrease (P < 0. 01) in the ENX group in the number of first growth phase (FGP) oocytes and atretic follicles (AF), whereas the number of medium-sized secondary growth phase (MSGP) oocytes and large-sized secondary growth phase (LSGP) oocytes increased (P < 0.01). There was a similar pattern of follicular kinetics in ENX+PS frogs. However, following PS, the number of FGP oocytes and AF increased (P < 0.01) and decreased (P < 0.01) in the MSGP and LSGP oocytes. The lower oviductal weight in PS frogs correlated with reduced SGP oocytes, the major source of estrogen. The importance of lateral eyes and the frontal organs in the transduction of environmental signals to the neuroendocrine-reproductive axis is indicated in this species. That recruitment of FGP to SGP is inhibited only in the PS group suggests that the frontal organ plays an important role in ovarian follicular kinetics.