A Phase 1 Study to Evaluate Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Savolitinib in Healthy Male Volunteers.

Savolitinib is an oral MET (hepatocyte growth factor receptor) tyrosine kinase inhibitor, with demonstrated preliminary efficacy in several cancer types. Previous pharmacokinetics assessments showed that savolitinib is rapidly absorbed but there are limited data on the absolute bioavailability and absorption, distribution, metabolism, and excretion (ADME) of savolitinib. This open-label, two-part, phase 1 clinical study (NCT04675021) used a radiolabeled micro-tracer approach to evaluate absolute bioavailability and a traditional approach to determine the ADME of savolitinib in healthy male adult volunteers (N = 8). Pharmacokinetics, safety, and metabolic profiling and structural identification from plasma, urine, and fecal samples were also assessed. Volunteers received a single oral savolitinib 600 mg dose followed by intravenous 100 µg of [14 C]savolitinib in Part 1 and a single oral 300 mg [14 C]savolitinib dose (≤4.1 MBq [megabecquerel] [14 C]) in Part 2. Following Part 1, absolute oral bioavailability was 69%, the median time of maximum observed concentration was 3.5 hours, and the mean terminal half-life was 6.1 hours. Following Part 2, 94% of the radioactivity administered was recovered, with 56% and 38% in urine and feces, respectively. Exposure to savolitinib and metabolites M8, M44, M2, and M3 accounted for 22%, 36%, 13%, 7%, and 2%, respectively, of plasma total radioactivity. Approximately 3% of the dose was excreted as unchanged savolitinib in urine. Most savolitinib elimination occurred via metabolism by several different pathways. No new safety signals were observed. Our data show that the oral bioavailability of savolitinib is high and the majority of savolitinib elimination occurs via metabolism and is excreted in the urine.

Extremity vascular trauma in civilian population: a seven-year review from North India.

This is a retrospective study of the experience with extremity vascular trauma at a tertiary level referral centre in North India where the majority of the population lives in villages and the incidence of high-speed automobile accidents and civilian violence is low. The aim was to study the aetiology, pattern of injuries and the mortality and morbidity rates due to vascular trauma in our population. Data relating to 148 patients presenting with vascular trauma requiring surgical intervention other than amputation between January 1996 and December 2002 were collected retrospectively. There were 132 males and 16 females with a mean age of 39 years presenting to the casualty with a median delay of 9.3 h after injury. Blunt trauma accounted for 84% of the injuries with extremities involved in 88%. The brachial artery was the most common artery injured with the femoral next most common. Repair without graft interposition was done in 74% and autogenous vein grafts were used in 23% of cases. Comparison of our results with those that would have been obtained, had the recommendations of Mangled Extremity Severity Score (MESS) been followed, showed that this scoring system had low sensitivity and specificity for prediction of salvageability of limbs. Eight percent patients died due to associated visceral organ injuries. Complications occurred in 32% patients and amputation was required in 6% of patients after an initial surgical repair mainly due to inadequate functional recovery. Eighty-eight percent of the survivors with salvaged limbs were able to achieve full functional recovery. Judicious selection and appropriate intervention can result in satisfactory limb salvage with good functional outcomes even with delayed presentations.

Current management of gall bladder perforations.

BACKGROUND: Gall bladder perforation is a serious complication of acute cholecystitis. The purpose of the present study is to evaluate the presenting symptoms, diagnosis and management of patients with gall bladder perforations. METHODS: A retrospective study was undertaken of 31 consecutive patients with gall bladder perforation in a single unit of a tertiary referral hospital, between January 1996 and December 2001. RESULTS: The incidence of gall bladder perforation was 5.9% of all cases of acute cholecystitis. Associated comorbidity was quite common (58%). Ultrasound and computed tomography scans of the abdomen are sensitive investigations. Ultrasound guided percutaneous drainage helps in tiding over the emergency. The morbidity (35%) and mortality (9.6%) is considerable. CONCLUSION: The patterns of presentations, diagnosis and management of gall bladder perforation are changing. But there is scope for improvement.

Pseudoaneurysm of the superior pancreaticoduodenal artery, a rare cause of hemosuccus pancreaticus: report of a case.

Chronic pancreatitis with a pseudoaneurysm is an established cause of hemosuccus pancreaticus. We herein describe a patient with chronic alcoholic pancreatitis associated with hemosuccus pancreaticus due to a pseudoaneurysm of the anterior superior pancreaticoduodenal artery rupturing in a pseudocyst of pancreas in the head region. Angiographic embolization was unsuccessful and therefore a laparotomy, ligation, and excision of the pseudoaneurysm with external drainage of pseudocyst were performed. Hemosuccus pancreaticus is a rare cause of upper gastrointestinal bleeding. Contrast-enhanced computed tomography and angiography is diagnostic in the majority of the cases. Surgery is the treatment of choice. Selective angiographic embolization may be helpful in tiding over the emergency until surgery can be performed.

Vascular complications of drug abuse: an Indian experience.

BACKGROUND: Vascular complications resulting from i.v. drug abuse constitute a range of clinical problems from simple to serious. In addition, patients who present with these complications frequently have viral infections, which are a hazard to health care workers. PATIENTS AND METHODS: The present study is a retrospective review of 46 male drug addicts with 52 vascular complications (45 arterial, seven venous). Pseudoaneurysm of the femoral artery was the most common complication (n = 35). Fourteen of these patients underwent ligation of the common, superficial and deep femoral arteries above and below the pseudoaneurysm. Twenty-one underwent bipolar ligation of the common femoral artery after complete excision of the pseudoaneurysm. The decision to revascularize was based on the presence or absence of postligation Doppler signal. Arterial reconstruction was performed in five patients. All eight brachial artery pseudoaneurysms were ligated and excised, and deep vein thrombosis was managed with anticoagulation. RESULTS: There was no mortality but three patients had to undergo late amputations of the lower limb after successful salvage following the initial surgery. The median postoperative ankle-brachial indices, after bipolar and triple ligations were 0.51 and 0.46, respectively. Positive blood cultures were present in 30% of patients and tissue cultures were positive in 72%, the most common organism isolated was methicillin-sensitive Staphylococcus aureus. Six patients were positive for viral markers. The median hospital stay was 43 days. CONCLUSION: Ligation and excision of pseudoaneurysms without revascularization is safe for drug addicts provided it is based on the presence of a postligation Doppler signal.

Treatment of Budd-Chiari syndrome with inferior vena caval occlusion by mesoatrial shunt.

OBJECTIVE: To report the effectiveness of a mesoatrial shunt in the treatment of Budd-Chiari syndrome caused by combined hepatic vein and inferior vena caval block. DESIGN: Retrospective study. SETTING: Tertiary care hospital, India. PATIENTS: 10 patients (4 men and 6 women; mean age 28, range 18-45) who had operations for Budd-Chiari syndrome between 1994 and 2000. INTERVENTION: Mesoatrial shunt. MAIN OUTCOME MEASURES: Graft patency, survival, liver function and symptoms. RESULTS: One patient died. All grafts were patent over a mean follow up period of 40 months (range 6-71). All survivors have normal liver function and were symptom free at the time of writing. CONCLUSION: Mesoatrial shunt is effective in the treatment of Budd-Chiari syndrome caused by combined hepatic vein and vena caval occlusion.