The metabolic disposition of an orally active pyridyl thiadiazinone cardiotonic agent (MPTD) in rat and baboon

1. Oral absorption and bioavailability of the orally active cardiotonic agent, (6RS)-6-methyl-5-(pyrid-4-yl)-3H,6H-1,3,4-[6-14C]thiadiaz in-2-one (MPTD) (5 mg/kg), in rat and baboon were high. Peak blood concentrations of MPTD and total radioactivity were reached by 1.5-4 h when MPTD accounted for 60-70% of total radioactivity. In both species, elimination of MPTD from blood was rapid (t 1/2 = 3-4 h), although total nonspecific radioactivity was eliminated more slowly. 2. Radioactivity was rapidly eliminated by both species mainly into urine. In rat, about 3% dose was collected as 14CO2 and 2% remained in the carcass after 4 days. Recovery from baboon was incomplete (78-86%). 3. Examination of urine indicated extensive metabolism of MPTD showing a marked species difference. In baboon, MPTD was metabolized largely by glucuronidation at the pyridyl nitrogen to yield a quaternary ammonium conjugate and only about 1% of the dose was excreted unchanged. In rat, the major urinary component was unchanged MPTD and no glucuronide conjugate was found. Both species formed the pyridine N-oxide of MPTD as well as a number of unidentified minor components. 4. Distribution of radioactivity in rat was rapid and extensive. In general, elimination from tissues was also rapid, although radioactivity was eliminated much more slowly from the nasal and bronchiolar epithelium and from the preputial gland.     

Thyroid function tests are rarely abnormal in patients with severe hyperemesis gravidarum

OBJECTIVES: There is considerable controversy in the literature as to the cause of hyperemesis gravidarum. The aim of this project was to measure a range of thyroid hormone levels in a group of hyperemetic pregnant women. PATIENTS: The study was carried out in 10 first trimester pregnant women with hyperemesis gravidarum. All had been admitted to hospital due to the severity of their symptoms. Fifty age matched, healthy first trimester pregnant women were used as controls. MEASUREMENTS: Blood samples from the women were analysed for total T3 (TT3), total T4 (TT4), free T4 (FT4), TSH, thyrotrophin receptor antibodies (TRAb), thyroid stimulating antibodies (TSAb) and thyroid microsomal and thyroglobulin antibodies. Human chorionic gonadotrophin (hCG) levels were also measured. RESULTS: While individual patients were found to have some abnormal thyroid function tests the group as a whole showed no consistent pattern of abnormality and did not differ significantly from a group of healthy first trimester pregnant women. hCG levels were also within the normal range in the hyperemetic patients. DISCUSSION: None of the women in this study received any antithyroid medication and their symptoms improved as the pregnancy progressed. These results would suggest that there is no underlying thyroid abnormality in patients with hyperemesis gravidarum. It would appear that neither thyroid hormones, nor hCG contribute to the pathogenesis of the condition.     

Time course of hypo-osmotic swellings of human spermatozoa: evidence of ordered transition between swelling subtypes

The hypo-osmotic swelling test (HOST or HOS test) usually takes into consideration the total HOS response value with no emphasis either on the value of the response subtypes or the response evaluation time. This study investigated the time course of HOS responses and analysed their physiological relevance. Raw semen spermatozoa and Percoll washed spermatozoa were used in the experiment. The morphological changes in the sperm tail were monitored by incubating the spermatozoa in the hypo- osmotic solution for 16 different time periods. The HOS reactive spermatozoa and the type of HOS reaction (swelling subtypes) of the samples subjected to different duration of treatment were identified under a phase contrast microscope. Also the fate of individual spermatozoa in a hypo-osmotic environment were monitored for 30 min. In spermatozoa exposed to a hypo-osmotic solution, the motility lasted usually less than 2 min and motility characteristics were uniquely different from that of the spermatozoa under iso-osmotic conditions. The HOS response development was permanent but the motility loss due to hypo-osmotic shock was reversible up to 1 min of incubation. There was an indication of ordered transition among the HOS swelling subtypes apparently initiating with subtype b destined to c, d, e, f and g. Further, the subtypes a and g showed gradual decrease and increase, respectively, while subtype b showed abrupt initial increase and then gradual decrease. Transition from b to g could be direct or via one or more than one subtypes. Ultrastructure based analysis indicated that HOS response subtypes are the apparent reflection of the differences in the cytoskeletal assembly of the sperm tail and thus may be identifying different physiological variants in the sperm population. These results indicate that shorter incubation is essential to document the kinetics of various HOS responses but the conventional HOS test misses these important HOS features because of lengthy incubation. Since the time course of ordered transition of HOS responses will vary more than the total HOS response in semen of different aetiologies, the importance of HOS response subtypes and response evaluation time should be taken into consideration when applying HOS test.      

Improved lesion detection with dimethyl-amino-diphosphonate: A report of two cases

In two patients with metastatic disease more lesions were detected on scintigraphs obtained with the low uptake bone-scanning agent dimethyl-amino-diphosphonate than on images produced using methylene diphosphonate. The results in these two patients provide practical support for the suggestion that bone-scanning agents with low uptake in normal bone, but high tumour-to-normal bone ratios, will allow better delineation of local bone abnormalities.     

The use of 111in-labeled lymphocyte imaging to evaluate graft rejection following cardiac transplantation in dogs

Lymphocytes separated from venous blood from six dogs who had heterotopic cardiac transplants have been labeled using ¹¹¹In-oxine. Labeled lymphocytes were reinjected into the dogs and imaging of the heart carried out over the successive 3 or 4 days. For comparison serial ECGs and punch biopsies of the heart were obtained. Abnormal uptake of labeled lymphocytes in the donor heart was clearly visible in three of the six dogs, faintly visible in two and not seen in one. 630 Ci ¹¹¹In was used in the dog where no uptake was seen and subsequent studies showed this amount of the radiopharmaceutical was toxic to lymphocytes. In the remaining five dogs the mean ratio of uptake of ¹¹¹In in donor to recipient heart was 14:1 (range 6.5:1–21:1). The lack of substantial uptake in the transplanted heart of two dogs is attributed to a delay in rejection relative to the time the labeled lymphocytes were injected. The results suggest that ¹¹¹In-labeled lymphocytes have potential as a noninvasive test for detecting rejection of cardiac transplants.J. McKillop is a Harkness Fellow of the Commonwealth FundJ. Wallwork is supported by National Heart Research Fund (UK)     

Alcohol and liver cancer.

Hepatocellular carcinoma is the eighth most frequent cancer in the world, accounting for approximately 500,000 deaths per year. Unlike many malignancies, hepatocellular carcinoma occurs predominantly within the context of known risk factors, with hepatic cirrhosis being the most common precursor to the development of hepatocellular carcinoma. After ethanol ingestion, the liver represents the major site of metabolism. Ethanol metabolism by alcohol dehydrogenase leads to the generation of acetaldehyde and free radicals that bind rapidly to numerous cellular targets, including components of cell signaling pathways and DNA. In addition to direct DNA damage, acetaldehyde depletes glutathione, an antioxidant involved in detoxification. Chronic ethanol abuse leads to induction of hepatocyte microsomal cytochrome P450 2E1, an enzyme that metabolizes ethanol to acetaldehyde and, in doing so, causes further free radical production and aberrant cell function. Cytochrome P450 2E1-dependent ethanol metabolism is also associated with activation of procarcinogens, changes in cell cycle, nutritional deficiencies, and altered immune system responses. The identification of oxidative stress in mediating many deleterious effects of ethanol in the liver has led to renewed interest in the use of dietary antioxidants as therapeutic agents. Included in this group are S-adenosyl-L-methionine and plant-derived flavanoids.     

Demonstration of increased concentrations of circulating glycated insulin in human Type 2 diabetes using a novel and specific radioimmunoassay

AIMS/HYPOTHESIS: Glycation of insulin, resulting in impaired bioactivity, has been shown within pancreatic beta cells. We have used a novel and specific radioimmunoassay to detect glycated insulin in plasma of Type 2 diabetic subjects. METHODS: Blood samples were collected from 102 Type 2 diabetic patients in three main categories: those with good glycaemic control with a HbA(1c) less than 7%, moderate glycaemic control (HbA(1c) 7-9%) and poor glycaemic control (HBA(1c) greater than 9%). We used 75 age- and sex-matched non-diabetic subjects as controls. Samples were analysed for HbA(1c), glucose and plasma concentrations of glycated insulin and insulin. RESULTS: Glycated insulin was readily detected in control and Type 2 diabetic subjects. The mean circulating concentration of glycated insulin in control subjects was 12.6+/-0.9 pmol/l ( n=75). Glycated insulin in the good, moderate and poorly controlled diabetic groups was increased 2.4-fold ( p<0.001, n=44), 2.2-fold ( p<0.001, n=41) and 1.1-fold ( n=17) corresponding to 29.8+/-5.4, 27.3+/-5.7 and 13.5+/-2.9 pmol/l, respectively. CONCLUSION/INTERPRETATION: Glycated insulin circulates at noticeably increased concentrations in Type 2 diabetic subjects.