Facilitated uptake of zinc into human erythrocytes. Relevance to the treatment of sickle-cell anaemia

The ability of a number of heterocyclic metal chelators to deliver zinc into red cells, to release the liganded zinc to haemoglobin and thereby cause a left shift in the oxygen dissociation curve of intact red cells has been investigated. Incubation of neutrally charged zinc-pyrone and zinc-pyridin-2-one complexes with red cells led to the rapid accumulation of zinc within cells, whereas unliganded zinc in the form of zinc acetate, zinc chloride or zinc sulphate accumulated only slowly. The rate at which zinc was delivered to red cells by pyrone and pyridin-2-one ligands increased with increasing lipid solubility of the ligands. The uptake of zinc into both normal adult and sickle red cells was associated with a dose-dependent increase in the oxygen affinity of haemoglobin. The degree of left shift in the oxygen dissociation curve following the incubation of red cells with zinc-pyrone and -pyridin-2-one complexes suggests that these complexes may find application as agents to increase the oxygen affinity of haemoglobin in sickle cell disease and thereby decrease the probability of intravascular sickling at low tissue oxygen tensions. Ethylmaltol appears to be a particularly useful agent due to its known low toxicity.     

Short term treatment by fenofibrate enhances oxidative activities towards long-chain fatty acids in the liver of lean Zucker rats

Lean Zucker rats were dosed orally for 1 week with fenofibrate (100 mg/kg/day). Liver weights of treated rats, expressed as per cent of body weight, were increased, while protein, DNA and triacylglycerol contents were not changed to any great extent per gram of liver, but increased when expressed per whole liver. Compared with the control animals, activities of fatty acid oxidase, of the peroxisomal fatty acid-oxidizing system and of catalase were markedly enhanced by fenofibrate, both per gram of liver and per total liver, while urate oxidase activity was slightly depressed when expressed per gram of liver. The activity of cytochrome c oxidase used as a mitochondrial marker was only higher when expressed per total liver. Besides, fenofibrate treatment induced a pronounced increase in the mitochondrial activities of carnitine palmitoyl- and acetyltransferases, of palmitoyl-CoA dehydrogenase and of carnitine-dependent oleate oxidation. Fenofibrate also enhanced significantly the carnitine content in liver and hepatic mitochondria. Malonyl-CoA content per gram of liver was found to be twice as high as in control rats, while the sensitivity of carnitine acyltransferase I to malonyl-CoA inhibition was hardly altered. The drug enhanced the percentage of palmitic acid in lipids of liver, but not in adipose tissues. The present data show that fenofibrate induced greater oxidative activities towards fatty acids, even in the lean animal. This stimulation could be related to the energy used for building new cells. In turn, at the same time of treatment, an enhanced fatty acid synthesis would provide specific fatty acids for the formation of new membranes. This latter effect will eventually disappear and the maintenance of a higher fatty acid oxidation may explain part of the overall hypolipaemic effect of fenofibrate.     

Immunochemical characterization of multiple forms of cytochrome P-450 in rabbit nasal microsomes and evidence for tissue-specific expression of P-450s NMa and NMb

Two unique forms of cytochrome P-450 (P-450), designated NMa and NMb, were recently isolated in this laboratory from nasal microsomes of rabbits. In the present study, polyclonal antibodies to the purified nasal cytochromes were prepared. Immunochemical analysis with specific rabbit anti-NMa and sheep anti-NMb antibodies indicated that P-450 isozymes identical to or having a high structural homology with NMa are present in both olfactory and respiratory mucosa, as well as in liver, but NMb was detected only in the olfactory mucosa. Neither form was detected in other tissues examined, including brain, esophageal mucosa, heart, intestinal mucosa, kidney, and lung. The specific occurrence of NMb in the olfactory mucosa was further substantiated by the detection and specific inhibition by anti-NMb of the formation of unique NMb-dependent metabolites of testosterone in olfactory microsomes but not in microsomes from liver or respiratory mucosa. Similar experiments with antibodies to previously purified rabbit hepatic P-450 isozymes indicated that not all of the hepatic cytochromes are expressed in the nasal tissues. Thus, P-450 isozymes structurally homologous to hepatic forms 2, 3a, and 4, but not 3b and 6, were found in the olfactory mucosa. On the other hand, only form 2 was detected in the respiratory mucosa. Immunoquantitation experiments revealed that NMa and NMb are the major P-450 forms in olfactory microsomes, whereas NMa and P-450 form 2 (or its homolog) constitute the major portion of the respiratory nasal microsomal P-450. The level of NMa in the liver is relatively low, accounting for less than 3% of total microsomal P-450 in this tissue. In addition, evidence is provided that NMa is the major catalyst in the dealkylation of two nasal carcinogens, hexamethylphosphoramide and phenacetin, in both olfactory and respiratory nasal microsomes.     

Giant hydronephrosis presenting as unilateral iliofemoral vein thrombosis

We report a case of left iliofemoral vein thrombosis with extension to the inferior vena cava associated with giant right hydronephrosis secondary to ureteropelvic junction obstruction. Surgery revealed marked infrarenal vena caval compression and deviation to the left side caused by the dilated right renal pelvis, with resultant kinking of the origin of the left iliac vein. It is postulated that the reduction in blood flow caused by this compression and distortion predisposed this patient to venous thrombosis.     

Evaluation of human sperm function

Our understanding of the causes of male infertility and our ability to develop an appropriate range of diagnostic tests are both dependent upon a knowledge of the cellular mechanisms responsible for the regulation of human sperm function. This review examines the intra- and extracellular factors regulating four separate components of human sperm function: sperm transport, sperm-egg recognition, the acrosome reaction and sperm-oocyte fusion. Within each of these areas the fundamental nature of the process, the control mechanisms involved, the availability of appropriate diagnostic tests and the relationship with human infertility have been considered.     

Pharmacological studies of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate. Effects on experimental pancreatitis

The effects of FUT-187 (6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, CAS 103926-82-5), a novel synthetic protease inhibitor, were examined in experimental rat and canine models of pancreatitis. 1. FUT-187 significantly increased the survival of rats with trypsin- and phospholipase A2-induced pancreatitis in a dose-dependent manner (10-100 mg/kg, p.o.). 2. FUT-187 decreased plasma enzymatic activity reflecting the degree of pancreatitis in rats with ethionine-induced pancreatitis, and showed a tendency to ameliorate histopathological changes in the pancreas (10-100 mg/kg p.o.). 3. FUT-187 (10 mg/kg) produced an obvious improvement of various biochemical parameters of pancreatitis and also reduced histopathological changes in the pancreas in animals with experimental pancreatitis produced by the closed duodenal loop method. In addition, FUT-187 significantly increased the survival of dogs when given by direct administration into the lumen of the closed duodenal loop. The therapeutic effects of FUT-187 in experimental pancreatitis were nearly equal in most instances to those of camostat mesilate. Thus, FUT-187 would appear to be an effective new agent for the treatment of pancreatitis.     

Kappa-opioid-receptor agonists modulate the renal excretion of water and electrolytes in anaesthetized rats.

1. Subcutaneous injection of the kappa-opioid agonists U50,488 (10 mg kg-1) and tifluadom (3.5 mg kg-1) into Inactin-anaesthetized, saline-infused rats was associated with a diuresis, antinatriuresis and antikaliuresis which lasted for up to 2 h. A high (5 mg kg-1), but not low (0.1 mg kg-1), dose of naloxone blocked the renal effects of U50,488. 2. U50,488 administration in anaesthetized, vasopressin-deficient Brattleboro DI rats was associated with an attenuated diuresis, though the antinatriuretic response remained intact. 3. The diuretic action of U50,488 was associated with an increase in glomerular filtration rate while fractional fluid reabsorption remained steady. In contrast, fractional sodium and potassium reabsorption were increased. 4. These data suggest that kappa-opioid agonists alter renal handling of both water and electrolytes. This appears to be mediated by two separate mechanisms: increased fluid loss largely reflects altered glomerular events while the fall in electrolyte excretion results from altered tubular handling.     

Levodopa up-regulates platelet alpha 2-adrenoceptors

Treatment of dogs for 21 days with oral levodopa (100 mg b.i.d.) plus benserazide (25 mg b.i.d.) induced a significant increase in the number of platelet alpha 2-adrenoceptors labelled by [3H] yohimbine with no change in Kd. The rise was maximal at the end of the treatment and remained significant during the month following the cessation of treatment. Plasma catecholamine levels did not vary. Competition experiments showed a low affinity of both dopamine and levodopa for platelet alpha 2-adrenoceptors. These results suggest that levodopa treatment regulates alpha 2-adrenoceptor number in dog platelets.     

Reduction using an immunomodulator of the level of respiratory infections in chronic bronchitis

Fifty-six patients with recurrent bronchopulmonary infections associated with chronic bronchitis were randomly allocated to 2 groups, to assess whether treatment with an immunomodulator, Diribiotin CK, could enhance resistance to infection. The double-blind, placebo-controlled prospective trial over a 9 month period showed that this immunomodulator was well tolerated and significantly reduced the rate of respiratory tract infection. The drug also significantly reduced the prescribing of antibiotic medication and the rate of absenteism from work. These effects have been demonstrated in a rigorously designed clinical study. This is the first time that a clear clinical activity has been attributed to an inducer of soluble mediators of immunity.