Synthesis of postulated hydroxylated metabolites of gliclazide is described together with their detailed structural analysis using 1H-NMR, two-dimensional 1H-NMR, and MS to characterize the products. Metabolism of gliclazide has been investigated in the urine of nine patients of different ethnic origins receiving gliclazide therapy for the treatment of diabetes. Urine extracts were analyzed by GC/MS to quantify and identify the metabolites excreted in urine and the metabolites compared with the synthesized products. Metabolic profiles in all diabetic patients were very similar and comparable with those reported for healthy human volunteers. In addition to the expected metabolites arising from oxidation of the 4-methylphenyl ring, four isomeric hydroxylated products of the azabicyclooctyl ring were identified and the structure of a fifth isomer postulated.

1. The comparative metabolism of fenfluramine was investigated in mouse, rat, dog and man following a single oral dose of 14C-(+/-)-fenfluramine hydrochloride (1 mg/kg), and also in rat after eight consecutive 12-h subcutaneous doses (24 mg/kg). 2. Main route of excretion of radioactivity in all species and at all doses was into urine (> 80%), with only minor amounts of radioactivity found in faeces. 3. From all species examined a total of 11 metabolites were observed in urine and plasma by t.l.c. and h.p.l.c. analysis and no metabolite was present in the plasma which was not present in urine. 4. All species dealkylate fenfluramine to the active metabolite norfenfluramine, to a relative greater or lesser extent, with plasma metabolic ratios (norfenfluramine/fenfluramine) showing inter-animal variation (rat >> dog >> mouse = man). 5. These differences are due to the efficient deamination of both compounds to polar inactive metabolites in man, with less dealkylation and lower plasma levels of norfenfluramine compared with the other species studied. 6. In conclusion, major species differences in the metabolism of (+/-)-fenfluramine, both qualitative and quantitative were observed, and no one species had a similar metabolic profile to that found in man.

The metabolism of (±)fenfluramine, 1-(m-trifluoromethylphenyl)-2-N-ethylpropane, an anoretic agent, was investigated in humans. The analysis method was based on the use of ion-exchange resin extraction, solid-phase purification on the Bond Elut™ C8 cartridge, gradient elution high-performance liquid chromatography, enzymic hydrolysis of conjugates, further purification by Bond Elut C8 cartridge, derivatisation and capillary column gas chromatography—mass spectrometry (GC—MS). After administration of a 1 mg kg−1 oral dose, four metabolites plus unchanged fenfluramine were recovered in the 0–24 h urine from human volunteers and characterised by GC—MS. In the unconjugated form, fenfluramine, norfenfluramine and m-trifluoromethylhippuric acid were detected by GC—MS. In the aglycone form, the major metabolite, 1-(m-trifluoromethylphenyl)-1,2-propane diol (fenfluramine diol), was monitored using GC—MS. The mass spectral characteristics of the m-trifluoromethylhippuric acid methyl ester, 1-(m-trifluoromethylphenyl)-1,2-propane ditrifluoroacetate derivatives and the norfenfluramine and fenfluramine free base obtained under electron-impact ionization are presented. The metabolism of fenfluramine is discussed including a metabolic pathway in man accounting for the formation of its biotransformation products.

The pharmacokinetics and metabolism of intravenously infused 14C-fotemustine (about 100 mg/m2) were examined in 2 cancer patients. Plasma levels of radioactivity increased to a maximum of 4.1 and 5.5 micrograms equivalents per g when the infusion stopped then declined triexponentially with mean half-lives of about 1/2, 10 and 80 h for the initial, mid and terminal phases, respectively. Plasma levels of intact drug were lower, with maximum levels of 1.1 and 2.8 micrograms/ml, and declined monophasically with a half-life of about 24 min. Plasma clearance was high (1426 and 764 ml/min) with the volume of distribution based on areas of 47.7 and 26.4 l. Most of the radioactivity was eliminated in urine (50.1 and 61.3%) over 7 days with smaller amounts in the feces (6.8 and 0.3%) and only minimal quantities (under 0.1%) as expired carbon dioxide. Metabolites of fotemustine were identified as chloroethanol and N-nitroso-1-imidazolone-ethyl-diethylphosphonate in plasma and as 1-hydantoin-ethyl-diethyl-phosphonate and acetic acid in urine.

Using the “neutron turbine” at the FRM reactor, Munich, as a pulsed source of ultracold neutrons, experiments have been performed on the polarization of very low energy neutrons (E ≈ 10−7 eV). Polarization and polarization analysis were accomplished by perpendicular transmission through thin monocrystalline iron foils magnetized in an easy direction. The data show that a high polarization efficiency of 95–98% was achieved within the expected interval 4.15<ν<8.2 m/s of neutron velocity, with almost no loss in intensity. The monocrystalline foils employed were prepared by epitaxial evaporation on NaCl crystals in a magnetic field.

Publisher Summary Observation of the cerebral blood flow profile following intravenous injection of a gamma-emitting isotope is a safe, atraumatic, and almost indefinitely repeatable method of obtaining clinically useful information about the cerebral circulation that is immediately available and readily interpreted by the responsible physician. The RCG in patients with A-V malformation is diagnostic, and can only be partly simulated by severe thyrotoxicosis. The state of spasm of the intracerebral vessels can be followed after subarachnoid hemorrhage without recourse to further angiography. This helps the surgeon to choose the optimum time for operative intervention. The management of intracranial hypertension is facilitated by knowledge of the behavior of the cerebral circulation in response to treatment by operation, intravenous hypertonic solutions and steroids. In the acute head injury maintenance or loss of autoregulation in response to changing blood pressure or arterial P, is an important guide to the use of positive pressure ventilation in the treatment of hypoxia. This function can be serially investigated by RCG. Cerebral vascular disorders can be investigated in both the acute and chronic stages of cerebral deprivation, and the RCG profile, basic and in response to treatment, is a valuable guide to both immediate therapy and prognosis. During radiological contrast studies, RCG can assist the radiologist in timing the X-ray exposures following injection and can inform him whether injection has temporarily increased or decreased blood flow.

Polymerization of methyl methacrylate (mma) in tetrahydrofuran (thf) may be photosensitized with benzophenone, 3,3′,4,4′-benzophenone tetracarboxylic dianhydride (btda) and 3,3′,4,4′-tetramethoxy carbonyl benzophenone (tmcb) with an efficiency comparable to that of azodiisobutyronitrile as a photosensitizer. The reactions show conventional chain kinetics for radical polymerizations in which initiation involves hydrogen abstraction from thf by triplet excited sensitizer, i.e. Ar2C = Ohv→(Ar2C = O)(S1)→(Ar2C = O)(T1)→Ar2C−OH + THF.

The first attempts at ultrasonic visualization of the cerebral ventricles were made by Dussik (1948), Ballantine, Ludwig, Bolt, and Hueter (1950), and Hueter and Bolt (1951), using the transmission method.The possible use of the pulse-echo method (echoencephalography) for the diagnosis of hy- drocephalus was suggested by Leksell (1956).Later

The effect of pulsed ultrasound on the human brain, for longer times than that administered in diagnostic work, in five adult patients and one child was studied by clinical evaluation, electro-encephalography, biochemical and histopathological studies.

By means of a simple isotope method, the cerebral blood-flow after subarachnoid hæmorrhage was measured in 50 patients. 48 of these patients also had angiographic studies. An increase in circulation-times was found to be related to the occurrence of arterial spasm as seen on the angiograms. This in turn was related to the postoperative morbidity and mortality. Serial observations were particularly helpful in indicating the best time for operative intervention.

By means of a simple isotope method, the cerebral blood-flow after subarachnoid hæmorrhage was measured in 50 patients. 48 of these patients also had angiographic studies. An increase in circulation-times was found to be related to the occurrence of arterial spasm as seen on the angiograms. This in turn was related to the postoperative morbidity and mortality. Serial observations were particularly helpful in indicating the best time for operative intervention.

COMPRESSIOK of important blood vessels to the spinal cord has been insufficiently stressed as a primary cause of the myelopathy associated with cervical spondylosis. Many articles on cervical myelopathy remark that, at operation, the cervical cord is seldom found to be compressed.l-" On this observation, most neurological surgeons are agreed. It should be considered together with the findings of Bradshaw4 and others that in less than half of these cases does the neurological level of dysfunction correspond to the level of the main bony lesions seen on x-ray films. These 2 observations together would suggest, prima facie, that the origin of the spinal cord disorder is not direct neuronal compression but vascular insufficiency caused by arterial or venous obstruction, or both. I t will be the object of this communication to demonstrate that this is so. The implications in treatment will be considered.

1958). In women also, the death-rate from lung cancer has increased considerably. The extensive statistical and epidemiological evidence associating tobacco smoking and lung cancer is clear for all to study. Much attention has been directed to carcinogens produced by tobacco combustion; the possible effects of nicotine on the tissues in relation to cancer should now be investigated. If it were shown that metabolic changes are caused by smoking tobacco, and since it is known that nicotine can pass through the placental circulation, the effects of nicotine on the developing foetus should be studied. Is it possible that cellular changes may be caused in utero which manifest their effects in later life ? In the prevention of lung cancer people should be dissuaded from beginning to smoke and smokers persuaded to stop. This is a great challenge to all, and doctors should help people to overcome a severe form of drug addiction. I have made some practical suggestions to help towards a solution of this problem (Raven, 1957), for I feel that elimination of the tobacco habit could be one of the greatest benefits conferred by preventive medicine.

Publisher SummaryThis chapter discusses the role of mucosal microbiota in the development, maintenance, and pathologies of the mucosal immune system. Most mucosal sites of lymphoid tissue—respiratory tract, adenoids, salivary glands, and urogenital tract—in healthy mammals are in a quiescent state and generally resemble the status of lymphoid areas in spleen and most peripheral lymph nodes (PLN). The intestinal tract, palatine tonsils, and occasionally the nasal-associated lymphoid tissue (NALT) are the exceptions. These mucosal lymphoid tissues are in a “physiologically normal state of inflammation.” The chapter focuses on how the intestinal microbes drive the development of gut-associated lymphoid tissue (GALT) during neonatal life and act to maintain its physiologically normal steady state of inflammation. Specific and adaptive, “natural” and semi-specific, and aspecific elements of the mucosal immune systems may benefit and be activated by host interactions with environmental antigens (Ags). To provide the experimental rationale for implicating intestinal or oral/nasal microflora in the development of GALT, palatine tonsil, and sometimes NALT and their steady state of inflammation, the chapter briefly contrasts the status of systemic lymphoid tissue in healthy mammals—spleen, PLN—with GALT, palatine tonsils, and NALT.