Correlation of flunisolide plasma levels to eosinopenic response in humans

Plasma levels of flunisolide were measured in healthy male volunteers after the administration of single doses of the drug by the intravenous, oral, intranasal, and bronchial inhalation routes. The systemic availability of a 1-mg dose orally was only 21%. After a single dose of approximately 0.117 mg intranasally plasma levels ranged up to 1 ng/ml. When 1 mg was administered by bronchial inhalation, peak or near peak plasma levels were recorded at 2 min and remained near this level throughout the first hour before declining at a rate similar to that observed after flunisolide intravenously (plasma ). Gargling with an alcoholic mouthwash immediately after inhalation reduced plasma levels at 30 and 60 min but not earlier, suggesting rate-limiting dissolution of flunisolide in bronchial fluids or rate-limiting diffusion across the mucociliary blanket or pulmonary membrane. The systemic availabilities of the inhaled-mouthwash and inhaled-no mouthwash doses were 32% and 39%, respectively. Systemic potency of flunisolide, measured by eosinopenic response, was oral < inhaled < intravenous and correlated with the systemic availability of flunisolide after drug administration by these three routes. These pharmacokinetic properties of flunisolide are clinically advantageous in that relatively small doses are delivered topically to the target organs, i.e., the nasal mucosa and lungs, whereas a large portion of the dose is swallowed and subsequently extensively metabolized to relatively inactive metabolites.     

Relapse of Philadelphia chromosome positive acute lymphoblastic leukaemia after marrow transplantation: sustained molecular remission after early and dose-escalating infusion of donor leucocytes

We present a patient who underwent sibling allogeneic BMT because of refractory Ph+ve ALL and remained BCR-ABL-positive after marrow grafting. Haemopoietic precursor cells were predominantly BCR-ABL-negative and of donor origin. In T cells an exclusively donor genotype was demonstrated. Despite donor leucocyte infusion (DLI), 20 weeks after BMT BCR-ABL fusion mRNA increased in semiquantitative polymerase chain reaction and leukaemic infiltration of the patient's bone marrow was seen. After a second course of DLI the patient achieved sustained molecular remission but he developed severe graft-versus-host disease (GvHD) and died from bacterial sepsis 9 months after DLI.     

Studies on the metabolic mechanism of reduced high density lipoproteins during anabolic steroid therapy

To explore the mechanism whereby stanozolol, a 17 alpha-methyl androgenic anabolic steroid, depresses high density lipoproteins (HDL), 6 subjects, aged 46-71 yr (4 postmenopausal women and 2 men), underwent paired studies of 125I-HDL turnover (including HDL2 and HDL3 and Apo A-I and A-II) and postheparin plasma (PHP) lipolytic activity (hepatic triglyceride lipase, HTGL, and lipoprotein lipase LPL) before and during treatment with stanozolol, 6 mg/day. While total cholesterol and triglyceride levels did not change during stanozolol, HDL-cholesterol decreased from 59 +/- 18 mg/dl (x +/- SD) to 29 +/- 7 mg/dl (p less than 0.01) and low density lipoprotein (LDL)-cholesterol increased from 160 +/- 36 mg/dl to 181 +/- 42 mg/dl (p less than 0.02). PHP-HTGL increased from 111 +/- 47 nmole/min/ml to 369 +/- 202 nmole/min/ml (p less than 0.04), while PHP-LPL did not change. At baseline the residence time of HDL2 (4.00 +/- 1.04 day) was shorter than that of HDL3 (6.79 +/- 1.00 day) (p less than 0.001). Residence times of both declined on stanozolol, to 3.25 +/- 0.83 day and 4.00 +/- 0.29 day, respectively (0.1 less than p less than 0.2); however, only the reduction in residence time of HDL3 was statistically significant (p less than 0.001). At baseline the residence time of apo A-I (4.93 +/- 1.32 day) was shorter than that of A-II (6.85 +/- 1.98 day) (p less than 0.025); on stanozolol these declined to 3.19 +/- 0.41 (p less than 0.02) and 5.10 +/- 1.13 (p = 0.07), respectively, still significantly different from each other (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of chronic digoxin treatment on cardiac function, electrolytes, and sarcolemmal ATPase in the canine failing heart due to chronic mitral regurgitation

This study was designed to determine whether digoxin therapy in the canine heart failing because of mitral regurgitation (MR) provides only hemodynamic benefit and accompanying subjective improvement or if it also reverses the changes in intracellular Ca++ and sarcolemmal Na+-K+-ATPase. The dogs were divided into four groups: control, MR of 3 months' duration, MR of 6 months', and digoxin treatment for 3 months after 3 months of MR. Six months of MR produced a marked decrease in the index of myocardial contractility and function associated with a decrease in intracellular Ca++ and Na+, and an increase in intracellular K+, extracellular space, sarcolemmal Na+-K+-ATPase, and Mg++-ATPase. Digoxin treatment tended to return the changes in the index of myocardial contractility and cardiac function, intracellular Ca++, Na+, K+, extracellular space, and sarcolemmal Na+-K+-ATPase of the failing heart toward control levels. Digoxin treatment did not affect Mg++-ATPase. The right ventricle, which did not fail, also did not show any significant changes in the parameters measured. The results showed that digoxin treatment not only improved the index of myocardial contractility and cardiac function of the failing heart but also tended to return the electrolytes and sarcolemmal Na+-K+-ATPase toward control levels.     

Effects of apolipoprotein C-II (apoC-II) on the lipolysis of very low density lipoproteins from apoC-II deficient patients

Lipoprotein lipase requires apolipoprotein C-II (apoC-II) from plasma very low density lipoproteins (VLDL) and high density lipoproteins (HDL) for maximal activity. To understand the mechanism by which apoC-II enhances the activity of the enzyme, the kinetic parameters for the hydrolysis of VLDL-triglycerides and phospholipids by purified bovine milk lipoprotein lipase have been determined in two patients with apoC-II deficiency. The absence of apoC-II in these patients was demonstrated by a specific radioimmunoassay for apoC-II (<0.05 mg apoC-II/dl plasma; normals ?5.0 mg/dl) and by isoelectric focusing of the isolated apoVLDL. The plasma levels of apoC-III, another apoprotein of VLDL, in the two subjects were 18.8 and 22.0 mg/dl (normals 11.1 ± 0.9 mg/dl). The kinetics of lipolysis of VLDL in either the presence or absence of apoC-II were monitored by using the patients' VLDL which were labeled in vitro with tri[1-¹⁴C]oleoyl glycerol and dansyl phosphatidylethanolamine (DPE). The release of [¹⁴C]oleic acid and the rate and extent of the DPE fluorescence increase were dependent on lipoprotein lipase and apoC-II concentration. Maximal hydrolysis of VLDL-triglycerides by lipoprotein lipase occurred at 2.5 μg apoC-II/mg triglyceride. The value of the Michaelis-Menten constant (K_m) of lipoprotein lipase for apoC-II deficient VLDL-triglycerides decreased from 7.8 mM in the absence of apoC-II to 1.0 mM at 2.5 μg of apoC-II; there was only a slight change in V_max. When normal HDL were used as the source of apoC-II, the rate of lipolysis of apoC-II deficient VLDL also increased and the value of K_m decreased to 1.0 mM. These results suggest that the effects of apoC-II on the rate of lipolysis of VLDL result from an apoC-II induced decrease in the apparent K_m of the enzyme for the substrate. One possible explanation for this decrease in K_m is that apoC-II enhances the interaction between lipoprotein lipase and triglyceride within the surface monolayer of the lipoprotein particle.     

Ph阳性急性淋巴细胞白血病合并肺、脑曲霉菌病

为了探讨Ph染色体阳性急性淋巴细胞白血病合并侵袭性曲霉菌病的临床特点和治疗措施,对1例Ph＋ALL患者进行了血常规、骨髓像、胸片、头颅CT扫描和细胞遗传学等检查,并先后给予DVCP、善唯达及格列卫联合诱导化疗.患者在骨髓抑制期发生侵袭性肺、脑曲霉菌感染,给予伊曲康唑、两性霉素等抗真菌治疗,进行了开颅病灶引流术.经过上述综合治疗,患者获得缓解,肺、脑曲霉菌感染临床治愈.结论：Ph＋ALL是一种常规方案化疗效果差的特殊亚型,格列卫联合化疗是其较好的治疗方案.由于临床真菌检出率低,早期经验性选用抗真菌药物如伊曲康唑,并结合手术切除病灶是治疗肺、脑曲霉菌的较好方法.     

Myokardiales Pumpversagen bei dilatativer Kardiomyopathie und Phäochromozytom

Zusammenfassung Bei einer 37 j?hrigen, bisher gesunden Patientin entwickelte sich eine über 2 Monate progrediente Dyspnoe. Radiologisch und echokardiographisch zeigte sich eine massive Dilatation s?mtlicher Herzh?hlen mit biventrikul?ren Thromben und eine stark herabgesetzte Kontraktilit?t. Die Endomyokardbiopsien wurden von 2 Instituten als Myokarditis eingestuft. Im weiteren Verlauf entwickelten sich thrombembolische Komplikationen und ein therapierefrakt?res Pumpversagen, in dem die Patientin schlie?lich verstarb. Bei der Obduktion fand sich au?er einem dilatierten 600 g schweren Herzen mit biventrikul?ren Thromben ein klinisch bisher unbekanntes Ph?ochromozytom der linken Nebenniere. Die eingehende histologische und immunhistologische Aufarbeitung des Herzmuskelgewebes einschlie?lich Reevaluierung der Endomyokardbiopsien führte zur Revision der ursprünglichen Diagnose: Das Krankheitsbild der 37 j?hrigen Patientin war durch eine katecholamininduzierte dilatative Kardiomyopathie verursacht worden.