DIHYDROGENATED ALKALOIDS OF ERGOT IN TREATMENT OF PERIPHERAL VASCULAR DISEASES

The dihydrogenated alkaloids of ergot, dihydroergocornine (DHO 180) and an equal mixture of dihydroergocornine, dihydroergocristine and dihydroergokryptine known as CCK 179 have been found to be therapeutic adjuncts in the medical treatment of peripheral vascular diseases. Their action is primarily that of adrenergic blockage, although depression of the brain stem is to be considered.The mixture of alkaloids (CCK 179) was found to be more effective than a single alkaloid, dihydroergocornine (DHO 180). A greater number of patients were benefited, relief of symptoms was greater and the dosage easier to establish. A favorable therapeutic response of clinical significance with the mixture was obtained in approximately 60 per cent of all cases investigated. It was of greater benefit in the organic occlusive diseases, where a larger percentage of favorable responses was obtained than in the purely vasospastic disorders.Orally and subcutaneously, CCK 179 exhibited vasodilating properties which compared favorably with paravertebral and peripheral nerve block, reflex heat, alcohol and sympathectomy. Surface temperatures were elevated, oscillometric readings increased and tolerance to cold increased in a statistically significant number of cases. Effects of sympathectomies were frequently enhanced. Following subcutaneous administration, increased surface temperatures of the extremities of one to two hours'' duration were obtained in 90 per cent of all cases.Paresthesias, nocturnal cramps and intermittent claudication were improved. A sense of well-being was occasionally exhibited.Blood pressure and pulse rates were rarely affected. Blood pressure was lowered in normotensive patients, but was rarely changed in hypertensive patients.Symptoms of overdosage appeared after two to three months of continuous therapy. These were manifested by lowered surface temperatures, decreased tolerance to cold, return of intermittent claudication and occasionally by vague general discomfort. These symptoms disappeared on cessation of therapy. Improvement frequently followed. In only one case was there an immediate reaction. Following subcutaneous administration of CCK, blood pressure and pulse rate increased and oscillometric readings and surface temperatures decreased.Frequent courses of therapy with interruptions were necessary for maintenance of improvement.     

Phosphorus magnetic resonance in studying energy metabolism in skeletal muscles

The present study objective involved evaluation of possibilities of magnetic resonance spectroscopy with phosphorus (31P-MRS) in diagnosis of metabolic disorders of skeletal muscles in patients with intermittent claudication, chronic heart failure and varicose disease of the lower extremities. In 20 patients with intermittent claudication, 10 patients with chronic heart failure, 10 patients with varicose disease and 10 volunteers, 31P-MRS was performed with 1.5 T MR system (Magnetom SP 63, Siemens). The following parameters were computed: phosphorus-creatinine index, intracellular pH in calf muscle, and time of half-recovery of the phosphorus-creatinine index. At rest, the phosphorus-creatinine indexes were similar in all groups; pH values at rest did not vary either. During isotonic exercise the phosphorus-creatinine index in the control group remained uncharged. In patients with intermittent claudication, the phosphorus-creatinine index at peak of exercise was decreased by 26.1% (p < 0.001), in patients with varicose disease--by 25.6% (p < 0.001), in patients with chronic heart failure by 8% (p < 0.001). PCr recovery half-time was increased in all patients. The patient group with intermittent claudication showed a reverse correlation between the pressure index and the degree of phosphorus-creatinine index decrease. CONCLUSION: 31P-MRS makes it possible to carry out non-invasive diagnosis of energy metabolic disorders of skeletal muscles in patients with impaired peripheral hemodynamics.     

Role of drugs in recovery of metabolic function of rat brain following severe hypoglycemia

Severe hypoglycemia with isoelectric EEG induced extensive deterioration of the energy state and gross alteration of amino acid contents on the rat cerebral and cerebellar cortex. During recovery, tissue glucose concentration returned to normal, while both lactate and pyruvate concentrations increased to above normal. In the recovery period, the ATP concentration increased but the adenine nucleotide pool remained reduced, even if the ADP and AMP contents were close to normal. Phosphocreatine was restored to normal concentration with reciprocal changes in creatine content. During recovery there was a rise in glutamate and glutamine concentrations, gamma-aminobutyrate content returning to normal value. Ammonia and aspartate decreased below normal, while alanine increased above normal. The effect of some pharmacological agents on the posthypoglycemic recovery was tested: (a) Ergot alkaloids (dihydroergocristine, dihydroergocriptine, dihydroergocornine); (b) Vinca minor alkaloids (vincamine TPS, (–) eburnamonine); (c) Rauwolfia serpentina alkaloids (reserpine, raubasine); (d) synthetic agent (piracetam). During the posthypoglycemic recovery, these different agents exhibited different, or even contrasting, interferences on glycolytic metabolites, amino acids and energy-rich phosphates. The metabolic alterations in the cerebellar cortex were qualitatively of the same character of those in neocortex. However, the metabolic alterations were less extensive and more sensitive to drug action.     

Impact of a walking program in people with down syndrome

The purpose of this study was to evaluate the efficacy of a pain-free treadmill walking program in intellectually disabled (ID) adults with arterial occlusive disease. Fourteen participants with mild ID participated in the walking program. Six patients showed stable intermittent claudication. A control (nontreadmill, n = 12) group consisted of 4 individuals with intermittent claudication. Noninvasive determinations of lower-limb hemodynamics included photoplethysmography and ankle-brachial pressure. Pain levels were measured according to a pain pathophysiology index. The treadmill program consisted of individually prescribed low-endurance walking at a 0% incline done at a comfortable speed 3 times per week. All participants completed the 15-week walking program and showed significant improvements (p < 0.05) in walking speed, distance, and duration. Pain levels were reduced in individuals suffering from intermittent claudication. Blood hemodynamic parameters also showed significant improvements. In conclusion, low-intensity treadmill walking significantly improved the functional capacities of adult individuals with mild ID with vascular occlusion and reduced pain levels.     

Thermal biofeedback in the treatment of intermittent claudication in diabetes: A case study

The objective of the present case study was to examine the therapeutic effects of thermal biofeedback-assisted autogenic training on a patient with non-insulin-dependent diabetes mellitus (NIDDM), vascular disease, and symptoms of intermittent claudication. The patient received thermal biofeedback from the hand for five sessions, then from the foot for 16 sessions, while hand and foot skin temperature were monitored simultaneously. In addition, the patient was instructed in autogenic training and practiced daily at home. Follow-up measurements were taken at 12 and 48 months. Within-session foot temperature rose specifically in response to foot temperature biofeedback and starting foot temperature rose between sessions. Posttreatment blood pressure was reduced to a normal level. Attacks of intermittent claudication were reduced to zero after 12 sessions and walking distance increased by about a mile per day over the course of treatment. It would appear that thermal biofeedback and autogenic training are potentially promising therapies for persons with diabetes and peripheral vascular disease.Preparation of this article was supported in part by NIDDK grant No. R0128288 and the Commonwealth of Virginia Diabetes Clinical Research Institute.     

福尔马林致痛对大鼠脊髓背角神经元神经肽CCK表达的影响

目的：本实验观察胆囊收缩素（CCK）在福尔马林致痛大鼠感觉信息传递中的作用。方法：用免疫组织化学技术,分别观察阴性对照、生理盐水、福尔马林致痛后1h和福尔马林致痛后3h大鼠脊髓背角的感觉神经元神经肽CCK表达的变化。结果：大鼠足底注射福尔马林1h后,脊髓背角Ⅰ、Ⅱ层神经元CCK表达阳性细胞数明显增加（P〈0．01）,且注射侧阳性细胞数明显高于非注射侧。注射福尔马林1h后,注射侧和非注射侧CCK表达阳性细胞的半定量光密度均值分别是0．397±0．014和0．295±0．007,差异有显著性（P〈0．01）;注射福尔马林3h后,注射侧和非注射侧脊髓背角CCK表达阳性细胞的半定量光密度均值分别是0．366±0．009和0．303±0．005,差异仍有显著性（P〈0．01）。结论：福尔马林致痛大鼠脊髓CCK表达阳性细胞的半定量光密度均值增加,进一步证实CCK在炎性痛信息传递通路的多个环节中参与了痛觉调制。     

Fate in intermittent claudication: outcome and risk factors.

The fate of 257 consecutive patients (100 women) aged 36-85 years (mean 65) first seen with intermittent claudication in 1977 was analysed after a mean of 6.5 (SD 0.5) years. When first seen none of the patients complained of rest pain or had ulcers or gangrenous lesions on the feet. At follow up 113 of the patients (44%) had died. Causes of death were no different from those in the general population. Mortality was twice that of the general population matched for age and sex. Mortality among the men was twice that among the women. In men under 60 mortality was four times that expected. The rate of clinical progression of the arteriosclerotic disease (that is, rest pain or gangrene) of the worst affected leg was 7.5% in the first year after referral. Thereafter the rate was 2.2% a year. An ankle systolic blood pressure below 70 mm Hg, a toe systolic blood pressure below 40 mm Hg, or an ankle/arm pressure index below 50% were individually significantly associated with progression of the arteriosclerotic disease. These findings show the importance of peripheral blood pressure measurements in the management of patients with intermittent claudication due to arteriosclerotic disease.     

TREATMENT OF MIGRAINE—Results with Dihydroergocornine Methanesulfonate (DHO-180) and Other Ergot Derivatives

A comparison of nicotinic acid, a non-narcotic analgesic and a series of injectable and oral ergot preparations tested by various methods in treating 40 patients with typical migraine indicate that ergot alkaloids are far superior in producing symptomatic relief.A comparison of ergotamine tartrate, dihydroergotamine (DHE-45) and dihydroergocornine (DHO-180) indicated that ergotamine tartrate is the most effective and perhaps the most toxic, DHE-45 is slightly less effective and considerably less toxic, and that DHO-180 is the least effective but also the least toxic. When given orally, these alkaloids were about half as effective as when given by injection. EC-110 (ergotamine nitrate with caffeine) was the most effective.DHO-180 in liquid form, given daily for one month, had a marked preventive effect on migraine attacks.     

TREATMENT OF MIGRAINE-Results with Dihydroergocornine Methanesulfonate (DHO-180) and Other Ergot Derivatives

A comparison of nicotinic acid, a non-narcotic analgesic and a series of injectable and oral ergot preparations tested by various methods in treating 40 patients with typical migraine indicate that ergot alkaloids are far superior in producing symptomatic relief.A comparison of ergotamine tartrate, dihydroergotamine (DHE-45) and dihydroergocornine (DHO-180) indicated that ergotamine tartrate is the most effective and perhaps the most toxic, DHE-45 is slightly less effective and considerably less toxic, and that DHO-180 is the least effective but also the least toxic. When given orally, these alkaloids were about half as effective as when given by injection. EC-110 (ergotamine nitrate with caffeine) was the most effective.DHO-180 in liquid form, given daily for one month, had a marked preventive effect on migraine attacks.     

Ozone therapy and viscosity of blood and plasma, distance of intermittent claudication and certain biochemical components in patients with diabetes type II and ischemia of the lower extremities]

Blood and plasma viscosity, total blood lipids, triglycerides, total cholesterol, free fatty acids, fibrinogen, hematocrit, and lipidogram were determined in patients with diabetes mellitus type II and coexisting symptoms of the obliterative arteriosclerosis of the lower limbs. Intermittent claudication distance has been measured parallel. The same tests have been carried out after ozone therapy. A significant improvement in the intermittent claudication and reduction in blood and plasma viscosity have been noted. There was statistically significant correlation between intermittent claudication decrease and blood viscosity reduction following ozone therapy.     

Intermittent claudication: is a supervised exercise class worth while?

Twenty-one patients (19 men and two women) with disabling exercise-related leg pain attended a physiotherapy department on one afternoon each week for an exercise training programme lasting one month. The clinical diagnosis of intermittent claudication and localisation of the atherosclerotic occlusions were confirmed in all but one case by pulse volume recordings and segmental Doppler systolic pressure measurements. Two patients whose symptoms worsened underwent arterial reconstruction. Post-training assessment at six months showed that the remaining 18 patients walked 80% further and performed 75% more step-ups. They also felt much healthier, having unduly restricted their activities before because they had feared the onset of ischaemic leg pain. These results suggest that supervised exercise training is a simple and effective method of treating patients with intermittent claudication.     

Effects of exogenous cholecystokinin and gastrin on the secretion of trypsin and chymotrypsin from yellowtail (Seriola quinqueradiata) isolated pyloric caeca

The humoral control of secretion of the proteolytic enzymes trypsin and chymotrypsin was studied in yellowtail (Seriola quinqueradiata). In vitro trials were performed to investigate the effects of cholecystokinin (CCK) and two commercially available gastrin peptides. Isolated preparations of pyloric caeca/pancreas release trypsin and chymotrypsin when incubated with cholecystokinin (CCK) at 10 microM and gastrin I (G1) at 50 microM after 15 min of incubation. On the other hand, G1 at 10 microM and gastrin-related peptide (G2) did not enhance trypsin and chymotrypsin secretion. The studies concerning the CCK effects at different incubation temperatures have shown that trypsin and chymotrypsin secretion at 25 degrees C was stimulated by CCK after 15 min, while at 10, 15 and 20 degrees C the stimulatory effects of CCK were observed only after 30 min of incubation. The CCK effects were increased at higher incubation temperatures and longer incubation periods.     

低浓度双氢哇巴因对豚鼠心室肌细胞内游离钙浓度的影响

用激光共聚焦显微镜检查研究低浓度双氢哇巴因（DHO）对豚鼠心室肌细胞内钙浓度（[Ca^2 ]i)的影响。DHO 1fmol/L-1 mmol/L可增加心室肌细胞的[Ca^2 ]i,尤其以10pmol/L DHO为显著,Nisoldipine,EGTA或TTX可分别部分抑制10pmol/L DHO的作用,去除胞外K^ 和Na^ 后,上述作用仍存在,以上结果表明,低浓度DHO中通过激活钙通道和TTX敏感的钠通道,或许还可直接促进胞内钙释放来增加[Ca^2 ]i,并有不依赖Na^ /K^ 泵而升高[Ca^2 ]i的作用。     

13C and 15N isotope effects for conversion of L-dihydroorotate to N-carbamyl-L-aspartate using dihydroorotase from hamster and Bacillus caldolyticus

In the pyrimidine biosynthetic pathway, N-carbamyl-L-aspartate (CA-asp) is converted to L-dihydroorotate (DHO) by dihydroorotase (DHOase). The mechanism of this important reaction was probed using primary and secondary 15N and 13C isotope effects on the ring opening of DHO using isotope ratio mass spectrometry (IRMS). The reaction was performed at three different temperatures (25, 37, and 45 degrees C for hamster DHOase; 37, 50, and 60 degrees C for Bacillus caldolyticus), and the product CA-asp was purified for analysis. The primary and secondary kinetic isotope effects for the ring opening of the DHO were determined from analysis of the N and C of the carbamyl group after hydrolysis. In addition, the beta-carboxyl of the residual aspartate was liberated enzymatically by transamination to oxaloacetate with aspartate aminotransferase and then decarboxylation with oxaloacetate decarboxylase. The 13C/12C ratio from the released CO2 was determined by IRMS, yielding a second primary isotope effect. The primary and secondary isotope effects for the reaction catalyzed by DHOase showed little variation between enzymes or temperatures, the primary 13C and 15N isotope effects being approximately 1% on average, while the secondary 13C isotope effect is negligible or very slightly normal (>1.0000). These data indicate that the chemistry is at least partially rate-limiting while the secondary isotope effects suggest that the transition state may have lost some bending and torsional modes leading to a slight lessening of bond stiffness at the carbonyl carbon of the amide of CA-asp. The equilibrium isotope effects for DHO --> CA-asp have also been measured (secondary 13K(eq) = 1.0028 +/- 0.0002, primary 13K(eq) = 1.0053 +/- 0.0003, primary 15K(eq) = 1.0027 +/- 0.0003). Using these equilibrium isotope effects, the kinetic isotope effects for the physiological reaction (CA-asp --> DHO) have been calculated. These values indicate that the carbon of the amide group is more stiffly bonded in DHO while the slightly lesser, but still normal, values of the primary kinetic isotope effect show that the chemistry remains at least partially rate-limiting for the physiological reaction. It appears that the ring opening and closing is the slow step of the reaction.     

Relation between intracellular Na ion activity and tension of sheep cardiac Purkinje fibers exposed to dihydro-ouabain.

The intracellular Na ion activity (aiNa) and the contractile tension (T) of sheep cardiac Purkinje fibers were simultaneously measured employing recessed-tip Na+-selective glass microelectrodes and a mechano-electric transducer. The aiNa of 6.4 +/- 1.6 mM (mean +/- SD, n = 56) was obtained in fibers perfused with normal Tyrode's solution. The changes in aiNa and T were measured during and after the exposure of fibers to a cardiac glycoside, dihydro-ouabain (DHO) in concentrations between 5 X 10(-8) M and 10(-5) M. The exposure time to DHO was 15 min. Both aiNa and T did not change in fibers exposed to 5 X 10(-8) M DHO, and the threshold concentration for the effect of DHO appeared to be around 10(-7) M. In DHO concentrations greater than the threshold, the increases in aiNa and T strongly correlated during the onset of DHO effects. The recoveries of aiNa and T were variable and slow, being dependent on the DHO concentration. In those fibers which recovered from the effects of DHO, the time-course of aiNa recovery was similar to that of T recovery. In fibers exposed to DHO of 5 X 10(-6) M or greater, the apparent toxic effects were observed in both action potential and contraction after an initial increase in T. The fibers manifesting the apparent toxic effects has a aiNa of approximately 30 mM or greater. The results of this study indicate that the increase in aiNa is associated with the positive inotropic action of the cardiac glycoside.     

Clinical assessment of treatment results for atherosclerotic ischemia of the lower extremities with intraarterial ozone injections]

Ten injections of O3 into femoral arteries were administered to 50 patients with atherosclerotic ischemia of the lower extremities and to 49 diabetic patients. All patients were assessed clinically with the ankle-arm index, measurement of intermittent claudication distance prior to and after the treatment. The treatment showed a significant improvement in both groups manifested by an increase in ankle-arm index, and prolongation of the intermittent claudication distance by more than twice. The treatment of atherosclerotic ischemia of the lower extremities with O3 is both valuable and safe.     

Mechanism of flavin reduction in the class 1A dihydroorotate dehydrogenase from Lactococcus lactis

Dihydroorotate dehydrogenases (DHODs) oxidize dihydroorotate (DHO) to orotate (OA) using the FMN prosthetic group to abstract a hydride equivalent from C6 and a protein residue (cysteine for class 1A DHODs) to deprotonate C5. The fundamental question of whether the scission of the two DHO C-H bonds is concerted or stepwise was addressed for the class 1A enzyme from Lactococcus lactis by determining kinetic isotope effects (KIEs) on flavin reduction in anaerobic stopped-flow experiments. Isotope effects were determined at two pH values. At pH 7.0, KIEs were approximately 2-fold for DHO labeled singly at the 5-position or the 6-position and approximately 4-fold for DHO labeled at both the 5- and 6-positions. At pH 8.5, the KIEs observed for DHO labeled at the 5-position, the 6-position, and the 5- and 6-positions were approximately 2-, approximately 3-, and approximately 6-fold, respectively. These isotope effects are consistent with a concerted oxidation of DHO. The pH dependence of reduction was also determined, and a pKa of 8.3 was found. This pKa can be attributed to the ionization of the active site cysteine which deprotonates C5 of DHO during the reaction. To further investigate the importance of the active site base, two site-directed mutants were also studied: Cys130Ala (removal of the active site base) and Cys130Ser (replacement with the active site base used by class 2 DHODs). Both mutant enzymes exhibited binding affinities for DHO similar to that of the wild-type enzyme. Reduction of both mutants was extremely slow compared to that of the wild type; the rate of reduction increased with pH, showing no sign of a plateau. Interestingly, double-deuterium isotope effects on the Cys130Ser mutant also showed a concerted mechanism for flavin reduction.     

beta blockade and intermittent claudication: placebo controlled trial of atenolol and nifedipine and their combination.

OBJECTIVE--To determine the effects of the beta 1 selective adrenoceptor blocker atenolol, the dihydropyridine calcium antagonist nifedipine, and the combination of atenolol plus nifedipine on objective and subjective measures of walking performance and foot temperature in patients with intermittent claudication. DESIGN--Randomised controlled double blind four way crossover trial. SETTING--Royal Hallamshire Hospital, Sheffield. SUBJECTS--49 patients (40 men) aged 39-70 with chronic stable intermittent claudication. INTERVENTIONS--Atenolol 50 mg twice daily; slow release nifedipine 20 mg twice daily; atenolol 50 mg plus slow release nifedipine 20 mg twice daily; placebo. Each treatment was given for four weeks with no washout interval between treatments. MAIN OUTCOME MEASURES--Claudication and walking distances on treadmill; skin temperature of feet as measured by thermistor and probe; blood pressure before and after exercise; subjective assessments of walking difficulty and foot coldness with visual analogue scales. RESULTS--Atenolol did not significantly alter claudication distance (mean change -6%; 95% confidence interval 1% to -13%), walking distance (-2%; 4% to -8%), or foot temperature. Nifedipine did not alter claudication distance (-4%; 3% to -11%), walking distance (-4%; 3% to -10%), or foot temperature. Atenolol plus nifedipine did not alter claudication distance but significantly reduced walking distance (-9%; -3% to -15% (p less than 0.003)) and skin temperature of the more affected foot (-1.1 degrees C; 0 to -2.2 degrees C (p = 0.05)). These effects on walking distance and foot temperature seemed unrelated to blood pressure changes. CONCLUSIONS--There was no evidence of adverse or beneficial effects of atenolol or nifedipine, when given singly, on peripheral vascular disease. The combined treatment, however, affected walking ability and foot temperature adversely. This may have been due to beta blockade plus reduced vascular resistance, which might also explain the reported adverse effects of pindolol and labetalol on claudication.     

Clinical,Haemodynamic, Rheological,and Biochemical Findings in 126 Patients with Intermittent Claudication

Increased blood viscosity has been shown to be an important factor in reducing blood flow in a review and analysis of the history, clinical findings, and haemodynamic, rheological, radiological, and biochemical measurements in 126 patients with intermittent claudication. In some patients increased viscosity seemed to be the determining cause of claudication. A raised plasma fibrinogen was the most common single biochemical abnormality. The results of conventional serum lipid and lipoprotein estimations were abnormal in the series as a whole but did not correlate with clinical findings or flow measurements at individual patient level. There was, however, a significant correlation between some clinical findings and the susceptibility of the red cells to autoxidation.     

Enhanced release of cholecystokinin by dietary amino acids in chicks (Gallus domesticus)

1. The effect of dietary amino acids and protein on cholecystokinin (CCK) release into plasma was investigated in chicks by feeding a meal through a stomach tube, followed by the CCK determination with specific CCK-8 antibody. 2. The results showed that both isolated soya protein and an amino acid mixture simulating the amino acid composition of the soya protein increased the release of CCK, though to a lesser extent with a delayed response in the former, when added to a protein-free diet. 3. Among amino acids added singly to the protein-free diet, phenylalanine was more efficient than arginine and valine, exerting a response almost identical to the complete amino acid mixture.