Utility of transcranial sonography in the diagnosis of drug-induced parkinsonism: a prospective study.

BACKGROUND AND PURPOSE: Drug-induced parkinsonism usually resolves after discontinuation of the causative agent. However, it persists in some patients, who actually have subclinical neurodegenerative parkinsonism. Identification of this condition is important because these patients could benefit from therapeutic measures. The objective of this study was to prove whether transcranial sonography, a technique used in the diagnosis of neurodegenerative parkinsonism, can be used for the said identification. METHODS: In this prospective study, patients with drug-induced parkinsonism were followed for at least 6 months after discontinuation of the causative drug and performance of blinded transcranial sonography. Patients were categorized as having iatrogenic parkinsonism if the clinical presentation had resolved or subclinical drug-exacerbated parkinsonism if it persisted. Once the patient was classified into one of the two groups, an expert assessed the transcranial sonography findings and their agreement with the clinical diagnosis. RESULTS: Twenty patients composed the group for analysis of results. Assessing hyperechogenicity in the substantia nigra >20 mm2 and/or hyperechogenic lentiform nucleus, differences were detected between the iatrogenic parkinsonism and the subclinical drug-exacerbated parkinsonism groups, although they did not reach statistical significance (Fisher's exact test 0.09). Joint assessment of sonographic alterations in both structures had a negative predictive value of 85.7% for diagnosis of drug-induced parkinsonism, with a negative likelihood ratio of 0.3. CONCLUSIONS: Although in our study statistically significant differences were not found between the transcranial sonography characteristics of subclinical drug-exacerbated parkinsonism and iatrogenic parkinsonism patients, we believe that transcranial sonography is a valid technique for diagnosis of drug-induced parkinsonism.

Efficacy and safety of extended-release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

BACKGROUND: Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction. However, niacin is underutilised because of the side effects of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). A combination tablet containing extended-release niacin and laropiprant (ERN/LRPT), a PGD(2) receptor (DP1) antagonist, offers improved tolerability. This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal based on their coronary heart disease risk category (high, moderate or low). METHODS: After a 2- to 6-week run-in statin (simvastatin 10 or 20 mg or atorvastatin 10 mg) period, 1216 patients were randomised equally to one of two treatment groups in a double-blind fashion: group 1 received ERN/LRPT (1 g) plus the run-in statin dose and advanced to ERN/LRPT (2 g) after 4 weeks for an additional 8 weeks, with no adjustments to the run-in statin dose; group 2 received simvastatin or atorvastatin at twice their run-in statin dose and remained on this stable dose for 12 weeks. RESULTS: ERN/LRPT added to statin (pooled across statin and statin dose) significantly improved key lipid parameters vs. the doubled statin dose (pooled): the between-treatment group difference in least squares mean per cent change [95% confidence interval (CI)] from baseline to week 12 in LDL-C (primary end-point) was -4.5% (-7.7, -1.3) and in high-density lipoprotein cholesterol (HDL-C) was 15.6% (13.4, 17.9) and in median per cent change for triglyceride (TG) was -15.4% (-19.2, -11.7). Treatment-related adverse experiences (AEs) related to flushing, pruritis, rash, gastrointestinal upset and elevations in liver transaminases and fasting serum glucose occurred more frequently with ERN/LRPT added to statin vs. statin dose doubled. CONCLUSIONS: The addition of ERN/LRPT to ongoing statin treatment produced significantly improved lipid-modifying benefits on LDL-C, HDL-C and TG and all other lipid parameters compared with doubling the statin dose in patients with primary hypercholesterolaemia or mixed dyslipidaemia. The types of AEs that occurred at a greater frequency in the ERN/LRPT group were those typically associated with niacin.

Clinical trials. A pending subject. / Ensayos clínicos. Una asignatura pendiente.

Clinical trials are essential tools for the progress of clinical medicine in its diagnostic and therapeutic aspects. Since the first trial in 1948, which related tobacco use with lung cancer, there have been more than 150,000 clinical trials to date in various areas (paediatrics, cardiology, oncology, endocrinology, etc.). This article highlights the importance for all physicians to participate, over the course of their professional career, in a clinical trial, due to the inherent benefits for patients, the progress of medicine and for curricular prestige. The authors have created a synthesis of their experience with clinical trials on hypertension, diabetes, dyslipidaemia and ischaemic heart disease over the course of almost 3 decades. Furthermore, a brief reference has been made to the characteristics of a phase I unit, as well as to a number of research studies currently underway.

Blood pressure-lowering effects of nifedipine/candesartan combinations in high-risk individuals: subgroup analysis of the DISTINCT randomised trial.

The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS-Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate<90 ml min-1, n=422), type 2 diabetes mellitus (n=202), hypercholesterolaemia (n=206) and cardiovascular (CV) risk factors (n=971), as well as the impact of gender, age and body mass index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a dose-response effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C combinations in each high-risk subgroup. The benefits of combination therapy vs monotherapy were additionally observed in patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy.

Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension.

In the double-blind Systolic Hypertension in Europe (Syst-Eur) Trial, active treatment was initiated with nitrendipine (10 to 40 mg/d) with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to <150 mm Hg. In the control group, matching placebos were used similarly. In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs, this report explored to what extent nitrendipine, administered alone, prevented cardiovascular complications. Age at randomization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg. Of 2398 actively treated patients, 1327 took only nitrendipine (average dose, 23.4 mg/d), and 1042 progressed to other treatments including nitrendipine (n=757; 35.7 mg/d), enalapril (n=783; 13.4 mg/d), and/or hydrochlorothiazide (n=294; 21.0 mg/d). Compared with the whole placebo group (n=2297), patients receiving monotherapy with nitrendipine had 25% (P=0.05) fewer cardiovascular end points, and those progressing to other active treatments showed decreases (P

Gram-negative bacillary pneumonia in the compromised host.

The clinical and radiological characteristics of 217 consecutive episodes of gram-negative bacillary pneumonia occurring in 189 adult cancer patients between November 1968 and December 1974 were analyzed. The majority of patients had acute leukemia (54%). Fever larger than or equal to 101 degrees F was the single most common symptom and sign of the presence of infection (90%). Next in frequency were crepitant rales (65%), cough (41%), dyspnea (19%) and chest pain (18%). Radiographic evidence of pneumonia was found in 83% of cases and it consisted mainly of alveolar infiltrates involving both lung fields and predominantly the bases. Up to one-third of the patients had normal chestx-ray examinations at the onset of infection, though they subsequently became abnormal in 42% of them. The majority of patients (81%) whose initial chest x-rays did not reveal the presence of pneumonia were neutropenic (less than 1000 circumlating neutrophils/mm3). Klebsiella sp. and Pseudomonas sp. were the most common infecting organisms. The overall cure rate was 61%; 70% for Klebsiella sp. infections and 64% for Pseudomonas sp. infections. Pulmonary abscesses occurred in 14% of the cases. Cures were related to the antibiotic sensitivity of the infecting organisms and to the number of circulating neutrophils during the period of infection. Best results were obtained with the administration of gentamicin, the newer aminoglycoside antibiotic sisomicin, tobramycin and amikacin, or the combination of gentamicin with carbenicillin or with cephalosporins. Early and vigorous therapy of gram-negative bacillary pneumonia with appropriate antibiotics has improved the prognosis of this infection at our institution.

Necrotizing colitis in patients with cancer.

Necrotizing lesions of the colon occur in patients with malignancy. We identified 26 patients with cancer (23 with acute leukemia and three with solid tumors) who died from necrotizing colitis. Autopsies revealed three pathologic categories: pseudomembranous colitis in 69 per cent, agranulocytic colitis in 19 per cent and ischemic colitis in 12 per cent. Most died from sepsis. A comparison of characteristics was made with a control population matched for diagnosis, age, cause of death and duration of neoplasia. Nearly all patients in both groups had fever and were granulocytopenic secondary to chemotherapy. Most received antineoplastic and antimicrobial regimens during the month prior to their terminal illness. Abdominal pain and distention, stomatitis and necrotizing pharyngitis were frequently associated with colitis. Hyperbilirubinemia was a frequent late complication in those with colitis and the control group. Single and multiorganism septicemia were found more frequently in patients with colitis. As antemortem diagnosis was unusual, aggressive attempts at diagnosis are necessary to assess the true incidence of this disorder and the best therapy.

Variations in magnesium and zinc in hypertensive patients receiving different treatments.

We studied the influence of captopril, atenolol, and verapamil on serum and intraerythrocyte concentrations of magnesium and zinc in 30 normotensive control subjects (12 men and 18 women, aged 30 to 65 years, mean +/- SD 45.76 +/- 12.15 years) and 30 patients with untreated mild or moderate essential hypertension (14 men and 16 women, aged 30 to 65 years, mean +/- SD 49.50 +/- 13.58 years). Ten each of the hypertensive patients were treated with captopril, atenolol, or verapamil. Physical examination and biochemical analyses (serum Mg and Zn) were done in all participants at baseline, and in patients after 3 and 6 months of treatment. The results were compared according to a nested design with Neumann-Keuls test. We found no significant differences between controls and patients in serum and intraerythrocyte concentrations of Zn at the start of the study, although there was a significant decrease in serum Zn in patients after 3 (P < .01) and 6 months (P < .001) of treatment, regardless of the drug used. This decrease was thought to be attributable to the zincuric effect of captopril or to dietary measures, or both. Intraerythrocyte Zn was not significantly affected by antihypertensive treatment. Serum and intraerythrocyte concentrations of Mg were significantly lower (P < .001) in hypertensive than in normotensive subjects, and serum Mg in patients treated with verapamil was significantly lower (P < .05) than after treatment with captopril or atenolol. Serum Mg concentration was related directly with serum concentrations of high density lipoprotein cholesterol (r = 0.4043, P < .05). We conclude that supplementation with Mg may benefit patients with hypertension.

Comparison of the antihypertensive effects of the fixed dose combination enalapril 10 mg/nitrendipine 20 mg vs losartan 50 mg/hydrochlorothiazide 12.5 mg, assessed by 24-h ambulatory blood pressure monitoring, in essential hypertensive patients.

Fixed combinations of calcium channel blockers and angiotensin converting enzyme inhibitors represent an alternative to diuretic-based combination therapy. The aim of the present study was to compare the antihypertensive efficacy of the combination enalapril 10 mg/nitrendipine 20 mg (E/N) vs losartan 50 mg/hydrochlorothiazide 12.5 mg (L/H), assessed by 24-h ambulatory blood pressure monitoring. This multicentre, double-blind, parallel study included 97 hypertensive patients (office diastolic blood pressure (DBP) 90-109 mmHg and daytime DBP > 85 mmHg). After a 2- to 3-week period of single-blind placebo, they were randomized to receive double-blind treatment with E/N (n = 48) or L/H (n = 49) for a 4-week period. The primary outcome measure was the difference in 24-h DBP reduction between treatments from randomization to the end of the double-blind period. Secondary efficacy variables included differences in 24-h systolic (S) BP reduction, daytime, night-time and office SBP and DBP reduction, proportion of responders and controlled patients, trough-to-peak ratio and smoothness indexes. Safety was assessed by the proportion of patients with adverse events and the detection of laboratory abnormalities. No significant differences were observed in the primary outcome measure. The group receiving E/N tended to show greater reductions in most measures (24 h, daytime and office SBP and DBP) and higher BP control rates, but only the difference in the rate of office SBP control (< 140 mmHg) reached statistical significance (42.2 vs 22.4%; P = 0.048). The trough-to-peak ratios and smoothness indexes were similar in both groups. The incidence of adverse events related to the treatment was 27.1% (95% CI 14.5-39.6%) in E/N-treated patients and 14.3% (95% CI 4.5-45.8%) in the L/H group, but differences were not significant. The kind of event more frequently observed were flushing and headache in E/N, and dizziness and asthenia in L/H; all observed adverse events were mild. We conclude that E/N and L/H have a similar antihypertensive efficacy, assessed by office or ambulatory blood pressure monitoring. E/N achieved a significantly higher office SBP control rate, but this was accompanied by an apparently higher proportion of mild adverse events.

Blood pressure and urinary excretion of electrolytes in Spanish schoolchildren.

Despite the importance of hypertension in adults, its effects on child health are poorly understood. This cross-sectional epidemiological study was designed to look for a relationship between elevated blood pressure (BP) in children and 24-h urinary excretion of sodium (Na) and potassium (K), and between BP and dietary salt intake. The study population was all 59 856 schoolchildren aged 6 to 14 years in the province of Almería in southern Spain, among whom 613 participants were chosen randomly for study. We measured 24-h urinary Na and K concentrations, systolic and diastolic BP, body weight and height. There was a weak correlation between Na excretion and systolic BP (r = 0.18, 95% confidence interval 0.10-0.26), and between K excretion and systolic BP (r = 0.49, 95% CI = 0.04-0.20). Body weight was the variable that best correlated with systolic (r = 0.49, 95% CI = 0.43-0.55) and diastolic BP, and with Na excretion (r = 0.48, 95% CI = 0.42-0.55). Multiple regression analysis also showed that body weight was the variable that best correlated with systolic BP (b = 0.58), although the variables in the equation explained little of the total variability in BP (26%). These correlations were significant at P < 0.05. In conclusion urinary electrolytes correlated poorly with BP in a sample of Spanish schoolchildren. Body weight was the only variable that showed a weak relationship with BP and Na excretion.

Hypertension in the Very Elderly Trial (HYVET): protocol for the main trial.

A number of trials and meta-analyses have demonstrated clear benefits of blood pressure (BP) reduction in patients aged <80 years with regard to the reduction in stroke and cardiovascular events. However, a variety of studies have suggested that the positive relationship between BP and cardiovascular mortality is weakened or indeed reversed in the very elderly. Most intervention trials to date have either excluded or not recruited sufficient patients aged > or =80 years to determine whether there is a significant benefit from treatment in this age group. A meta-analysis of intervention trials that recruited patients aged > or =80 years has suggested a benefit in terms of stroke reduction but has also raised the possibility of an increase in total mortality. The benefit to risk ratio therefore needs to be clearly established before recommendations can be made for treating very elderly patients with hypertension. The Hypertension in the Very Elderly Trial (HYVET) pilot recruited 1283 patients aged > or =80 years and showed the feasibility of performing such a trial in this age group. It was a Prospective Randomised Open Blinded End-Points (PROBE) design but the main trial has additional pharmaceutical sponsorship to run a double-blind trial. Therefore, the main trial is a randomised, double-blind, placebo-controlled trial designed to assess the benefits of treating very elderly patients with hypertension. It compares placebo with a low dose diuretic (indapamide sustained release 1.5mg daily) and additional ACE inhibitor (perindopril) therapy if required. As in the pilot trial, the primary end-point is stroke events (fatal and non-fatal) and the trial is designed to determine whether or not a 35% difference occurs between placebo and active treatment. The main objective will be achieved with 90% power at the 1% level of significance. Secondary outcome measures will include total mortality, cardiovascular mortality, cardiac mortality, stroke mortality and skeletal fracture. 2100 patients aged > or =80 years are to be recruited and followed up for an average of 5 years. Entry BP criteria after 2 months of a single-blind placebo run-in period are a sustained sitting systolic BP (SBP) of 160 to 199mm Hg and a diastolic BP of 90 to 109mm Hg. The standing SBP must be >140mm Hg. The trial will be carried out in accordance with the principles of Good Clinical Practice. We describe in detail the protocol for the main trial and discuss the reasons for the changes from the pilot, the use of the drug regimen, and the BP criteria to be used in the trial.

ECG diagnostic errors due to improper connection of the right arm and leg cables.

Two patients were erroneously diagnosed as having acute myocardial infarction or accelerated junctional rhythm due to improper connection of the right arm and right leg cables. In both cases the error led to unsuitable modifications in treatment. A key sign for identifying the technical oversight is minimal voltage in DII in all P, QRS and T waves (dwarf complexes).

Terminal notching of the QRS complex in V1 and V2 in seborrheic patients.

Widening of the QRS complex by terminal notching in leads V1 and V2 was observed in 6 seborrheic patients with adequate personal hygiene. This anomaly disappeared when the presternal skin was degreased thoroughly with cationic detergent before placing the conductive paste and electrodes. We attribute these electrocardiographic alterations to variations in the apocrine secretions in the presternal region, which modified the resistance of the skin to electrical potentials.

Differential effects of hepatic cirrhosis on the plasma protein binding of drugs.

The binding of sulfisoxazole (sulfafurazole-INN) (100 micrograms/ml), diazepam (3 micrograms/ml) and digitoxin (0.025 micrograms/ml) has been studied in plasma from normal volunteers and from patients with hepatic cirrhosis. The free fraction of sulfisoxazole and diazepam in plasma was increased in these patients (22.9 +/- 3.0% and 6.5 +/- 0.7%) vs 6.6 +/- 0.6% and 3.1 +/- 0.2% in normal subjects, respectively), but binding of digitoxin did not greatly change (13.7 +/- 3.95% vs 13.9 +/- 2.27% in the control group). The increase in the free fraction of sulfisoxazole and diazepam correlated well with decreased serum albumin levels; but a change in albumin affinity, perhaps due to increased bilirubin levels, should also to be taken in consideration to explain this decreased drug binding in hepatic cirrhosis.

[Nocturnal arterial pressure and the cardiovascular risk factors in patients with arterial hypertension]. / Presión arterial nocturna y factores de riesgo cardiovascular en pacientes con hipertensión arterial.

BACKGROUND: Blood pressure (BP) has a circadian rhythm. Most of the people presents a BP fall between 10-20% during nighttime hours (dipper condition). Measurement of these circadian variations is performed by continuous blood pressure ambulatory monitoring. We have studied the possible relation between blood pressure nocturnal fall and cardiovascular risk factors in hypertensive patients. METHODS: We selected 100 hypertensive patients from the Hypertension and Lipids Unit of San Cecilio University Hospital of Granada, Spain. They were divided into two groups: dippers group and non-dippers, depending of whether or not the fall of nocturnal systolic and diastolic BP was > 10%. All patients included in the study underwent complete clinical history, exhaustive physical examination, complementary examinations, urine and hematology tests, and continuous blood pressure ambulatory monitoring by the Space Labs system. RESULTS: The heart rate was found to be significantly higher (p = 0.0253) in the hypertensive dippers group than in the non-dippers. The latter showed higher plasma creatinine values (p = 0.0343) and lower potassemia values (p = 0.0140) than the dippers group. The dippers group presented concentrations of HDL-cholesterol significantly higher (p = 0.008) and diurnal diastolic BP values (p = 0.0211) also higher than the other group. CONCLUSIONS: Non dippers hypertensive patients present a higher number of cardiovascular risk factors as well as a higher tendency to renal lesions, and worse prognosis than the dippers group.

Acute pancreatitis and microcrystals. Importance of the bile collection and biochemical parameters.

For a substantial number of patients with acute pancreatitis, no recognizable causes can be identified and such cases are called "idiopathic". With the introduction of duodenal bile collection for microscopic examination, it became possible to detect minor constituents of the bile, such as cholesterol and/or calcium bilirrubinate crystals. The mechanism by which crystals produce pancreatitis seems to be related to migration of aggregate crystals through the papilla, inducing papillary trauma or temporary impaction which can cause a biliopancreatic reflux. We now report a series of 45 patients with acute pancreatitis idiopathic, 120 with gallstones and 22 alcoholic. Of the patients with idiopathic pancreatitis whom we studied by biliary drainages, 22 were found to have abnormal drainages (MC+) (20 cholesterol crystals and 2 calcium bilirrubinate), 9 patients had more than 10 crystals per slide. The microcrystals positive (MC+) group had significantly higher values for AST (69.8 +/- 1.7) (mean +/- SEM), ALT (123.3 +/- 28.1), FA (252 +/- 28.1), G-GT (144.6 +/- 26.7) and BT (1.83 +/- 0.37) than the microcrystals negative group: AST (19.6 +/- 2.5), ALT (28.3 +/- 5.8), FA (170.5 +/- 15.1), G-GT (54.3 +/- 10.7) and BT (0.76 +/- 0.09). The more 10 crystals group had higher values (AST: 82.0 +/- 29.1, ALT: 143.1 +/- 43.5, FA: 294.8 +/- 57.2, G-GT: 171.8 +/- 38.4, BT: 2.61 +/- 0.82) than in the microcrystals negative group. We concluded that in the absence of other overt causes, the presence of crystals in bile of patients with pancreatitis justifies etiology. The number is not important.

[20 cases of carcinoid tumors of the digestive system]. / Estudio de 20 casos de tumores carcinoides de aparato digestivo.

We are presenting 20 cases of carcinoid tumors of the digestive system. We shall evaluate: age, sex, localization and histopathology, symptomatology, therapeutics and evolution. Appendicular carcinoids were the most frequent: 13 cases. All were chance findings in the histopathological examination of surgically resected appendix in eight acute appendicitis and in four laparotomies for other reasons. Histologically the classic pattern predominated, with formation of cellular nidus, with the cells being argentaffin. These characteristics permit classifying them as tumors derived from the embrionary middle intestine. No appendicular carcinoid developed metastasis. The extirpation was always curative, partially due to the small size and to the facility of obstructing the appendicular lumen. Four cases were gastric carcinoids. Their cells grouped forming trabeculas or were arranged irregularly, being negative for argyrophil and argentic tinction (tumors derived from the cephalic intestine). Two of them presented associated peptic ulcer (histamine implication). The two remaining ones came for studies related to asthenia, anorexia and weight loss, and in both cases hepatic metastasis without carcinoid syndrome were found. Two less frequent localizations were Meckel's diverticulum and ampulla of Vater. The latter developed hepatic metastasis without carcinoid syndrome. The only carcinoid syndrome was found in a patient who died due to adult respiratory distress without having localized the primary tumor.

[Does the diuretic effect of calcium inhibitors play an important role in the hypertensive efficacy?]. / L'effet diurétique des inhibiteurs calciques joue-t-il un rôle important dans l'efficacité antihypertensive?

Calcium ions play an important role in the pathophysiology of hypertension. Calcium antagonists, a group of first line drugs in the treatment of hypertension, reduce the intracellular content of calcium in vascular smooth muscle cells, and decrease the peripheral vascular resistance and blood pressure. These drugs differ from other vasodilators in that they also have natriuretic effects; thus they can affect the kidney on three levels: Renal haemodynamics are affected by increased renal blood flow, and increased glomerular filtration rate. Changes in the renin-angiotensin system can decrease aldosterone secretion. Finally, they affect sodium management by acting directly on the renal tubule, increasing sodium excretion and inhibiting tubular reabsorption of this ion. The natriuretic effect of calcium antagonists is independent of the subject's sodium balance. The vasodilating action of these drugs is therefore accompanied by a natriuretic effect that makes satisfactory control of hypertension possible without placing the patient on a low-salt or salt-free diet.