A safety assessment of fixed combinations of acetaminophen and acetylsalicylic acid, coformulated with caffeine.

Overuse and abuse of phenacetin-containing mixed analgesics has contributed to end-stage renal disease. Combination analgesics, especially those coformulated with caffeine, have been implicated as imparting a greater risk of analgesic-associated nephropathy (AAN) than single or coformulated analgesics without caffeine. This has led to a recommendation that the sale of "two plus caffeine" analgesic mixtures be reclassified from over-the-counter to prescription only availability. There is a rational basis for coformulating acetylsalicylic acid (ASA) and acetaminophen (paracetamol) as this reduces the dose of each, without altering efficacy. The coformulation of caffeine with these analgesics has a significant adjuvant effect and increases analgesic efficacy 1.4-1.6-fold. Currently available animal and human data do not support the notion that the nephrotoxic risk from coformulated ASA and acetaminophen is higher than the risk from either ASA or acetaminophen alone, in equivalent analgesic doses. There are no epidemiological data that implicate caffeine in AAN, and only limited evidence that links excessive acetaminophen usage to renal disease. There is no evidence that caffeine increases analgesics papillotoxicity directly. The presence of caffeine in mixtures of analgesics are no more addictive than other sources of caffeine. There is no evidence to suggest that adding caffeine to analgesic mixtures enhances the potential for promoting analgesic misuse in the general population. Thus distinct therapeutic benefits of ASA, acetaminophen and caffeine appear to outweigh any known risk. It is doubtful if preventing the availability of these products will significantly affect the role of analgesic abuse/overuse in end-stage renal disease. Better risk management would come from a focused educational program, developed in a close collaboration between industry, healthcare professionals and consumer organizations, such a program must warn against the potential dangers of analgesic and non-steroidal anti-inflammatory drug misuse.

Pain assessment after intramuscular injection.

Several parameters (pH, osmotic pressure) influencing the local tolerance of injectable drugs have been well-documented; however, little attention has been paid to pain following an injection--a common problem in clinical practice. A pain questionnaire was used to record pain up to 24 h after a deep ventrogluteal injection. Two groups of healthy volunteers were recruited: the first group (n = 6) received 3 different cotrimoxazole preparations and placebo and the second group (n = 10) received 4 different multivitamin preparations and placebo (double-blind, cross-over). Parameters monitored during and after injection included pain localization (line drawing), pain intensity (visual-analog scale: VAS) and verbal description of pain (pain rating index: PRI). In both groups, the equality of pain (VAS, PRI) induced by the preparations was rejected in all cases (Friedman's test, p < or = 1%). The pairwise comparisons of the groups showed significant differences (p < or = 5%) between various preparations. The correlation (Spearman's rank correlation) between pain parameters VAS and PRI was high. The present investigations have shown that the pain questionnaire is a valuable tool to investigate the subjective pain symptoms during and after the injection of different preparations.

Multiple biochemical blood testing as a case-finding tool in ambulatory medical patients.

PURPOSE: The usefulness and costs of multiple biochemical blood tests as a case-finding tool in ambulatory medical patients are not well known. Recommendations are lacking or based upon results of screening asymptomatic persons. We designed a study to determine prospectively the yield, potential disadvantages, and patient charges of routine biochemical testing at our medical outpatient clinic. PATIENTS AND METHODS: Twenty-three biochemical parameters were evaluated in 493 consecutive patients. Parameters not considered indicated for diagnostic or management purposes by the staff physicians at the first visit were classified as routine tests. The main outcome measures were the number and the nature of new diagnoses leading to a new management, the number of additional tests and visits, and patient charges. RESULTS: New diagnoses resulting in new management were found in 25 patients (5%). They were mainly lipid disorders. Seven additional visits and 74 further tests were caused by abnormal results of routine tests. The net charges for the detection of the new diagnoses leading to new management were $12,682. Secondary analysis revealed that the determination of only three routine tests (cholesterol, glucose, alanine aminotransferase) would have detected all clinically important diagnoses and would have reduced the charges by 30%. CONCLUSIONS: Routine biochemical testing is a useful case-finding tool with acceptable costs in middle-aged medical outpatients of a university teaching setting. However, the spectrum of newly detected disorders leading to changes in patient management is small. The results suggest that a reduced routine battery consisting of cholesterol, glucose, and alanine aminotransferase might be preferable because it will detect the clinically important diagnoses and lead to a substantial reduction of patient charges.

[Does routine ultrasonography of the abdominal organs affect the subsequent management of the patient?]. / Beeinflusst die routinemässige Sonographie abdominaler Organe die weitere Patientenbetreuung?

When abdominal ultrasound is performed it is general practice to examine not only the organs needed to answer the clinician's question but also the remaining abdominal and pelvic organs for which there is no clinical indication (= routine examinations). We investigated the effect of these routine examinations on the further management in 533 medical outpatients (222 women; 311 men; age 45 +/- 16 years). Of 7684 organs examined, 6194 (81%) were routine examinations, 469 of which revealed unexpected abnormalities. Only 19 of these were considered clinically relevant enough to warrant further work-up, and long-term follow-up was regarded as necessary in 6 patients only. However, an abnormal finding on routine examination had no eventual therapeutic implications in any patient. We conclude that in middle-aged medical outpatients it is sufficient to perform sonography on those abdominal and pelvic organs which need to be examined to answer the clinician's questions. Failure to routinely examine the remaining organs does not lead to a relevant loss of information, but may save time and money on fruitless work-up of unexpected findings.

[Is flexible sigmoidoscopy as preventive measure for colorectal carcinoma in asymptomatic patients over 45 practicable?]. / Ist die flexible Sigmoidoskopie bei über 45jährigen asymptomatischen Patienten als Vorsorgeuntersuchung für kolorektale Karzinome praktikabel?

The efficacy of flexible sigmoidoscopy as a screening method for colorectal cancer is still undetermined, and a reduction in mortality due to this cancer by mass screening has not been demonstrated so far. An important precondition for the practicability of screening sigmoidoscopy is its acceptability by the persons to be screened. Acceptability was tested in 294 volunteers without abdominal symptoms from a general medical outpatients clinic. Mean age of participants was 58 years (45-86), 65% were men and 35% women. Sigmoidoscopy was judged harmless by 221 persons (75.1%), painful by 62 (21.1%), very painful by 11 (3.7%), and unacceptable by none. Every participant would have agreed to repeat the examination. In 36 patients 52 polyps were detected, comprising one carcinoma, 18 adenomas (in 15 patients), 32 hyperplastic polyps and one lipoma. We conclude that sigmoidoscopy was well accepted in this study and should be evaluated further as a mass screening method for colorectal cancer.

Quality of emergency room triage of medical inpatients to an acute care clinic or chronic health care facilities.

OBJECTIVE: To evaluate the accuracy of emergency room triage by general internists assigning medical patients to four different health care settings. DESIGN: Prospective trial. SETTING: Medical emergency room of a university hospital providing primary and referral care. PATIENTS: 974 consecutive patients admitted for acute medical care, excluding patients admitted to intensive care units. INTERVENTION AND MEASUREMENTS: After primary evaluation patients were assigned to one of four groups: A) acutely ill requiring acute care in a general medical ward (n = 598); B) acutely ill requiring acute care limited to two to three days (n = 201); C) chronically ill with realistic chances for rehabilitation (n = 77); and D) chronically ill requiring definite referral to skilled nursing home care (n = 98). Nine months later, outcome and placement after index hospitalization were evaluated in surviving patients. MAIN RESULTS: 159 (16%) patients died; three (1%) were lost to follow-up. Evolution confirmed the appropriateness of the initial triage of 90% of the remaining 812 patients (83%). Allocations were correct in 96%, 95%, and 91% of cases in groups A, B, and C, respectively. In group D, only 44% were definitely transferred to nursing homes; 56% were rehabilitated and returned to their previous social settings or entered homes for the aged. CONCLUSIONS: Clinical judgment of general internists in an emergency room adequately identifies patients requiring acute care of regular or short duration and chronically ill patients with realistic prospects for rehabilitation. But the need for nursing home placement is overestimated. To avoid patient misplacement the authors propose direct access to a specialized geriatric assessment facility.

[Diagnostic value of emergency ultrasonography of the abdomen]. / Diagnostische Wertigkeit bei dringlich durchgeführter abdominaler Sonographie.

We evaluated the diagnostic usefulness of abdominal ultrasound performed by trained MDs at a general internal medicine clinic in 104 patients with acute abdominal problems. In 30% (31 patients) sonography was diagnostic or was able to guide the further evaluation of the patient. Most diagnoses concerned problems of the nephrologic, urologic or hepatobiliary systems. In 70% (73 patients) sonography was normal or showed unimportant findings; none of these patients had a final diagnosis which should have been detected by sonography. Only 10 of these 73 patients had a diagnosis which needed specific treatment (urinary tract infection n = 5, peptic ulcer disease n = 3, carcinoma of the colon n = 2). In conclusion, sonography proved to be a very useful, highly diagnostic and reliable method even when performed by non-radiologists.

[Oat bran as lipid-lowering agent?]. / Haferkleie als Lipidesenker?

Hypercholesterolemia is one of the major risk factors for ischemic heart disease and for the development of atherosclerotic plaques. Water soluble plant fibers do exert a binding of intestinal cholesterol and are not digested or metabolized. We have investigated the effect of a highly water soluble fiber containing oat brain on serum cholesterol concentrations in 14 volunteers (nine males, five females, age 39 to 67 years, serum cholesterol concentration: 7.14 +/- 0.80 mmol/l; x +/- SD) during an intervention with 50 g oat brain per day for nine weeks. We have documented in the whole study population a modest, but significant reduction of serum cholesterol levels of 4.2% (p less than 0.05) at six weeks; however at nine weeks the efficacy of this regimen was less pronounced (3.2%, p = n.s.) speaking for a decreased compliance although this regimen was well tolerated and accepted. In subsets of high risk volunteers for coronary heart disease of male gender (n = 9), with hypercholesterolemia (n = 8) or essential hypertension (n = 8) the reduction of serum cholesterol levels was more consistent (5.6%, p less than 0.05) with no change in normolipemic volunteers.

Effect of acitretin on the response to an intravenous glucose tolerance test in healthy volunteers.

The effect of the synthetic retinoid acitretin (A) on the disposition of blood glucose and on the serum insulin response following the IV infusion of 139 mmol glucose over 10 min (IGTT) has been investigated in six healthy subjects. The IGTT was performed on Days 1, 10 and 24. On Days 3 to 10 A 50 mg/d was administered. Several parameters of glucose disposition and insulin response (K-values, AUC) were assessed. As a methodological variant, the profiles over time of blood glucose and serum insulin were evaluated by model calculations using the 'minimal model'. Acitretin did not influence any parameter of glucose disposition. The area under the insulin-time curve (baseline corrected) was significantly decreased from 1.20 mU.min.l-1 on Day 1 to 0.89 mU.min.l-1 on Day 10, and was 0.91 mU.min.l-1 on Day 24. The model-derived 'insulin sensitivity' increased from 13.10(-4) l.mU-1.min-1 on Day 1 to 20.10(-4) l.mU-1.min-1 on Day 10 and was 18.10(-4) l.mU-1.min-1 on Day 24. The results suggest that A increased sensitivity to endogenous insulin. It supports a recent report showing greater insulin sensitivity in patients treated with the synthetic retinoid etretinate.

Usefulness of complete blood counts as a case-finding tool in medical outpatients.

OBJECTIVE: To determine the usefulness of routine complete blood counts as a case-finding tool in medical outpatients. DESIGN: Prospective evaluation in a consecutive, unselected cohort. SETTING: A university-based outpatient clinic providing primary and referral care in general internal medicine. PATIENTS: A total of 595 patients (mean age [+/- SD], 40 +/- 15 years) making their initial clinic visit. INTERVENTION: A complete blood count was done in all patients. Components of the complete blood count that were not indicated for diagnostic or management purposes at the initial visit were classified as routine tests. MAIN OUTCOME MEASURES: The number and nature of new diagnoses leading to new patient management; the number of additional visits and diagnostic tests precipitated by positive results. MAIN RESULTS: Of the 2378 tests done, 1540 (65%) were routine tests. The percentages of abnormal test results for the four hematologic test components were as follows: leukocyte count, 7.6%; hemoglobin, 5.8%; mean corpuscular volume (MCV) of red blood cells, 7.9%; and platelet count, 4.5%. In only three patients (0.5%) was a new diagnosis made that led to a new management strategy (treatment of iron deficiency). Further work-up was unprofitable in 14 patients (2.4%). Two additional visits were necessary because of abnormal results on routine tests. No abnormality-associated clinical disease developed during a 15-month follow-up period in patients with unexplained abnormal results on routine hematologic tests. CONCLUSIONS: The routine complete blood count has limited usefulness as a case-finding tool and has a minimal effect on care in middle-aged medical outpatients.

High frequency of human immunodeficiency virus-associated autonomic neuropathy and more severe involvement in advanced stages of human immunodeficiency virus disease.

We conducted a controlled trial to determine frequency and severity of autonomic neuropathy in patients infected with the human immunodeficiency virus (HIV). We studied 25 HIV-seropositive patients and 10 seronegative controls in HIV risk groups by means of five cardiovascular tests, and autonomic neuropathy was graded with a scoring system. The overall autonomic test score differed between patients and controls and was higher in patients with advanced (Centers for Disease Control class IV) disease than in those with earlier (class II or III) HIV disease. Of the patients, 60% had findings of autonomic dysfunction. Our data demonstrate a high prevalence of autonomic neuropathy in HIV-infected patients. Advanced HIV disease is associated with more severe involvement than earlier disease states.

[Quality of treatment in hypercholesterolemia in ambulatory patients]. / Qualität der Behandlung von Hypercholesterinämien bei ambulanten Patienten.

In 1989 serum cholesterol was determined as a routine procedure in 534 consecutive patients. The response of the physicians to elevated cholesterol levels and factors associated with a treatment decision were analyzed. A follow-up was obtained in treated patients after at least one year. 105 patients (20%) had hypercholesterolemia, 84 of whom were available for evaluation; only in 34 (40%) was treatment initiated. Patients were more likely to be treated (p less than 0.05) if they had cholesterol greater than 1 mmol/l above normal, if they were between 41 and 50 years old, and if cholesterol had been determined at the physician's special request. The decision to treat was not influenced by sex, presence of further risk factors or by manifest atherosclerosis. After one year, 11 of 26 patients were still well controlled and treated. Their mean cholesterol level was significantly lower as compared to pretreatment levels. We conclude that initial as well as long-term management of patients with hypercholesterolemia should be improved.

Epidemiologic study of analgesic abuse: mortality study in 7275 working women (1968-1987).

In a prospective, longitudinal investigation over a period of 20 years in 7275 working women 30 to 49 years old, we examined the effect of the ingestion of analgesics on cause-specific mortality. Evidence of intake of phenacetin and salicylate containing analgesics was obtained at a urine screening in 1967 and was shown to relate to intake between 1968 to 1978. Life table analysis of the effect of phenacetin intake on overall mortality showed significant differences between the groups of women with intake (N = 613) versus no intake (N = 4175): for total [relative risk (RR) = 2.1, P less than 0.001], urorenal (RR = 24.4, P less than 0.001), cardiovascular (RR = 4.5, P less than 0.001), and cancer mortality (RR = 1.9, P less than 0.001). No significant effects on overall or cause-specific mortality were found for salicylate intake. These results make a causal relationship between the amount of analgesic containing phenacetin consumed and the risk of death from urorenal disease likely. Furthermore, the data show an elevated risk for cardiovascular disease and cancer for phenacetin intake. No such relationships are demonstrable for the use of salicylate.

An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987)

BACKGROUND: Phenacetin abuse is known to produce kidney disease; salicylate use is supposed to prevent cardiovascular disease. We conducted a prospective, longitudinal epidemiologic study to examine the effects of these drugs on cause-specific mortality and on cardiovascular morbidity. METHODS: In 1968 we evaluated a study group of 623 healthy women 30 to 49 years old who had evidence of a regular intake of phenacetin, as measured by urinary excretion of its metabolites, and a matched control group of 621 women. Salicylate excretion was also measured. All subjects were examined over a period of 20 years. RESULTS: Life-table analyses of mortality during the 20 years, with adjustment for the year of birth, cigarette smoking, and length of follow-up, revealed significant differences between the groups in overall mortality (study group vs. control group, 74 vs. 27 deaths; relative risk, 2.2; 95 percent confidence interval, 1.5 to 3.3), deaths due to urologic or renal disease (relative risk, 16.1; 95 percent confidence interval, 3.9 to 66.1), deaths due to cancer (relative risk, 1.9; 95 percent confidence interval, 1.1 to 3.3), and deaths due to cardiovascular disease (relative risk, 2.9; 95 percent confidence interval, 1.5 to 5.5). The relative risk of cardiovascular disease (fatal or nonfatal myocardial infarction, heart failure, or stroke) was 1.8, and the 95 percent confidence interval 1.3 to 2.6. The odds ratio for the incidence of hypertension was 1.6, and the 95 percent confidence interval 1.2 to 2.1. The effects of phenacetin on morbidity and mortality, with adjustment for base-line salicylate excretion, were similar. In contrast, salicylate use had no effect on either mortality or morbidity. CONCLUSIONS: Regular use of analgesic drugs containing phenacetin is associated with an increased risk of hypertension and mortality and morbidity due to cardiovascular disease, as well as an increased risk of mortality due to cancer and urologic or renal disease. The use of salicylates carries no such risk.

[Adrenal cortex and gonadal function in HIV infected patients]. / Nebennierenrinden- und Gonadenfunktion bei HIV-infizierten Patienten.

Several studies have demonstrated diminished gonadal or adrenal function in patients infected with the human immunodeficiency virus (HIV). We have evaluated gonadal and adrenal function in 18 unselected ambulatory patients seropositive for HIV and clinically categorized as asymptomatic (n = 6), AIDS-related complex (ARC, n = 8) or acquired immunodeficiency syndrome (AIDS, n = 4). None of the patients was critically ill at the time of the hormone studies. Adrenal function was assessed using the 30 minute ACTH-test, and gonadal function by determination of the free testosterone serum level, both simple screening tests easily performable in practice. All male patients had normal free testosterone serum levels. In 5 (29%) of 17 patients (one asymptomatic, 3 with ARC, and 1 with AIDS) serum cortisol concentrations responded subnormally to synthetic ACTH, suggesting diminished adrenal cortisol reserve. The etiological role of the cytomegalovirus (CMV), which is said to be the most frequent cause of adrenal insufficiency in these patients, was unclear in our patients, because 4 of the 5 cases with the subnormal as well as 11 of the 12 with the normal test had antibodies against CMV in serum.

Pharmacokinetic modelling of the plasma concentration-time profile of the vitamin retinyl palmitate following intramuscular administration.

Seven healthy male volunteers (21-24 y) received by the ventro-gluteal route a single dose of 100,000 I.U. of the vitamin retinyl palmitate (RP) in a water-miscible preparation (W) and 5 weeks later the same dose in an oily solution (S). After administration of W median (range) peak plasma concentrations of 5.6 (4.4-8.7). 10(3) micrograms l-1 were reached after 12 h and high levels persisted for another 50 h. At 144 h levels were still, by a factor 3, higher than baseline. Plasma levels of RP after S remained close to baseline (20-50 micrograms.l-1) suggesting negligibly low bioavailability. The plasma level profile of RP after W could well be described by use of a one-compartment model with Weibull-type absorption and Michaelis-Menten elimination. The median (range) absolute bio-availability (estimates of lower limits) was 42 (32-52) per cent.

[Asymptomatic microhematuria: follow-up in 39 patients]. / Asymptomatische Mikrohämaturie: Verlaufsbeobachtung bei 39 Patienten.

We have studied 39 patients with asymptomatic microhematuria (AM) over a mean period of 3.7 years (2.6 to 5.3). In 28 patients, the etiology of the AM had remained unknown despite extensive work-up at the time of AM diagnosis. During follow-up, the urine was examined by the dipstick method and a urine sediment was prepared by standard techniques. Erythrocyturia was judged as grade I or grade II (3-9 or less than 9 erythrocytes/hpf) and classified by phase-contrast microscopy as glomerular or non-glomerular (greater than 30% or less than 30% of erythrocytes with glomerular characteristics). The results were as follows. All patients were in good health during the whole follow-up. None developed significant proteinuria or gross hematuria. AM persisted in 28 of the 39 patients (72%) and in 22 of the 28 with AM of unknown etiology (79%). Persistence of AM was independent of grade and morphology of AM. Among the patients with AM of unknown cause, the fifteen who initially showed grade I AM had grade I AM in 92% and grade II AM in 8% of follow-up urinalyses, and the seven with grade II AM at the first examination had grade II AM in 65% and grade I AM in 35% of follow-up urinalyses (p = 0.007). The last morphologic classification of AM corresponded to the first in all patients with grade II AM, but only in 74% of patients with grade I AM. The following conclusions were drawn. (1) Most AM of unknown etiology persists over several years irrespective of grade and morphology of erythrocyturia.(ABSTRACT TRUNCATED AT 250 WORDS)

[Etiology of diarrheal diseases in immunocompetent and HIV-positive patients]. / Atiologie von Durchfallserkrankungen bei immunkompetenten und HIV-positiven Patienten.

In 1986 and 1987 the stool samples of 206 patients of the Medical Outpatient Clinic Basel were examined prospectively for bacteria, protozoa and worms. Clinical data of the patients were recorded by questionnaire. The patient group comprised 63 immunocompetent patients as well as 23 HIV-infected patients, all with symptoms of acute enteritis. The control group consisted of 120 healthy persons. Pathogenic organisms were found in the stools of 17.5% of the immunocompetent patients with enteritis. The most common germs were Campylobacter jejuni, Giardia lamblia and Salmonella enteritidis. Isospora belli, found in 2 cases (8.7%), was the only pathogen found in HIV-infected patients. The most frequent pathogen found in 7.5% of the control group was Giardia lamblia. The facultative pathogenic protozoon Blastocystis hominis was found in 16.7-19.0% of the 3 groups. There was no correlation between clinical symptoms and the results of stool examinations. Stool examinations in the immunocompetent patients corresponded to the known distribution of pathogenic germs in Switzerland. The homogeneous distribution of Blastocystis hominis in the 3 groups examined proves the high rate of infection. There is no evidence of a significant correlation between clinical symptoms of enteritis and infection with Blastocystis hominis in immunocompetent patients.

Effects of timing of food and fluid volume on cefetamet pivoxil absorption in healthy normal volunteers.

Cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 16 male subjects (age, 23.4 +/- 1.7 years; weight, 73.9 +/- 7.0 kg) 1 h before (BE), with (WI), and 1 h after (AF) a standard breakfast. The time to peak concentration of cefetamet in plasma (Tmax) was increased from 3.25 +/- 1.44 h in the BE group to 4.31 +/- 1.54 and 4.13 +/- 1.54 h in the WI and AF groups, respectively (P less than 0.05). The maximum cefetamet concentration in plasma (Cmax) and the area under the plasma cefetamet concentration-time profiles (AUC) in the BE, WI, and AF groups were 5.50 +/- 1.06, 5.47 +/- 1.4, and 6.57 +/- 0.93 micrograms/ml and 38.2 +/- 10.1, 35.7 +/- 11.9, and 42.8 +/- 6.8 micrograms.h/ml, respectively. The Cmax and AUC values were not different between the BE and WI groups (P greater than 0.05). However, differences in these values were found between the WI and AF groups (P less than 0.05). The effect of fluid volume intake on cefetamet pivoxil (1,000 mg orally) absorption was evaluated in 12 male subjects (age, 23.8 +/- 2.3 years; weight, 74.9 +/- 9.0 kg) under fasted and WI conditions. Increasing fluid volume intake from 250 to 450 ml under the fasted condition had no effect on the absorption of the prodrug (Tmax, 2.50 +/- 0.52 versus 2.83 +/- 0.94 h; Cmax, 4.89 +/- 1.04 versus 4.84 +/- 0.89 micrograms/ml; AUC, 29.6 +/- 5.1 versus 30.7 +/- 7.1 micrograms.h/ml; P greater than 0.05. Thus, independent of fluid volume intake, cefetamet pivoxil absorption is enhanced when it is given within 1 h of a meal, and it is recommended that the prodrug should be taken during this period of increased bioavailability.