Angiotensin-converting enzyme inhibitor associated cough: deceptive information from the Physicians' Desk Reference

Background

Dry cough is a common, annoying adverse effect of all angiotensin-converting enzyme (ACE) inhibitors. The present study was designed to compare the rate of coughs reported in the literature with reported rates in the Physicians' Desk Reference (PDR)/drug label.

Methods

We searched MEDLINE/EMBASE/CENTRAL for articles published from 1990 to the present about randomized clinical trials (RCTs) of ACE inhibitors with a sample size of at least 100 patients in the ACE inhibitors arm with follow-up for at least 3 months and reporting the incidence or withdrawal rates due to cough. Baseline characteristics, cohort enrolled, metrics used to assess cough, incidence, and withdrawal rates due to cough were abstracted.

Results

One hundred twenty-five studies that satisfied our inclusion criteria enrolled 198,130 patients. The pooled weighted incidence of cough for enalapril was 11.48% (95% confidence interval [CI], 9.54% to 13.41%), which was ninefold greater compared to the reported rate in the PDR/drug label (1.3%). The pooled weighted withdrawal rate due to cough for enalapril was 2.57% (95% CI, 2.40-2.74), which was 31-fold greater compared to the reported rate in the PDR/drug label (0.1%). The incidence of cough has increased progressively over the last 2 decades with accumulating data, but it has been reported consistently several-fold less in the PDR compared to the RCTs. The results were similar for most other ACE inhibitors.

Conclusion

The incidence of ACE inhibitor-associated cough and the withdrawal rate (the more objective metric) due to cough is significantly greater in the literature than reported in the PDR/drug label and is likely to be even greater in the real world when compared with the data from RCTs. There exists a gap between the data available from the literature and that which is presented to the consumers (prescribing physicians and patients).     

Decision-making dysregulation in first-episode schizophrenia

Studies with chronic schizophrenia patients have demonstrated that patients fluctuate between rigid and unpredictable responses in decision-making situations, a phenomenon which has been called dysregulation. The aim of this study was to investigate whether schizophrenia patients already display dysregulated behavior at the beginning of their illness. Thirty-two first-episode schizophrenia or schizophreniform patients and 30 healthy controls performed the two-choice prediction task. The decision-making behavior of first-episode patients was shown to be characterized by a high degree of dysregulation accompanied by low metric entropy and a tendency towards increased mutual information. These results indicate that behavioral abnormalities during the two-choice prediction task are already present during the early stages of the illness.     

Adenylate cyclase and guanylate cyclase activity in normal and leukemic human lymphocytes

Adenylate cyclase (AC) and guanylate cyclase (GC) activities were studied in normal B-enriched and T-enriched lymphocytes, in lymphocytes of children with acute lymphocytic leukemia (ALL), and in lymphocytes of adults with chronic lymphocytic leukemia (CLL). AC activity was greater in normal B than T lymphocytes (215 pmole/min/mg protein versus 80 pmole in the membrane-enriched fraction) and i both increased greatly after stimulation with isoproterenol and more so with prostaglandins E and F2 alpha. In leukemic lymphocytes, AC showed depressed activity (20 pmole in ALL cells and 55 pmole in CLL cells) and was less sensitive to hormonal stimulation: this loss of sensitivity occurred to a greater extent in ALL than in CLL lymphocytes. GC activity was greater in normal T than B cells (in membrane-enriched fraction: 10.2 pmole versus 5.3 pmole). It increased little with isoproterenol and prostaglandins stimulation, and much more with sodium azide and dehydroascorbic acid stimulation. GC activity was increased in both types of leukemic lymphocytes (23 pmole for ALL cells and 18 pmole for CLL cells) and was insensitive to stimulation. Possible derangement of cyclase and cyclic nucleotide regulation in leukemic cells is suggested.     

Body weight changes with beta-blocker use: results from GEMINI

Purpose

Patients with type 2 diabetes are commonly overweight, which can contribute to poor cardiovascular outcomes. β-blockers may promote weight gain, or hamper weight loss, and are a concern in high-risk patients. The current analysis of the Glycemic Effect in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial evaluates the effects of carvedilol and metoprolol tartrate on weight gain in patients with type 2 diabetes and hypertension.

Methods

This prespecified secondary analysis of the GEMINI study (n=1106) evaluated change in body weight after 5 months.

Results

Mean (±SE) baseline weights were 97.5 (±20.1) kg for carvedilol and 96.6 (±20.1) kg for metoprolol tartrate. Treatment difference (c vs m) in mean (±SE) weight change from baseline was −1.02 (±0.21) kg (95% confidence interval [CI], −1.43 to −0.60; P <.001). Patients taking metoprolol had a significant mean (±SE) weight gain of 1.19 (±0.16) kg (P <.001); patients taking carvedilol did not (0.17 [±0.19] kg; P =.36). Metoprolol tartrate-treated patients with body mass index (BMI) >30 kg/m² had a statistically significant greater weight gain than comparable carvedilol-treated patients. Treatment differences (c vs m) in the obese (BMI >30 kg/m²) and morbidly obese groups (BMI >40 kg/m²) were −0.90 kg (95% CI, −1.5 to −0.3; P =.002) and −1.84 kg (95% CI, −2.9 to −0.8; P =.001), respectively. Pairwise correlation analyses revealed no significant associations between weight change and change in HbA_1c, HOMA-IR, or blood pressure.

Conclusions

Metoprolol tartrate was associated with increased weight gain compared to carvedilol; weight gain was most pronounced in subjects with hypertension and diabetes who were not taking insulin therapy.     

Primary optic nerve decompression in mid-face fractures

In severe craniofacial-frontobasal injuries the optic nerve is quite often damaged. We report the findings and the visual outcome in 21 patients with severe mid-face fractures, who underwent primary optic nerve decompression after showing an afferent pupillary defect. During the subcranial exploration and the optic nerve decompression, fractures of the optic canal were found in 13 cases; a dislocated bone fragment could be removed in 6 patients. 9 eyes remained blind, but another 9 eyes regained good final visual acuity between 0.5 and 1.0. We conclude that fractures of the optic canal and dislocated bone fragments are often causes of optic nerve damage in mid-face injuries. The primary subcranial decompression of the optic nerve is a safe method to prevent secondary damage.     

Validation of the PHQ-9 as a screening instrument for depression in diabetes patients in specialized outpatient clinics

Background  

For the treatment of depression in diabetes patients, it is important that depression is recognized at an early stage. A screening method for depression is the patient health questionnaire (PHQ-9). The aim of this study is to validate the 9-item Patient Health Questionnaire (PHQ-9) as a screening instrument for depression in diabetes patients in outpatient clinics.     

Mineral balance and whole body bone mineral content in very low-birth-weight infants

Fat and mineral metabolic balance studies were performed in 25 normal very low-birth-weight infants ( 1500 g at birth) fed either pooled pasteurized human milk supplemented with calcium, phosphorus and magnesium, or a preterm formula. Calcium, phosphorus and magnesium intake were similar in both groups and averaged 100mg/kg/day, 72 mg/kg/day and 8 mg/kg/day, respectively. Calcium and phosphorus retention was higher in the subjects fed fortified human milk than in those receiving a preterm formula (65±14 and 62±9mg/kg/day versus 55±12 and 47±7mg/kg/day respectively). The difference was only significant for phosphorus. Magnesium retention was similar in the two groups and averaged 3 mg/kg/day. Fat intake and absorption was significantly higher in the preterm formula fed group than in the one fed fortified human milk (5.5±0.4 g/kg/day and 88±4% versus 4.2±1 g/kg/day, 79±6% respectively). Assessment of the whole body bone mineral content by dual energy X-ray absorptiometry was performed at 3 and 6 months of age in another group of 25 low-birth-weight infants fed either fortified human milk or a preterm formula. Whole body bone mineral content (BMCt) was low (43.3±30.8 g of hydroxyapatite) at 3 months of age (theoretical term) compared to normal full-term newborns at birth. There was no significant influence of the diet. At 6 months of age, BMCt reached 168.6±36.6g, a value similar to that of full-term newborns, with no significant difference between the two regimen groups. The deficit in the 12 subjects who had a BMCt under 30 g at 3 months of age had been corrected at age 6 months. Premature babies fed a pooled pasteurized human milk enriched with calcium, phosphorus and magnesium favored a better retention of calcium and phosphorus. However, no significant influence of the two diets studied was observed on the gain in BMCt over the first 6 months of life.     

Morphometric estimation of regional differences in the rat lung

To provide a safe basis for the sampling of tissue in future morphometric investigations of the rat lung, we searched for quantitative regional differences in pulmonary structure at light microscopic (LM) and electron microscopic (EM) levels. The lungs of 11 male rats about 6 weeks of age were fixed by standard intratracheal instillation of glutaraldehyde in the supine position and embedded either in paraffin for LM or in epoxy resin for EM investigation. Sampling of tissue was designed to test for differences between lobes and between central and peripheral lung parenchyma. LM morphometry was performed by manual point counting and by using a version of an improved automated image analyzer, Quantimet 720. EM morphometric results were obtained by manual point and intersection counting only. LM point counting showed that the proportion of parenchyma was highly constant in all lobes, varying only between 79.9% and 81.5%. In the left lung, which was partitioned into two equal halves, the amount of parenchyma was significantly lower in the apical region (mean values, 72.6% compared to 83.1%; p less than 0.002), which regularly contained the hilum. Quantimet analysis of central and subpleural lung portions revealed intralobar differences. The volume density of interalveolar septa and the air space surface density were significantly decreased in subpleural compared to central lung regions (by 7% and 4.6%, respectively). EM morphometry demonstrated that the interalveolar septa were evenly structured in all lobes except for the harmonic mean thickness of the air-blood barrier, which was lower in upper lobes. In addition, the volume density of interstitial cells was found to be significantly increased in central compared to peripheral parenchyma. The results indicate that for quantitative LM analysis the smallest possible sampling unit is an entire lobe. For EM morphometry, the often practiced approach to consider information drawn from one lobe representative for the whole lung seems to be appropriate for most parameters. In view of the structural differences between central and peripheral lung parenchyma, however, attention has to be paid to applying a properly weighted sampling procedure. Depending on the size of the lobe, the peripheral mantle (2 mm thick) can represent up to 75% of the lobar volume.