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Does atorvastatin influence serum lipoprotein(a) levels?

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A pharmacist developed occupational asthma and rhinitis after working with a number of oriental herbal materials.

The Effect of Atorvastatin on Serum Lipids, Lipoprotein(a) and Plasma Fibrinogen Levels in Primary Dyslipidaemia -- A Pilot Study Involving Serial Sampling

J. A. Goudevenos, Department of Internal Medicine; E. Th. Bairaktari, Biochemistry Laboratory, Medical School, University of Ioannina, Ioannina, Greece; K. G. Chatzidimou, Department of Internal Medicine; H. J. Milionis, D. P. Mikhailidis, and M. S. Elisaf, Department of Molecular Pathology and Clinical Biochemistry, Royal Free and University College Medical School and the Royal Free Hampstead NHS Trust, London, UK.

[Current Medical Research and Opinion 16(4):269-275, 2001. © 2001 LibraPharm Limited]


We conducted an open-label study to test the effects of atorvastatin on serum lipids, lipoprotein(a) [Lp(a)] and plasma fibrinogen levels. A total of 90 dyslipidaemic, non-smoking patients (45 patients with primary hypercholesterolaemia and 45 patients with primary mixed hyperlipidaemia) aged 48 ± 11 years were studied. The patients were treated with 20 mg of atorvastatin for 24 weeks, in a single nocturnal dose. At baseline and every eight weeks, the fasting lipid profile, together with serum Lp(a) and plasma fibrinogen levels (Clauss method), were measured. Atorvastatin was highly effective in normalising the serum lipid profile. No significant change in median serum Lp(a) levels was observed in the whole group of patients (0.14 g/l before, vs. 0.16 g/l after, treatment) as well as in patients with raised (> 0.30 g/l) baseline levels (n = 32). A small non-significant increase of plasma fibrinogen was found (3.04 g/l vs. 3.14 g/l) after 24 weeks of atorvastatin administration. The effects of atorvastatin on both these variables did not differ in patients with hypercholesterolaemia or mixed hyperlipidaemia.

In conclusion, our findings suggest that the effect of atorvastatin on plasma fibrinogen levels in dyslipidaemic patients without evident vascular disease is not clinically relevant. Furthermore, any rise in fibrinogen levels that may occur is likely to be transient in nature. Further studies are necessary to clarify this issue. There was no evidence that atorvastatin influences serum Lp(a) levels.


Atorvastatin is a new synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which safely and effectively reduces low-density lipoprotein cholesterol (LDL) levels in patients with hypercholesterolaemia or mixed dyslipidaemia.[1,2] However, the effects of atorvastatin on other variables, such as on lipoprotein(a) [Lp(a)] and fibrinogen concentrations, which are associated with cardiovascular disease,[3-6] are less well documented.[7-10] There has also been some controversy recently as to whether this statin raises fibrinogen levels.[7-12]

We undertook the present study to investigate prospectively the influence of conventional doses of atorvastatin on these parameters in dyslipidaemic patients. We also planned serial sampling (over a period of 24 weeks) because of the possibility of a transient rise in plasma fibrinogen levels.[7-12]

Materials and Methods

Patients attending our lipid clinic were recruited for the study. Men and women with dyslipidaemia and a body mass index (BMI) 32 kg/m2 were screened for eligibility by medical history, physical examination and clinical laboratory evaluation, including the lipid profile. No participant had symptomatic ischaemic heart disease or any other vascular disease. Any lipid lowering medications had to have been discontinued for at last four weeks.

Patients were assigned to the National Cholesterol Education Program (NCEP)[13] step 1 diet for six weeks. They followed this diet throughout the study. Fasting serum lipid level entry criteria were LDL cholesterol > 160 mg/dl (4.16 mmol/l) at weeks -4 and -2 and/or triglycerides > 200 mg/dl (2.26 mmol/l). A total of 90 patients (56 men and 34 women; mean age 48 ± 11 years) were recruited. Of these, 45 had primary hypercholesterolaemia (LDL cholesterol > 160 mg/dl (4.16 mmol/l)); triglycerides < 200 mg/dl (2.26 mmol/l) and 45 had primary mixed hyperlipidaemia (LDL cholesterol > 160 mg/dl (4.16 mmol/l); triglycerides > 200 mg/dl (2.26 mmol/l)). Smokers, as well as patients with impaired hepatic or renal function, proteinuria, diabetes mellitus (fasting blood glucose > 126 mg/dl (7.0 mmol/l)), raised TSH levels, or any other medical conditions that might preclude successful completion of the study, were excluded. Some patients were taking drugs such as angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists or calcium channel blockers. Those receiving drugs possibly affecting the laboratory parameters tested, were excluded.

After a six-week baseline period patients were given atorvastatin 20 mg per day in a single nocturnal dose for 24 weeks. A food-record rating score was calculated from three-day diaries kept by the participants in order to assess compliance with the diet throughout the study.[14] Blood samples were collected after a 14-hour overnight fast for the determination of serum lipid and plasma fibrinogen levels, as well as liver and muscle enzymes at baseline and every eight weeks during follow-up.

Any interference from the acute-phase reaction, exercise or intercurrent infection was ruled out by history and physical examination, as well as by normal values of C-reactive protein and erythrocyte sedimentation rate, which did not change significantly throughout the study (data not shown).

Laboratory Determinations

Levels of cholesterol and triglycerides were determined by an enzymatic colorimetric assay using an RA-1000 analyser (Technicon Instruments Ltd, Terrytown, New York, USA). HDL cholesterol was determined enzymatically from the supernatant after precipitation of other lipoproteins with dextran sulphate magnesium. Levels of LDL cholesterol were calculated using the Friedewald formula.[15] Serum levels of apolipoproteins AI and B were measured by immunonephelometry using a Beckman array analyser (Beckman Instruments, Fullerton, California, USA).

Lp(a) levels were measured using a monoclonal antilipoprotein(a) antibody technique and enzyme-linked immunoassay (Terumo Medical Corporation, Diagnostic Division, Elkron, Maryland, USA). The lower limit of detectability was 0.08 g/l when Lp(a) levels were < 0.08 g/l; the value of 0.08 g/l was used for statistical analysis. The intra-assay and inter-assay coefficients of variation were < 6% and 10.3%, respectively. According to the authors of a recent report on this monoclonal antibody, there was no cross-reactivity with plasminogen, LDL, very low density lipoprotein (VLDL), and high density lipoprotein (HDL).[16] Plasma fibrinogen levels were measured by the Clauss method (clotting activity), as previously described.[17]

Statistical Analysis

All variables were expressed as mean values ± SD, except for Lp(a) and fibrinogen levels, which were expressed as median and range. Analysis of variance (ANOVA) for repeated measurements was used to assess changes in variables after atorvastatin administration. When differences were found, Scheffe's test was used to evaluate the effects of atorvastatin on the changes from baseline. For non-normally distributed data, the Friedman one-way ANOVA, followed by Wilcoxon signed-rank test (two-tailed) for paired comparisons, was carried out. The mean percentage change from baseline of the efficacy parameters at week 24 was compared between patients with primary hypercholesterolaemia and patients with primary mixed hyperlipidaemia using analysis of covariance (ANCOVA). The primary model included the effects of treatment and baseline values as covariates. For parameters with skewed distributions, they were rendered Gaussian by logarithmic transformation before inclusion in the analysis. Relationships between variables were assessed by the Pearson's correlation coefficient or the Spearman's rank-order coefficient, where appropriate.

Differences were considered to be significant at p < 0.05.


All patients completed the study. The maintenance of the hypolipidaemic diet was supervised throughout the trial and there was no significant change in mean body weight during the study. Additionally, the food-record rating score did not change from baseline to the end of the study.

Atorvastatin was highly effective in normalising the serum lipid profile (Table 1). This statin significantly decreased the total cholesterol by 30.7%, LDL by 34.5%, triglycerides by 25% and Apo B by 28.5%. HDL and apolipoprotein AI levels did not change significantly from baseline. As expected, the fall in triglyceride levels was greater in the patients with mixed dyslipidaemia when compared with those with hypercholesterolaemia (28.5% vs. 14.5%, respectively). However, this difference was not significant.

No significant changes in serum Lp(a) levels were observed after atorvastatin administration in the whole group of patients (Table 2) or in patients with increased (> 0.30 g/l) baseline levels (n = 32) [changed from 0.40 (0.30-1.08) g/l to 0.42 (0.31-1.06) g/l]. There was no correlation between the changes in serum Lp(a) and lipid variables, including serum triglycerides.

A small non-significant increase in plasma fibrinogen levels was seen throughout the trial. However, an increase that was nearly statistically significant (p = 0.06) was noticed after eight weeks of treatment. This significance was lost thereafter. No correlation was found between the change in plasma fibrinogen levels and the baseline fibrinogen levels at any time during the study. No significant change in plasma fibrinogen levels was found in any tertile of fibrinogen levels. The changes in plasma fibrinogen levels were not related to any other lipid parameters, including serum triglycerides. The effects of atorvastatin on the lipid parameters and fibrinogen levels were not significantly different when considered separately in patients with primary hypercholesterolaemia or patients with primary mixed hyperlipidaemia.

At the end of the study (week 24) all patients at low risk for coronary heart disease according to the NCEP classification[13] reached a target LDL of 160 mg/dl (4.16 mmol/l). For patients at medium risk for coronary heart disease, 88.2% of those with primary hypercholesterolaemia and 86.6% of those with primary mixed hyperlipidaemia reached the target LDL cholesterol (130 mg/dl (3.4 mmol/l)).

Atorvastatin was well tolerated and there was no significant change in the levels of muscle and liver enzymes. A small increase in the serum levels of both alanine and aspartate aminotransferases (to less than three times the upper limit of the reference range) was recorded in four patients. A small increase in creatine kinase (CK) activity (to less than twice the upper limit of the reference range) was also observed in two patients.


As in previous studies, atorvastatin was highly effective and well tolerated.[1,2,18] At week 24, the majority of the patients with primary hypercholesterolaemia and mixed hyperlipidaemia treated with 20 mg of atorvastatin reached the NCEP lipid targets.[13]

No significant changes in serum Lp(a) levels were found after atorvastatin administration in the whole group of patients as well as in patients with raised baseline levels. These findings agree with some previously published studies,[8,12,19] but not with the results of others,[9] who showed that atorvastatin can significantly increase serum Lp(a) concentrations in patients with raised (> 0.30 g/l) levels. The reasons for these discrepancies are not clear, but they may be related to several factors. For example, the numbers of patients with elevated Lp(a) levels in both the Nair et al. study[9] (n = 21) and our study (n = 32) was relatively small. Furthermore, differences in the distribution of Apo(a) phenotypes and ethnic background, together with methodological inaccuracies, may have contributed to the discrepancies.[20,21] However, Apo(a) phenotyping was available in 22 patients in our study (10 and 12 patients with low- and high-molecular-weight phenotypes, respectively). In neither group was there a significant change in Lp(a) levels (data not shown). This finding suggests that atorvastatin does not significantly influence circulating Lp(a) levels whatever the distribution of Apo(a) phenotypes. Some authors reported a slight decrease in Lp(a) immunoreactivity after storage.[22,23] However, storage at -70oC is recommended to retain immunoreactivity.[22] Our samples were kept at -70°C for < 2 months. We also used an enzyme-linked immunosorbent assay that is less affected by the conditions of storage.[23]

There are conflicting results concerning the influence of atorvastatin on plasma fibrinogen levels.[1,7-9,12,24-31] Some studies reported a marked increase in fibrinogen levels, while others failed to show this change.[1,7-9,12,24-31] The heterogeneous nature of patients recruited,[7] the duration of treatment,[24] sampling at a single time point,[7,8,24] variations in drug dosage[1,7-9,12,24-31] and different assay methods[26] may account, at least in part, for these discrepancies. Bertolotto et al.[26] reported an increase in plasma fibrinogen concentration after atorvastatin when using an immunonephelometric method. The change in fibrinogen observed by the Clauss (clotting) method did not achieve significance although there was a trend towards a rise (+14%).[26] This is of interest because the immunonephelometric method may be affected by a fall in triglyceride levels. Wierzbicki et al. compared the efficacy of simvastatin 80 mg and atorvastatin 80 mg in 26 patients with familial hypercholesterolaemia over 12 weeks.[27] Fibrinogen levels were measured using an immunoturbidimetric method.[27] Atorvastatin raised median fibrinogen levels by 15% compared with a non-significant 5% increase with simvastatin (p = 0.05).[27] However, Singhal et al. reported no difference in plasma fibrinogen levels in dyslipidaemic patients on continuous ambulatory peritoneal dialysis receiving either atorvastatin or simvastatin.[28] Furthermore, in a single-blinded study of 22 hyperlipidaemic patients, Dujovne et al. showed that atorvastatin 80 mg daily over 12 weeks did not significantly affect fibrinogen levels measured by the Clauss (clotting) method.[29]

We avoided interference on plasma fibrinogen levels (as part of the acute phase reaction)[32] by defining exclusion criteria (exercise, change in dietary habits, smoking and circadian variation). However, there was a transient, non-significant (p = 0.06) increase in plasma fibrinogen levels after eight weeks of treatment. The clinical relevance of this effect is questionable. It is possible to speculate that it was related to an inflammatory response associated with changes in plaque structure. This interpretation is compatible with the significant decrease in carotid intima media thickness (IMT) after treatment with atorvastatin (20 mg/day; the same dose as in our study) in patients with peripheral vascular disease.[30]

It is possible that all statins elevate plasma fibrinogen levels. However, this rise may be transient, depending on the statin used, and it could occur at different times after initiation of treatment. These factors need to be considered when planning future studies. These studies should also include clinical events so as to assess the relevance of any observed changes.

The 'haemostatic' effects of lipid lowering drugs are varied (e.g. affecting coagulation,[33] platelets[34] and homocysteine[30] levels) and poorly documented. They deserve further investigation.

In conclusion, this study suggests that atorvastatin does not exert a major effect on fibrinogen and Lp(a) levels in patients with primary hypercholesterolaemia and primary mixed hyperlipidaemia in the absence of clinically evident vascular disease. Any effect of atorvastatin on plasma fibrinogen levels is likely to be transient and may be restricted to certain patient groups.

Table 1. Effect of atorvastatin on serum lipids. Values are expressed as mean ± SD

Variables (mg/dl) Baseline After 8 weeks After 16 weeks After 24 weeks p*
T-Chol 312 ± 102 218 ± 80a 215 ± 70a 216 ± 60a 0.001
LDL 220 ± 65 140 ± 45a 139 ± 36a 144 ± 32a 0.001
HDL 45 ± 12 44 ± 10 44 ± 9 46 ± 9 NS
TRG 240 ± 120 170 ± 95b 160 ± 90a 180 ± 86b 0.01
ApoA1 146 ± 21 145 ± 19 146 ± 22 149 ± 18 NS
ApoB 182 ± 46 125 ± 36a 128 ± 40a 130 ± 37a 0.01

T-Chol, total cholestorol; LDL, LDL cholestorol; HDL, HDL cholesterol; TRG, triglycerides; Apo, apolipoprotein
Conversion factors:
To convert cholesterol values (T-Chol, LDL and HDL) from mg/dl to mmol/l, multiply by 0.026. To convert triglycerides (TRG) from mg/dl to mmol/l multiply by 0.0113
Statistical analysis (see Statistics section for details):
*p based on repeated comparisons using ANOVA
ap < 0.001 compared to baseline values
bp < 0.01 compared to baseline values

Table 2. Effect of atorvastatin on serum Lp(a) and plasma fibrinogen levels. Values are expressed as median and (range)

  Baseline After 8 weeks After 16 weeks After 24 weeks p*
Serum Lp(a) (g/l) 0.14 (0.08-0.64) 0.15 (0.08-0.62) 0.16 (0.08-0.68) 0.15 (0.08-0.64) NS
Plasma fibrinogen (g/l) 3.04 (1.73-5.00) 3.26 (1.80-5.40)a 3.22 (1.80-5.80) 3.14 (1.75-5.20) NS

Statistical analysis (see Statistics section for details):
*p by Friedman ANOVA
ap = 0.06 (Wilcoxon paired test, baseline versus 8 weeks)
p < 0.01 compared to baseline values


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  13. Summary of the second report of the National Cholesterol Educational Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (1993). J. Am. Med. Assoc., 269, 3015-3023.
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  16. Silberman, S. R., Armentout, M. A., Vella, F. A., Saha, A. I. and Macra, T. L. (1990). Lp(a) for quantitation of human lipoprotein (a) by enzyme linked immunoassay. Clin. Chem., 36, 91.
  17. Montgomery, H. E., Clarkson, P., Nwose, O. M., Mikhailidis, D. P., Jagroop, I. A., Dollery, C., Moult, J., Benhizia, F., Deanfield, J., Jubb, M., World, M., McEwan, J. R., Winder, A. F. and Humphries, S. (1996). The acute rise in plasma fibrinogen with exercise is influenced by the G-453-A polymorphism of the B-fibrinogen gene. Arterioscler. Thromb. Vasc. Biol., 16, 386-391.
  18. Alaupovic, P., Heinonen, T., Shurzinske, L. and Black, D. M. (1997). Effect of a new HMG-CoA reductase inhibitor, atorvastatin, on lipids, apolipoproteins and lipoprotein particles in patients with elevated serum cholesterol and triglyceride levels. Atherosclerosis, 133, 123-133.
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  20. Garnotel, R., Monier, F., Lefevre, F. and Gillery, P. (1998). Long-term variability of serum lipoprotein (a) concentrations in healthy fertile women. Clin. Chem. Lab. Med., 36, 317-321.
  21. Tate, J. R., Rifai, N., Berg, K., Couderc, R., Dati, F., Kostner, G. M., Sakurabayashi, I. and Steinmetz, A. (1998). International Federation of Clinical Chemistry standardization project for the measurement of lipoprotein (a). Phase I. Evaluation of the analytical performance of lipoprotein (a) assay systems and commercial calibrators. Clin. Chem., 44, 1629-1640.
  22. Lippi, G. and Guidi, G. (1998). Standardization and clinical management of lipoprotein (a) measurements. Clin. Chem. Lab. Med., 36, 5-16.
  23. Craig, W. and Ledue, T. (1992). The effects of long term storage on serum Lp(a) levels. Atherosclerosis, 93, 261.
  24. Marais, A. D., Firth, J. C., Bateman, M. E., Byrnes, P., Martens, C. and Mountney, J. (1997). Atorvastatin: an effective agent in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol., 17, 1527-1532.
  25. Bakker-Arkema, R. G., Davidson, M. H., Goldstein, R. J., Davignon, J., Isaacsohn, J. L., Weiss, S. R., Keilson, L. M., Brown, V., Miller, V. T., Shurzinske, L. J. and Black, D. (1996). Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. J. Am. Med. Assoc., 275, 128-133.
  26. Bertolotto, A., Bandinelli, S., Ruocco, L., Lo Faro, A., Penno, G. and Navalesi, R. (1999). More on the effect of atorvastatin on plasma fibrinogen levels in primary hypercholesterolemia. Atherosclerosis, 143, 455-457.
  27. Wierzbicki, A. S., Lumb, P. J., Chik, G. and Crook, M. A. (1999). Comparison of therapy with simvastatin 80 mg and atorvastatin 80 mg in patients with familial hypercholesterolaemia. Int. J. Clin. Pract., 53, 609-611.
  28. Singhal, M. K., Bhaskaran, S., Szabo, T. and La Rosa, R. (1999). No difference in plasma fibrinogen levels between CAPD patients taking atorvastatin and simvastatin. Perit. Dial. Int., 19, 89-91.
  29. Dujovne, C. A., Harris, W. S., Altman, R., Overhiser, R. W. and Black, D. M. (2000). Effect of atorvastatin on hemorheologic-hemostatic parameters and serum fibrinogen levels in hyperlipidemic patients. Am. J. Cardiol., 85, 350-353.
  30. Davis, M., Atwal, A. S., Nair, D. R., Jagroop, I. A., Seifalian, A. M., Mikhailidis, D. P. and Hamilton, G. (2000). The effect of short term lipid lowering with atorvastatin on carotid artery intima media thickness in patients with peripheral vascular disease: a pilot study. Curr. Med. Res. Opin., 16, 198-204.
  31. Wierzbicki, A. S., Crook, M. A., Nair, D. R., Mikhailidis, D. P. and Winder, A. F. (2000). More on the effect of atorvastatin on plasma fibrinogen levels in primary hypercholesterolaemia. Atherosclerosis, 148, 204.
  32. Breimer, L. H., Ganotakis, E. S. and Mikhailidis, D. P. (1997). Fibrinogen as a cardiovascular risk factor. Rev. Port. Cardiol., 16, 245-250.
  33. Milionis, H. J., Elisaf, M. S. and Mikhailidis, D. P. (2000). Treatment of dyslipidaemias in patients with established vascular disease: a review of the fibrates. Curr. Med. Res. Opin., 16, 21-32.
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2001 Pediatric Vaccine Update

Marcia L. Buck, Pharm.D., FCCP

[Pediatric Pharmacotherapy 7(3), 2001. © 2001 Stephen M. Borowitz, MD, Children's Medical Center, University of Virginia]


There have been a number of changes in the routine childhood immunization schedule within the past several years. Some of these changes, for example the addition of the pneumococcal conjugate vaccine, provide the opportunity to reduce or eliminate a significant cause of morbidity and mortality in the pediatric population. Other changes, such as the transition to inactivated poliovirus vaccine and the use of acellular pertussis, have reduced the risks associated with vaccine administration. This issue of Pediatric Pharmacotherapy will review several new case reports, surveillance studies, and announcements from the Food and Drug Administration (FDA) related to vaccines.

Tetanus Toxoid Shortage to Continue

Most healthcare providers are now aware of a shortage of tetanus toxoid in the United States. This shortage is primarily a result of the decision by Wyeth-Lederle to discontinue production of tetanus toxoid (TT), tetanus and diphtheria toxoid (Td), and their diphtheria-tetanus-acellular pertussis (DTaP) vaccine, ACEL-IMMUNEâ. This leaves Aventis Pasteur as the sole manufacturer of TT and Td in the United States. Aventis Pasteur, who also produces the Tripediaâ brand of DTaP, and GlaxoSmithKline, maker of the Infanrixâ brand of DTaP, are attempting to increase production to offset this change. Despite their increased production schedule, it is anticipated that the shortage may last as long as 12 to 18 months.[1]

Thimerosal Elimination Nearing Completion

In related news, the FDA recently announced the approval of a new formulation of Aventis Pasteur's DTaP vaccine, Tripediaâ. The new product contains no preservatives and only trace amounts of thimerosal. This represents a greater than 95% reduction in the amount of thimerosal compared to the original formulation.

The removal of thimerosal from vaccines has been the result of a call from the American Academy of Pediatrics and the United States Public Health Service to eliminate this preservative as a source of mercury exposure in infants.[2] While there have been no case reports of mercury toxicity associated with the use of thimerosal, there was a perceived need to reduce the potential for mercury accumulation during childhood. Since the initial recommendation on July 8, 1999, vaccine manufacturers have voluntarily responded by reformulating their products. At this time, all vaccines in the recommended childhood immunization schedule are available in at least one thimerosal-free or reduced-thimerosal formulation.

No Link Found Between Autism and MMR

An association between autism and administration of the combined measles, mumps, rubella (MMR) vaccine was first suggested in 1996. Fudenberg and colleagues had studied a new therapy in 40 children with autism; and as an aside, reported that 15 of the children developed their symptoms of autism within one week of receiving the MMR vaccine. While this first paper garnered little attention in the medical literature[3], a second paper by Wakefield and colleagues[4] generated much more interest. In this paper, the authors described 12 children with chronic enterocolitis and regressive developmental disorders. The onset of symptoms was temporally related to the administration of an MMR dose in eight of the children. In both papers, the authors suggested a potential relationship between autism and MMR, but could not establish causality.

An accompanying editorial to the Wakefield paper and several letters to the editor immediately called to attention the implausibility of the link. Since that time, a number of small surveillance studies have found no relationship between autism and MMR immunization. Recently, two large-scale database analyses have also refuted the link.[5,6] In the February 24th issue of the British Medical Journal, Kaye and colleagues published their evaluation of data contained in the United Kingdom General Practice Research Database.[5] The authors evaluated two groups, one included all children with autism diagnosed between the years 1988 and 1999, and a cohort of boys aged 2 to 5 years born between 1988 and 1993. The authors theorized that, if the MMR were linked to autism, a parallel would be found between number of patients vaccinated and the frequency of autism. While the prevalence of MMR vaccination remained relatively unchanged during that period (over 95% in the cohort group), the incidence of autism increased sevenfold. The greatest percentage of the increase occurred in boys, with a peak at 3 to 4 years of age. The authors concluded from their analysis that no correlation existed between the prevalence of MMR vaccination and the rapid rise in the diagnosis of autism.

A similar time trend analysis, published earlier this month in JAMA, was carried out by Dales and coworkers using kindergarten enrollment records in California.[6] The authors compared immunization rates with the number of children diagnosed with autism who were enrolled in the state's Department of Developmental Services system over the period 1980 through 1994. As with the British paper, MMR immunization rates remained relatively unchanged throughout the study period (with an increase of 14%), while the rate of autism increased by 373%. Based on their assessment, the authors made a similar conclusion to the Kaye study, that the data do not suggest an association between MMR immunization and the current increase in cases of autism.

Pneumococcal Vaccine Reduces Otitis Media

In addition to demonstrating a reduction in invasive disease, premarketing trials of the conjugate pneumococcal vaccine (PCV7) also showed a 7% reduction in otitis media among treated children.[7] This effect has now been reproduced in a study conducted in Finland and published in the February 8th issue of the New England Journal of Medicine.[8] The Finnish Otitis Media Study Group enrolled 1,662 infants in a randomized, double-blind study comparing PCV7 to a control (hepatitis B vaccine given at the same 2, 4, 6, and 12 month visits). PCV7 administration reduced the overall occurrence of otitis media by 6%. Subset analysis revealed a 34% reduction in otitis caused by Streptococcus pneumoniae and a 57% reduction in cases caused by the seven serotypes contained in the vaccine. While this reduction may seem small at first, the impact is expected to be sizable. In the United States, a reduction of this magnitude could result in a healthcare cost savings of 300 to 500 million dollars annually.

New Combination Under Investigation

With the inclusion of the conjugate pneumococcal vaccine in the routine childhood immunization schedule and the conversion to inactivated poliovirus vaccine, the average child will receive more than 20 injections by 6 years of age. Healthcare providers and parents have become sensitive to this issue. In an attempt to reduce the number of injections, several new combination vaccine products are under development.

GlaxoSmithKline has produced a combination vaccine which incorporates their DTaP vaccine, Infanrixâ, with hepatitis B and inactivated poliovirus vaccines. While preliminary studies appear favorable, release of this product is likely to be delayed for another year. On March 7th, the FDA Vaccines and Related Biological Products Advisory Committee voted six to five to recommend that the combination not be approved at this time.[9] While the committee members acknowledged the benefit of the 5-vaccine product, they requested additional efficacy data to better establish the antigenicity of the individual components. In particular, members expressed concern about the immunologic response to the combination when given at the same time as the conjugate pneumococcal vaccine and about the rate of fever in recipients. In Phase III trials, fever occurred in 43% of infants vaccinated with the combination product versus 26% of those receiving standard immunizations.

Progress Made Towards Eradication of Polio

While the goal of global eradication of poliomyelitis by the year 2000 was not achieved, the end does appear to be in sight. On October 29, 2000, the Western Pacific region of the World Health Organization (WHO) was certified as free of indigenous wild poliovirus transmission.[10,11] The Western Pacific region incorporates 37 countries and approximately 27% of the world's population. This is the second of the six WHO regions to be declared polio-free; the first was the Americas in 1994. The European region is expected to be the next area to achieve eradication. No new indigenous cases have been reported in this region since November 1998.

Additional Information

The 2001 Immunization Schedule is available from the American Academy of Pediatrics at or in the journal Pediatrics.[12] The schedule is also published on the Centers for Disease Control (CDC) website for the National Immunization Program at This site contains a number of other educational tools for both healthcare providers and the lay public. The CDC vaccine information sheets for parents are also available in the publications section of this website.


The reduction of infectious diseases resulting from the use of vaccines has been one of the past century's greatest public health successes. The achievement of eradication or near-eradication of many pediatric infections has been the result of continued research, active governmental involvement, and the work of countless healthcare providers. The United States childhood immunization program continues to evolve, incorporating new vaccines and modifications of older products in an effort to continue to improve safety and efficacy.


  1. Anon. Update on the supply of tetanus and diphtheria toxoids and of diphtheria and tetanus toxoids and acellular pertussis vaccine. MMWR 2001;50(10):189-90.
  2. American Academy of Family Physicians, American Academy of Pediatrics, Advisory Committee on Immunization Practices, United States Public Health Service. Joint statement concerning removal of thimerosal from vaccines at…/ thimerosal/joint_statement_00.htm (accessed 3/20/01).
  3. Fudenberg HH. Dialysable lymphocyte extract in infantile onset autism: a pilot study. Biotherapy 1996;9:143-7.
  4. Wakefield AJ, Murch SH, Anthony A, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637-41.
  5. Kaye JA, del Mar Melero-Montes, M, Hershel J. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. Brit Med J 2001;322:460-3.
  6. Dales L, Hammer SJ, Smith NJ. Time trends in autism and in MMR immunization coverage in California. JAMA 2001;285:1183-5.
  7. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-95.
  8. Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403-9.
  9. Anon. FDA advisory panel urges agency not to approve GlaxoSmithKline vaccine. Reuters Medical News. March 7, 2001.
  10. Anon. Public health dispatch: certification of poliomyelitis eradication---Western Pacific region, October 2000. MMWR 2001;50(1):1-3.
  11. John JT. The final stages of the global eradication of polio. New Engl J Med [editorial] 2000;343:806-7.
  12. Committee on Infectious Diseases, American Academy of Pediatrics. Recommended childhood immunization schedule-United States, January-December 2001. Pediatrics 2001;107:202-4.

Pharmacology Literature Review

Antihistamine Safety Review

For anyone using antihistamines in their clinical practice, this extensive review is an excellent resource. The authors divide antihistamines into three generations. With each generation, they cover both common and rare adverse effects in children, including cardiac toxicity, as well as symptoms of overdose. The authors pay special attention to the long-term effects of some antihistamines on learning and school performance, an often unrecognized problem. Ten Eick AP, Blumer JL, Reed MD. Safety of antihistamines in children. Drug Safety 2001;24:119-47.

Budesonide Review

This article focuses on the newest formulation of budesonide, a liquid suspension for nebulization. The author gives a brief overview of the drug itself, then devotes the remainder of the review to efficacy and safety trials performed in the United States and abroad. Particular attention is paid to those studies evaluating the effects of inhaled budesonide on hypothalamic-pituitary-adrenal axis function and growth. Szefler SJ. A review of budesonide inhalation suspension in the treatment of pediatric asthma. Pharmacotherapy 2001;21:195-206.

Protease Inhibitors in Children

The authors of this observational study evaluated the safety and efficacy of protease inhibitors (ritonavir, nelfinavir, indinavir, and saquinavir) in 21 children over a period of 3 years. Viral load was reduced in the ritonavir, nelfinavir, and indinavir groups, while CD4+ counts increased with all protease inhibitors. Overall, compliance was 70%, relatively high for a complex chronic regimen. The most frequently reported adverse effects were diarrhea and vomiting. Ritonavir was associated with the greatest number of adverse effects (28 reported in 19 children). The most frequent alterations in laboratory values were increases in cholesterol, serum creatinine, and triglycerides. Temple ME, Koranyi KI, Nahata MC. The safety and antiviral efficacy of protease inhibitors in children. Pharmacotherapy 2001;21:287-94.

Sotalol Pharmacokinetics

The pharmacokinetics of sotalol, a beta-adrenergic blocker used in patients with tachycardia, were evaluated in 26 children and adults to evaluate age-related differences. The study involved 4 newborns (13-26 days), 11 infants and toddlers (1 month to 3 years), 5 children (6-9 years), and 5 adolescents and adults (13-35 years). All patients enrolled were previously receiving sotalol, with daily oral doses between 1.90 and 6.86 mg/kg. The infant/toddler group showed significantly faster clearance than the adolescent/adult group (3.93+1.25 versus 2.00+0.29 ml/min/kg), resulting in a shorter elimination half-life (5.0+1.4 versus 7.7+1.3 hrs). The group of 6-9 year olds fell between the values for infants/toddlers and adolescents/adults. Newborns had a longer elimination half-life than the infant/toddler group. In contrast, volume of distribution, when normalized for weight, did not vary significantly among the groups. The authors suggest that infants and young children may require dosing three times daily to achieve maximal response. Laer S, Wauer I, Behn F, et al. Pharmacokinetics of sotalol in different age groups of children with tachycardia. J Pediatr Pharmacol Ther 2001;6:50-9.

Tacrolimus Clearance in Children

Serum tacrolimus concentrations from 18 children, aged 4 months to 16 years, were used to evaluate the influence of several covariates on drug elimination. The authors built a nonlinear mixed-effects model (NONMEM) for tacrolimus clearance using 287 serum concentrations. The covariates having the greatest degree of influence on clearance with this model were total body weight, time since the onset of therapy, serum bilirubin, and ALT values. The authors suggest that despite the apparent value of these covariates in determining clearance, there remains considerable interpatient variability in response. As a result, they suggest that their mathematical calculation not be used for initial dosing, but may be of use during routine dosage adjustment. For clinicians not routinely using NONMEM, the study still has value. It highlights some of the routine laboratory values, other than serum concentration, that may be of use in predicting changes in tacrolimus clearance. Garcia Sanchez MJ, Manzanares C, Santos-Buelga D, et al. Covariate effects on the apparent clearance of tacrolimus in paediatric liver transplant patients undergoing conversion therapy. Clin Pharmacother 2001;40:63-71.

Therapies for Otitis Media

This review of antibiotics for the prevention and treatment of otitis media focuses on the recent recommendations of the Centers for Disease Control. The authors discuss the expert panel's guidelines and the ensuing controversy over their antibiotic selection. Erramousepe J, Heyneman CA. Treatment and prevention of otitis media. Ann Pharmacother 2000;34:1452-68.

Formulary Update

The following actions were taken by the Pharmacy and Therapeutics Committee at their meeting on 2/23/01:

  1. Polyethylene glycol 3350, NF (Miralaxâ) was added to the Formulary for the management of refractory constipation in children. Its use is restricted to the Pediatric Gastroenterology Division. The usual dose of Miralaxâ is 1 tablespoonful in 8 ounces of water daily.
  2. Intravenous chlorothiazide sodium (Sodium Diurilâ) was also added. It is restricted to use in the Neonatal Intensive Care Unit for infants requiring long-term diuretic therapy who might be at risk from developing renal calcifications or metabolic bone loss with loop diuretics. The usual intravenous dose of chlorothiazide in infants is 2-8 mg/kg/day in two divided doses.
  3. Remifentanil (Ultivaâ), a short-acting opioid analgesic, was also added to the Formulary. During surgery, dosing is dependent on the concomitant anesthetics used. In the postoperative period, an infusion of 0.025-0.2 mcg/kg/min is recommended for adults and children > 2 years of age.
  4. Iohexol (Omnipaqueâ), a nonionic imaging agent, was added for intrathecal or intravascular administration in children and adults.
  5. A product line extension was approved for budesonide respules (Pulmicort Respulesâ). This product is indicated for the treatment of asthma in children 1 to 8 years of age. The recommended dose is 0.5 to 1 mg per day, in one or two doses.

Some MI Patients With Contraindications Could Benefit From Thrombolytic Therapy

WESTPORT, CT (Reuters Health) May 10 - Some patients with acute myocardial infarction for whom thrombolytic therapy is not indicated or is contraindicated by current criteria could nonetheless benefit from the therapy, according to a report in the May issue of the Journal of the American College of Cardiology.

Dr. Michael Mundt Ottesen, from Gentofte University Hospital of Copenhagen, and colleagues in the TRACE Study Group collected data, drawn from actual clinical practice, on 6676 consecutive AMI patients. They determined that thrombolytic therapy was underutilized in 14.3% of the patients (not used even though there was no contraindication) and overutilized in 12.9% (used despite no indications or at least one contraindication).

In total, 41% of the study group received thrombolytic therapy. It reduced mortality in every subgroup studied, including patients without an accepted indication and in patients with prior stroke. In addition, thrombolytic therapy did not increase the risk of in-hospital stroke, even among patients with a history of stroke, Dr. Ottesen's group noted.

"It is tempting to use the results we have presented to conclude that contraindications and lack of indications should be ignored and that thrombolytic therapy should be given to many more patients. But the correct conclusion is that physicians are able to select those patients who are beyond the standard indications but who will benefit from thrombolytic therapy," Dr. Ottesen and colleagues advise.

In a journal editorial, Dr. Peter Sleight from John Radcliffe Hospital in Oxford, UK, agrees that thrombolysis is underused "not only in entirely eligible patients...but it is also underused in high risk patients with conventional contraindications."

He goes on to note that "the value of these new data is to contrast real life with clinical trials. The latter always enroll fitter and often younger patients than the 'garden' variety seen in district hospitals."

J Am Coll Cardiol 2001;37:1581-1589.

Herbal Remedy Exposure Leads to Occupational Asthma

WESTPORT, CT (Reuters Health) May 11 - A pharmacist developed occupational asthma and rhinitis after working with a number of oriental herbal materials, Korean researchers report in the April issue of the Annals of Allergy, Asthma and Immunology.

Dr Hae-Sim Park of Ajou University School of Medicine in Suwon and colleagues observe that their patient, a 35-year-old man who had worked in a herbal remedy shop for 15 years, had symptoms including cough and shortness of breath which improved when he was on vacation.

Skin prick testing showed strong positive reactions to herbs including Ostericum koreanum (Kangwhal), thought to be an antinflammatory; Angelica radix (Danggui), believed to be a vascular volume expander; Cnidii rhizoma (Chunkung), said to be an autonomic nervous system modulator; Dioscorea radix (Sanyak), a gastrointestinal remedy; Zingiberis rhizoma (Kunkang), a digestive; and Pinellia ternata (Banha), which is used as a cough suppressant.

Bronchial challenge showed an early asthmatic reaction to Danggui extract and serum-specific IgE antibodies to Chunkung, Banha and Sanyak. No specific IgE binding was seen to Kangwhal, Danggui or Kunkang.

The researchers, who note that there was a recent report of Banha causing asthma in a pharmaceutical employee, conclude that multiple herbal materials "can induce occupational asthma [and] IgE and non-IgE mediated responses, in a single exposed patient."

Ann Allergy Asthma Immunol 2001;86:469-474.

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