The association between calcium dobesilate and pancytopenia in type 2 diabetes: A case report
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ABSTRACT: A study was carried out in Greece with the aim of assessing the prevalence of chronic venous insufficiency (CVI) in Greece and to discuss the role of general practice in the epidemiology, early diagnosis, and initial management of this disease. Design: a prevalence study was carried out in rural Greece between January 17 and December 30, 1997. Setting: 13 GPs, 11 of those working in 13 rural primary health centers, 1 in the University Hospital of Heraklion and 1 private sector from different Greek districts were invited to participate in the study. Participants and methods: patients with the following criteria were entered into the study: weight, pain, cramps, burning, itching, formication and swelling. Complete information about patients' history was collected by the general practitioners (GPs) who used a semi-structured questionnaire. The diagnosis of CVI was established with Doppler ultrasound. Data were based on 6,119 questionnaires and GPs observed 4,502 randomly selected patients. The diagnosis of CVI was established in 993 patients and its prevalence was found to be 11.9% in males and 39.8% in females. Varicose veins were the most frequent clinical finding in patients with vein reflux and diabetes mellitus was the most common co-existing disease in males and hypertension in females. The prevalence of venous insufficiency (VI) appears to be a frequent health problem in general practice in Greece. It requires further investigation in order to explore the observed differences between various groups.International angiology: a journal of the International Union of Angiology 04/2002; 21(1):86-92. · 1.01 Impact Factor
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ABSTRACT: The aim of the present review is to consider the adverse effects and the safety profile of calcium dobesilate. Calcium dobesilate (Doxium) is a veno-tonic drug, which is widely prescribed in more than 60 countries from Europe, Latin America, Asia and the Middle East for three main indications: chronic venous disease, diabetic retinopathy and the symptoms of haemorrhoidal attack. Data sources used for this review comprise the international literature (1970-2003), a postmarketing surveillance (PMS) report for calcium dobesilate from OM Pharma (Geneva, Switzerland) covering the period 1974-1998, and periodic safety update reports (PSUR) covering the period 1995-2003 from the French Regulatory authorities pharmacovigilance database and OM Pharma. Data from the PMS report for 1974-1998 indicated that adverse events with calcium dobesilate did not occur very frequently and had the following distribution in terms of frequency: fever (26%), gastrointestinal disorders (12.5%), skin reactions (8.2%), arthralgia (4.3%), and agranulocytosis (4.3%). No deaths were attributed to calcium dobesilate in the PMS report. Using data on product use in the Swiss Compendium we estimated the prevalence of agranulocytosis to be 0.32 cases/million treated patients, i.e. ten times less than the calculated prevalence of agranulocytosis in the general population. Most adverse events are type B, i.e. rare and unrelated to the pharmacological properties of calcium dobesilate. This review concludes that the risk of an adverse effect with calcium dobesilate 500-1500 mg/day is low and constant over time. The recently raised problem of agranulocytosis (a total of 13 known cases drawn from all data sources) appears to be related to methodological bias. Such a review reinforces the need for a strong international pharmacovigilance organisation using similar methods to detect and analyse the adverse effects of drugs.Drug Safety 02/2004; 27(9):649-60. · 2.62 Impact Factor
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ABSTRACT: In the last 20 years, some cases of agranulocytosis associated with calcium dobesilate consumption in Spain have been reported. A high risk of dobesilate-associated agranulocytosis (121 cases per million per year) calculated using both a case-control and a case-population strategy has been published. However few spontaneous reports have been noted in the same period of time. No explanation exists for this disagreement. Estimated incidence rates of agranulocytosis in the IAAAS study and the calculated risk of dobesilate-associated agranulocytosis were used as background risks in a Poisson-based methodology, to calculate the number of coincidental reports of agranulocytosis among patients treated with dobesilate. The influence of treatment duration, notification rate and population characteristics were calculated. During the period 1978-2000, a total of 23 cases would have taken place if the background risk of agranulocytosis were 4.7 per million per year (IAAAS's risk); however, only 9 spontaneous cases of agranulocytosis associated to dobesilate were noted. A simulation showed that with notification rates equal to or higher than 17%, it was not possible to exclude that the 9 cases were false-positives. With notification rates equal or inferior to 16%, it would be unlikely that cases of agranulocytosis were noted in this population with a risk of 4.7 per million per year; therefore, it is necessary to assume a higher agranulocytosis risk. More than 1 case per year could be a false-positive if the background risk of agranulocytosis is 9.5 per million per year, this being the appropriate risk for a population of patients older than 60 years. The duration of treatment beyond 30 days increases the probability of a random coincidence of the intake of drug and an agranulocytosis event. The disagreement between calculated dobesilate-associated agranulocytosis risk and the number of noted spontaneous reports may be explained by at least three different factors: under-reporting, duration of treatment and age of patients. It is possible, with the methodology presented, to estimate the influence of these factors to avoid confusion with possible false-positive cases and then to design the correct prospective trial that can provide the true agranulocytosis risk.European Journal of Clinical Pharmacology 04/2003; 58(11):767-72. · 2.70 Impact Factor
77Letter to the Editor
The association between calcium dobesilate and
pancytopenia in type 2 diabetes: A case report
Tip 2 diyabet hastasında kalsiyum dobesilat ile pansitopeni ilişkisi:
Bir olgu sunumu
Aylin Cesur1, Meltem Aylı2, Mustafa Cesur3, Sibel Ertek4
1Department of Biochemistry, Medical Faculty, Gazi University, Ankara, Turkey
2Department of Hematology, Medical Faculty, Ufuk University, Ankara, Turkey
3Department of Endocrinology and Metabolic Diseases, Guven Hospital, Ankara, Turkey
4Department of Endocrinology and Metabolic Diseases, Medical Faculty, Ufuk University, Ankara, Turkey
Address for Correspondence: M.D. Sibel Ertek, Department of Endocrinology and Metabolic Diseases, Medical Faculty, Ufuk University, Ankara, Turkey
Phone: +90 312 204 42 30 E-mail: firstname.lastname@example.org
To the Editor,
Diabetic patients with polypharmacy are prone
to unexpected drug side effects. Chronic venous
insufficiency (CVI) is frequent in the type 2 diabetic
population due to advanced age and obesity, and is
associated with increased podiatric risk [1,2].
Calcium dobesilate (CaD) is a widely prescribed
veno-tonic drug for CVI, diabetic retinopathy, and
the symptoms of hemorrhoid attacks . To date,
all published cases of CaD-induced agranulocytosis
are >60 years of age [4,5-10]. Ibanez et al. recently
reported that CaD was strongly associated with the
risk of agranulocytosis . Herein we present a
case of CaD-induced pancytopenia in an 80-year-
old male diabetic patient. We had written informed
consent from the patient.
The patient presented to our hospital with a fever
of 39°C. He had been type 2 diabetic for 25 years and
was treated with repaglinide 2mg b.i.d. and insulin
glargine 20U o.p.d. He was also hypertensive and
dyslipidemic, and was using atenolol 50 mg/day,
lisinopril 20 mg/day, amlodipine 10 mg/day,
hydrochlorothiazide 50 mg/day, atorvastatin 10 mg/
day, and acetylsalicylic acid 100 mg/day for last 8
years. Six weeks before he presented to hospital he
was diagnosed with CVI and CaD 500 mg b.i.d. was
started following a cardiovascular surgery
After 6 weeks of the treatment leukopenia,
thrombocytopenia, and anemia were observed. His
hematoxylin-eosin-stained blood smear confirmed
markedly decreased platelet and leucocyte counts,
accompanied by normochromic normocytic red
cells (Table). CaD treatment was withdrawn
because of the potential side effects. On physical
examination the patient did not have organomegaly
or palpable lymph nodes. His iron, ferritin, vitamin
B12, and folate levels, and reticulocyte count were
within normal limits, and ANA (anti nuclear
antibody) and anti-double stranded DNA test results
were negative. The patient was hospitalized and
was prescribed intravenous ceftriaxone 2 g/day and
clarithromycin 400 mg/day, following the diagnosis
of pneumonia. The patient was discharged after 1
week of hospitalization with improved hemogram
results (Table 1).
Three months after discharge he was again
admitted to our hospital with a fever of 38.6°C. It
was learned that he again had started taking CaD.
Pancytopenia was diagnosed, CaD was withdrawn,
and the same intravenous antibiotic therapy was
started again. Bone marrow biopsy and aspiration
were performed from the iliac crest. Wright staining
of the bone marrow aspiration smear microscopically
showed normal erythroid and myeloid cell lines.
The patient was discharged with a normal blood
count after 1 week.
In conclusion, we want to emphasize the
potential for serious side effects that affect the
immune system in polypharmacy diabetic patients,
such as granulocytopenia, and the importance of
pharmacovigilance in patients with chronic diseases
and the risk of comorbidity.
Conflict of interest statement
None of the authors of this paper has a conflict of
interest, including specific financial interests,
relationships, and/or affiliations relevant to the
subject matter or materials included.
1. Lionis C, Erevnidou K, Antonakis N, Argyriadou S,
Vlachonikolis I, Katsamouris A; CVI Research Group.
Chronic venous insufficiency . A common health prob-
lem in general practice. Int Angiol 2002;21:86-92.
Fowkes FGR, Ewans CJ, Lee AJ. Prevalance and risk
factors of chronic venous insufficiency. Angiology
Allain H, Ramelet AA, Polard E, Bentue-Ferrer D. Safety
of calcium dobesilate in chronic venous disease, dia-
betic retinopathy and haemorrhoids. Drug Saf.
Zapater P , Horga JF, Garcia A. Risk of drug-induced
agranulocytosis: the case of calcium dobesilate. Eur J
Clin Pharmacol. 2003;58:767-72.
Ibanez L, Ballarin E, Vidal X, Laporte JR. Agranulocytosis
associated with calcium dobesilate clinical course and
risk estimation with the case-control and the case-
population approaches. Eur J Clin Pharmacol.
Kulessa W, Becker EW, Berg PA. Recurrent agranulocy-
tosis after taking calcium dobesilate. Dtsch Med
Wochenschr. 1992;117:372-4. [CrossRef]
Garcia Benayas E, Garcia Diaz B, Perez G. Calcium
dobesilate-induced agranulocytosis. Pharm World Sci.
Azaceta G, Sáenz-Cusi A, Olave T, Palomera L.
Agranulocitosis inducida por dobesilato cálcico: a
propósito de un nuevo caso. An Med Interna 2000;17:
Duggal L, Thukral R, Kumar S. Calcium dobesilate-
induced agranulocytosis. J Assoc Physicians India.
10. Ibanez L, Vidal X, Ballarin E, Laporte JR. Population-
based drug-induced agranulocytosis. Arch Intern Med.
Cesur et al.
Pancytopenia with calcium dobesilate
Turk J Hematol 2011; 28: 77-8
Table 1. The patient’s complete blood count during the follow-up peri-
od, with and without medication
Before 6 Weeks After 1 Week After 3 months later,
WBC (×109 L-1) 6.2 2.4 5.93 4.0
Neutrophils (%) 67 34 70 74
Lymphocytes (%) 20 48 21 16
Basophiles (%) 9 16 7 6
Eosinophils (%) 1 1 1 2
3 1 1 2
Hb (g dL-1) 13.1 10.3 11.4 10.8
Platelet (×109 L-1) 219 122 235 101
Platelet (×109 L-1) 219 122 235 101
CaD: Calcium dobesilate; WBC: white blood cells; Hb: hemoglobin