known adverse effects of ginseng.1 We present a case of menstrual alter-
ations related to ginseng consumption.
lance centres in the European Community. Pharmacoepidemiol Drug Saf
1992;1:87-9.
Case Report. A 48-year-old woman was admitted to the hospital with a three-
week history of metrorrhagia. The patient had never experienced menstrual disor-
ders before. On questioning, she described self-medication with three daily cap-
sules of Pharmaton Complex (dimethylaminoethanol bitartrate; standardized gin-
seng G115 extract equivalent to 120 mg/d; vitamins A, B1, B2, B6, B12, C, D3, and
E; nicotinamide; calcium pantothenate; rutoside; iron; calcium; phosphorus; sodi-
um fluoride [Fluor]; copper; potassium; manganese; magnesium; zinc) for two
months because a companion advised her to take it to improve her work perfor-
mance. She was not taking any other medication, including over-the-counter prod-
ucts and cosmetics, that might contain hormonal compounds. The physical exami-
nation, echography, gynecologic study, sex hormones, complete blood count, co-
agulation, and biochemical tests were normal. The metrorrhagia disappeared four
days after discontinuing Pharmaton Complex administration. The patient experi-
enced no menstrual alteration in the following six months and declined taking the
medication again.
4. Punnonen R, Lukola A. Oestrogen like effect of ginseng. Br Med J 1980;
281:1110.
5. Greenspan EM. Ginseng and vaginal bleeding (letter). JAMA 1983;249:
2018.
6. Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream and un-
explained vaginal bleeding. Am J Obstet Gynecol 1988;159:1121-2.
7. D’Arcy PF. Adverse reactions and interactions with herbal medicines.
Part 1. Adverse reactions. Adverse Drug React Toxicol Rev 1991;10:
189-208.
8. Vademecum Internacional. 39th ed. Madrid: Medicom SA, 1998:513.
9. Catálogo de especialidades farmacéuticas 1999. Consejo General de
Colegios Oficiales Farmacéuticos. Madrid: EINSA, 1999:396.
Discussion. The causal relation between Pharmaton Complex and
metrorrhagia is probable in this case,2,3 because (1) isolated cases of
vaginal bleeding have been reported4-7 in women taking ginseng (an ac-
tive component of Pharmaton Complex), apparently as a result of its es-
trogenic effect; (2) a clear temporal relationship was observed; (3) the
bleeding stopped after withdrawing the medication; (4) other alternative
causes were discarded, including a possible influence of the other active
components associated to ginseng, for which no such reactions have
been reported; and (5) the objective evidence of the adverse reaction was
that the patient had never experienced menstrual disorders before taking
the medication and presented no further such problems in the six months
following withdrawal of the drug.
In Spain, ginseng is commercialized in the form of Panax ginseng or
Korean ginseng, as well as in the form of Siberian ginseng or Electhero-
coccus senticosus. In terms of Spanish drug formulation,8,9 16 medica-
tions presently contain ginseng. The technical specifications provided for
most of these products make no mention of menstrual alterations as a po-
tential adverse effect; Pharmaton Complex is no exception to this. Al-
though this adverse effect may be infrequent, the growing consumption
of products containing ginseng suggests the need to include this sub-
stance as an etiologic factor in menstrual disorders.
Comment: potential risk of valproic acid therapy in patients who
are HIV-positive
TO THE EDITOR: We read with great interest the case report by Hugen et
al., entitled Carbamazepine–Indinavir Interaction Causes Antiretroviral
Therapy Failure (2000;34:465-70). We commend the authors on their re-
port of a timely topic that is problematic for many neurologists and HIV
clinicians; that is, the treatment of neurologic disorders in the HIV-posi-
tive patient.1 We agree with the authors that HIV disease is often associ-
ated with multiple neurologic manifestations that occur secondary to dis-
ease progression, adverse effects from highly active antiretroviral thera-
py (HAART), or opportunistic infections, as presented in the case that
they describe. Disorders such as seizures, headaches, depression, bipolar
disorders, and neuropathies are common in patients who are HIV-posi-
tive. As the authors stated, these conditions are frequently refractory to
traditional therapy, yet responsive to treatment with antiepileptic drugs
(AEDs) such as carbamazepine, phenytoin, and phenobarbital. Unfortu-
nately, however, these drugs are inducers of the cytochrome P450 (CYP-
450) enzyme system and, therefore, have the potential to compromise
HAART therapy, as occurred in this case.
Additionally, we agree with the authors’ call for additional studies
evaluating these potentially therapy-compromising drug–drug interac-
tions, as well as their recommendations of using alternative agents until
the safety of combining these AEDs with HAART can be established.
However, we do question the authors’ recommendation of using valproic
acid (VPA) as an alternative anticonvulsant agent in these patients.1,2 It
has been demonstrated in small in vitro studies1-6 that replication of HIV
was stimulated in the presence of VPA. This phenomenon may occur
secondary to VPA-mediated decreases in red blood cell glutathione re-
ductase. As intercellular concentrations of reduced glutathione drop, T-
cell activation is affected, and HIV replication subsequently increases.3,4
Alternatively, it has also been demonstrated5,6 that VPA plays a direct
role in HIV transcription and expression, an effect that seems to be inde-
pendent of its ability to alter glutathione synthesis. These effects are, in-
terestingly, not unique to HIV, as valproate has also been demonstrated7
to stimulate cytomegalovirus (CMV) replication. The mechanism of its
effect on CMV replication is unclear; however, VPA is a short-chain fat-
ty acid that does not affect the CMV promoter and may be analogous to
sodium butyrate in its potentiation of CMV replication.6,8,9
Vicente Palop-Larrea MD PhD
Specialist in Family and Community Medicine
Service of Internal Medicine
Hospital de la Ribera
Alzira, Valencia, Spain
José Luís Gonzálvez-Perales MD
Specialist in Family and Community Medicine
Service of Internal Medicine
Hospital de la Ribera
Carlos Catalán-Oliver MD
Specialist in Family and Community Medicine
Service of Internal Medicine
Hospital de la Ribera
Angel Belenguer-Varea MD
Specialist in Family and Community Medicine
Service of Internal Medicine
Hospital de la Ribera
We concede that no immediate clinical correlation has been estab-
lished with these in vitro studies. However, the potential ramifications of
VPA-induced viral replication may be analogous to the results observed
with nonadherent or subtherapeutic HAART therapy. Given even the
theoretical risk of this phenomenon, we are reluctant to recommend the
use of VPA in any HIV-infected individual. Additionally, we believe that
this interaction deserves attention equal to that given to possible therapy-
compromising CYP450 drug–drug interactions, as both may contribute
to the emergence of viral resistance and HAART failure. Further re-
search may also be necessary to evaluate the safety and efficacy of other
AEDs, such as lamotrigine and gabapentin.
Inocencia Martínez-Mir MD PhD
Senior Researcher
Research Service
Valencia University General Hospital
Avda. Tres Cruces s/n
46014-Valencia, Spain
FAX 34 963503964
E-mail martinez_ino@gva.es
REFERENCES
1. Palop V, Catalán C, Rubio E, Martínez-Mir I. Ginecomastia en un varón
y ginseng (letter). Med Clin (Barc) 1999;112:758.
2. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A
method for estimating the probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30:239-45.
Comments on articles previously published are submitted to the authors of those arti-
cles. When no reply is published, either the author chose not to respond or did not do
so in a timely fashion. Comments and replies are not peer reviewed.–ED.
3. Meyboom RHB, Royer RJ. Causality classification at pharmacovigi-
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2000 November, Volume 34
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