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112802 oral miltefosine for indian visceral leishmaniasis


C o py r ig ht 2 0 0 2 by t he Ma s s ac h u s e t t s Me d ic a l S o c ie t y V O L U M E 3 4 7
N U M B E R 2 2
ORAL MILTEFOSINE FOR INDIAN VISCERAL LEISHMANIASIS
SHYAM SUNDAR, M.D., T.K. JHA, M.D., C.P. THAKUR, M.D., JUERGEN ENGEL, PH.D., HERBERT SINDERMANN, PH.D., CHRISTINA FISCHER, KLAUS JUNGE, PH.D., ANTHONY BRYCESON, M.D., AND JONATHAN BERMAN, M.D., PH.D.
ABSTRACT
Background
fection of the visceral reticuloendothelial visceral leishmaniasis, which occurs primarily in the Indian subcontinent. Almost all untreated patients die, from sandfly bites. There are approximate- and all the effective agents have been parenteral. Mil- ly 500,000 cases per year, with the majority in north- tefosine is an oral agent that has been shown in small eastern India, Nepal, and Bangladesh. Other areas numbers of patients to have a favorable therapeutic where visceral leishmaniasis is endemic include East index for Indian visceral leishmaniasis. We performed Africa, the littoral region of the Mediterranean, and a clinical trial in India comparing miltefosine with the Brazil.1 The disease presents with fever, hepatospleno- most effective standard treatment, amphotericin B.
Methods
megaly, and pancytopenia. Almost all untreated pa- comparison, in which 299 patients 12 years of age or tients die, generally because of intercurrent infection.
older received orally administered miltefosine (50 or Both standard treatment and secondary treatment are 100 mg [approximately 2.5 mg per kilogram of body parenteral. Standard treatment consists of daily injec- weight] daily for 28 days) and 99 patients received in- tions of pentavalent antimonial compounds for 28 travenously administered amphotericin B (1 mg per days. In regions of India where there is a high frequen- kilogram every other day for a total of 15 injections).
cy of resistance to antimony, amphotericin B in a dose Results
of 15 to 20 mg per kilogram of body weight is admin- age, weight, proportion with previous failure of treat- istered intravenously over a period of 30 to 40 days.4 ment for leishmaniasis, parasitologic grade of splenic In patients who can pay for liposomal amphotericin B, aspirate, and splenomegaly. At the end of treatment, 5 mg per kilogram is administered intravenously over splenic aspirates were obtained from 293 patients in the miltefosine group and 98 patients in the ampho-tericin B group. No parasites were identified, for an Miltefosine (hexadecylphosphocholine) is an alkyl- initial cure rate of 100 percent. By six months after the phosphocholine analogue that was originally devel- completion of treatment, 282 of the 299 patients in the oped as an antitumor agent but proved to be clinically miltefosine group (94 percent [95 percent confidence ineffective. Although the antileishmanial biochemical interval, 91 to 97]) and 96 of the 99 patients in the am- mechanism remains unclear, miltefosine has good ef- photericin B group (97 percent) had not had a relapse; ficacy against leishmania in vitro6 and, with oral ad- these patients were classified as cured. Vomiting and ministration, in animals.7,8 Within the past five years, diarrhea, generally lasting one to two days, occurred four phase 1–2 studies of the efficacy and tolerability in 38 percent and 20 percent of the patients in the mil- of oral miltefosine for Indian visceral leishmaniasis Conclusions
safe treatment for Indian visceral leishmaniasis. Mil- 29 of 30 patients (97 percent) were cured with 100 mg tefosine may be particularly advantageous becauseit can be administered orally. It may also be helpful in From the Institutes of Medical Sciences, Banaras Hindu University, Vara- regions where parasites are resistant to current agents.
nasi (S.S.); the Kala-azar Research Center, Brahmpura, Muzaffarpur (T.K.J.); and Balaji Utthan Sanastan, Patna (C.P.T.) — all in India; Zentaris–AstaMedica, Frankfurt am Main, Germany (J.E., H.S., C.F., K.J.); the London Copyright 2002 Massachusetts Medical Society.
School of Hygiene and Tropical Medicine, London (A.B.); and the WalterReed Army Institute of Research, Silver Spring, Md. (J.B.). Address reprintrequests to Dr. Berman at the National Center for Complementary and Al-ternative Medicine, 6707 Democracy Blvd., Ste. 401, Bethesda, MD 20892,or at bermanjo@mail.nih.gov.
N Engl J Med, Vol. 347, No. 22 · November 28, 2002 · www.nejm.org · 1739
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne of miltefosine per day (a mean of 2.5 mg of miltefo- tional Cancer Institute.13 Parasitologic analysis of splenic aspirates sine per kilogram per day) for 28 days.
was performed at the end of therapy and was repeated at six-month We report the results of a phase 3 trial of miltefo- follow-up in patients with signs and symptoms suggestive of vis-ceral leishmaniasis. Male patients of reproductive age were queried sine. The objectives of the trial were to investigate the a median of 23 months (range, 11 to 31) after the completion of efficacy and toxicity of miltefosine in larger numbers therapy regarding the numbers and health of children born to their of patients and in comparison with the efficacy and toxicity of amphotericin B, the most potent clinical Efficacy End Points
antileishmanial agent currently in use.
The density of parasites was graded on a log scale from 0 (no parasites per 1000 fields of 1000¬ power) to 6 (>100 parasitesper field).14 Cure was defined as an absence of parasites at the end Study Design
of therapy or a parasite density of 1 with no parasites on repeated We undertook a randomized, open-label, phase 3 trial comparing smear one month later (initial cure) plus no relapse during the six oral miltefosine with the drug considered to represent the stand- months of follow-up. Relapse was defined by signs or symptoms ard of care, intravenous amphotericin B. All authors participated suggestive of leishmaniasis and appearing after an initial cure, fol- fully in the design of the study, had access to all study data, and lowed by a positive test for leishmania in a splenic aspirate. Treat- take responsibility for data analysis. The authors who are not em- ment failure was defined as either the lack of initial cure or relapse.
ployees of the sponsoring company had authority over the prep-aration of the manuscript. The study was conducted in parallel at Statistical Analysis
three medical centers in Bihar, India. The ethics committees at the The end point of this trial designed to assess noninferiority was three clinical centers approved the study protocol, the consent the proportion of patients with a final cure. The considerations forms, and all amendments. The initial visits of all study patients for the sample size and the confirmatory analysis were determined were completed between July 1999 and July 2000.
on the basis of the restricted maximum-likelihood estimation of thevariance of the test statistic,15 with a one-sided alpha of 0.025, a Study Drug
power of 0.80, a margin of noninferiority of 15 percent, assumed Miltefosine (Zentaris) was administered orally for 28 days in a cure rates for miltefosine of 88 to 92 percent and for amphotericin dose as close to 2.5 mg per kilogram per day as was practicable. Pa- of 94 to 98 percent, and a ratio of 3:1 for the random assignment tients weighing more than 25 kg received 100 mg daily (one 50-mg of patients to miltefosine and amphotericin. The number of patients capsule in the morning and one capsule in the evening after meals); patients weighing 25 kg or less received 50 mg each morning. Am-photericin B (Fungizone, Bristol-Myers Squibb) was administered intravenously at a total dose of 15 mg per kilogram over a periodof 30 days (1 mg per kilogram every other day for a total of 15 in- Base-Line Characteristics of the Patients
fusions). All patients were hospitalized during treatment, which was Base-line characteristics of the patients are summa- rized in Table 1. Approximately 10 percent of screened Study Patients
patients with visceral leishmaniasis were excluded Potentially eligible patients were 12 years of age or older with vis- from the trial because they had severe disease (data not ceral leishmaniasis suspected on the basis of clinical presentation (fe- shown). Ultimately, 299 patients received miltefosine, ver, splenomegaly, and cytopenia) and diagnosed by the presence and 99 patients received amphotericin.
of leishmania in splenic aspirates. Criteria for exclusion were a plate- Except for sex, the base-line characteristics were let count below 50,000 per cubic millimeter, a white-cell count be-low 1000 per cubic millimeter, a hemoglobin concentration of less similar in the two treatment groups. The mean par- than 6 g per deciliter, results on liver-function tests (serum aspartate asite density was approximately grade 3 (defined as aminotransferase and alanine aminotransferase concentrations) more 1 to 10 parasites per 10 fields); mean splenomegaly than three times the upper limit of normal, a bilirubin concentra- was 6.9 cm. Most patients had moderate pancytope- tion more than twice the upper limit of normal, serum creatinineor blood urea nitrogen values more than 1.5 times the upper limit nia. The serum aspartate aminotransferase and alanine of normal, other major medical illness including human immuno- aminotransferase concentrations were above the up- deficiency virus infection or severe malaria, pregnancy or lactation, per limit of normal in 82 percent of the patients in the inability to maintain use of contraception for the period of treat- miltefosine group and 77 percent of those in the am- ment plus two months, and previous therapy with amphotericin B.
photericin group. Twenty-eight percent of patients Study Procedures
had previously been treated with pentavalent anti- After written informed consent and data to evaluate eligibility had been obtained, patients were centrally registered and randomlyassigned at each site to miltefosine or amphotericin therapy in a Efficacy
3:1 ratio with the use of permuted blocks of four patients each.
The efficacy of the treatments is shown in Table 2.
Treatment was administered as described above. Weekly duringtherapy, at the end of therapy (on day 28 for patients receiving mil- At the end of the course of treatment, splenic aspirates tefosine and on day 30 for those receiving amphotericin), and six were obtained from 293 of the 299 patients in the mil- months after the completion of therapy, patients were monitored tefosine group and 98 of the 99 patients in the ampho- for subjectively reported adverse events, hematologic variables, se- tericin group. All were parasitologically negative. Thus, rum chemistry as on admission, and the size of the spleen as meas-ured in centimeters below the left costal margin. Adverse events for both treatment groups, the rate of initial cure was were graded according to the Common Toxicity Criteria of the Na- 100 percent among patients for whom parasitologic 1740 · N Engl J Med, Vol. 347, No. 22 · November 28, 2002 · www.nejm.org
M I LT E F O S I N E F O R I N D I A N V I S C E R A L L E I S H M A N I AS I S
TABLE 1. BASE-LINE CHARACTERISTICS OF THE PATIENTS.*
CHARACTERISTIC
MILTEFOSINE GROUP
AMPHOTERICIN GROUP
NORMAL VALUE
Splenomegaly — cm below left costal margin Serum aspartate aminotransferase — U/liter Serum alanine aminotransferase — U/liter *Plus–minus values are means ±SD. To convert values for serum creatinine to milligrams per deciliter, divide by 88.4.
To convert values for blood urea nitrogen to millimoles per liter, multiply by 0.357.
†Data for this patient were analyzed with those for the amphotericin group.
‡Density ranges from 0 to 6, with higher scores indicating greater splenic parasite load.
TABLE 2. EFFICACY OF MILTEFOSINE AS COMPARED WITH THAT OF AMPHOTERICIN.*
MILTEFOSINE
AMPHOTERICIN
EFFICACY
At completion of therapy
Parasitologic cure — no. (% [95% CI])
Difference between cure rate with miltefosine and cure rate with amphotericin —% (lower 95% confidence limit) At 6 mo
Final cure — no. (% [95% CI])
Difference between cure rate with miltefosine and cure rate with amphotericin —% (lower 95% confidence limit) analysis was performed. In both groups, at the end tefosine group and 16 in the amphotericin group had of therapy, the mean size of the spleen below the cos- symptoms that were potentially indicative of leishma- tal margin had decreased dramatically to 1.0 cm.
niasis. In 86 of these 113 patients, causes other than At the six-month follow-up visit, 291 patients in the leishmaniasis were identified. The 27 patients in whom miltefosine group and 96 patients in the amphotericin relapse of leishmaniasis could not be ruled out clini- group were evaluated. A total of 97 patients in the mil- cally were all in the miltefosine group. In most of these N Engl J Med, Vol. 347, No. 22 · November 28, 2002 · www.nejm.org · 1741
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 3. TOXIC EFFECTS.*
MILTEFOSINE
AMPHOTERICIN
VARIABLE
Symptoms
Vomiting — no. (%)
Laboratory values§
Serum aspartate aminotransferase
Mean change from base line — U/liter (%) Mean change from base line — U/liter (%) patients, the abnormality seen at that time was anemia.
months (90 percent) or in 88 of the 96 patients in the Splenic aspiration was performed in these 27 patients, amphotericin group evaluated at that time (92 per- and aspirates from 9 patients tested positive for leish- cent). There were eight patients in the miltefosine maniasis. Thus, there were nine patients in the milte- group and three patients in the amphotericin group fosine group (3 percent) and no patients in the ampho- who could not be assessed at the six-month follow- tericin group with a relapse of visceral leishmaniasis up. The cure rate for miltefosine was therefore 282 of after therapy. Spleens were not palpable in 262 of the 299, or 94 percent, as compared with 96 of 99, or 97 291 patients in the miltefosine group evaluated at six percent, for amphotericin. Among the patients who 1742 · N Engl J Med, Vol. 347, No. 22 · November 28, 2002 · www.nejm.org
M I LT E F O S I N E F O R I N D I A N V I S C E R A L L E I S H M A N I AS I S
TABLE 3. CONTINUED.
MILTEFOSINE
AMPHOTERICIN
VARIABLE
Laboratory values§ (continued)
Serum creatinine
Mean change from base line — µmol/liter (%) Corrected QT interval on electrocardiography *To convert values for serum creatinine to milligrams per deciliter, divide by 88.4. To convert values for blood urea nitrogen to millimoles per liter, multiply by 0.357.
†For vomiting, a Common Toxicity Criteria grade of 1 signifies 1 episode per day, grade 2 signifies 2 to 5 episodes per day, grade 3 signifies 6 to 10 episodes per day, and grade 4 signifies more than10 episodes per day.
‡For diarrhea, a Common Toxicity Criteria grade of 1 signifies an increase of 2 to 3 stools per day, grade 2 an increase of 4 to 6 stools per day, grade 3 an increase of 7 to 9 stools per day, and grade4 an increase of 10 or more stools per day.
§Base-line values are shown in Table 1.
¶For aspartate aminotransferase and alanine aminotransferase, Common Toxicity Criteria grade 1 signifies values at least 2.5 times the upper limit of normal, grade 2 values 2.6 to 5.0 times the upperlimit of normal, and grade 3 values 5.1 to 20 times the upper limit of normal.
¿For creatinine, Common Toxicity Criteria grade 1 signifies values less than 1.5 times the upper limit of normal, grade 2 values 1.5 to 3.0 times the upper limit of normal, and grade 3 values 3.1 to6.0 times the upper limit of normal.
**For blood urea nitrogen, Common Toxicity Criteria grade 1 signifies values less than 1.5 times the upper limit of normal, grade 2 values 1.5 to 2.4 times the upper limit of normal, and grade 3values more than 2.4 times the upper limit of normal.
were evaluated at six months, the cure rate was 282 Cure Rate among Patients with Premature
of 291 (97 percent) for miltefosine and 96 of 96 (100 Discontinuation of Drug Treatment
Of the nine patients in the miltefosine group in whom drug treatment was discontinued prematurely, Patients with Relapses
one withdrew from the study and eight discontinued The nine patients who had a relapse did not differ the drug because of a lack of tolerance or intercurrent from the cured patients in terms of the following base- disease. Of these eight patients, four did not return line characteristics. For the patients with relapse, the for the six-month follow-up. Of the other four pa- mean values were as follows: age, 36 years; extension tients, three had a final cure: one who discontinued of the spleen below the costal margin, 6.7 cm; parasite treatment after 14 days because of a high bilirubin density, 2.1; proportion that had received previous concentration, one who discontinued treatment after treatment, 67 percent; and daily dose, 2.3 mg per kil- 6 days because of Stevens–Johnson syndrome, and one who discontinued treatment after day 21 because N Engl J Med, Vol. 347, No. 22 · November 28, 2002 · www.nejm.org · 1743
The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne of bleeding hemorrhoids. The fourth patient, who grade 3 increase in blood urea nitrogen on day 21.
discontinued treatment after 11 days because of ar- The creatinine and blood urea nitrogen concentrations partially regressed on day 28 despite continued ther-apy. In the amphotericin group, 60 percent of patients Cure Rate among Patients with Previous Therapy
had elevated blood urea nitrogen or creatinine levels for Leishmaniasis
In the miltefosine group, the cure rate among pa- Hemoglobin, leukocytes, and platelets increased tients who had previously been treated was identical steadily in both treatment groups (data not shown), to the cure rate among patients who had not (94 in accord with the resolution of disease. Electrocardi- ography (Table 3) and ophthalmologic examination inboth treatment groups did not show clinically relevant Toxic Effects
Signs and symptoms of toxic effects are summa- rized in Table 3. The percentage of patients in the mil- Reproductive Capacity
tefosine group who had vomiting or diarrhea was In rats, high-dose miltefosine impairs male repro- higher than that in the amphotericin group. Howev- ductive capacity. In this study, we tracked the number er, such effects were mild (grade 1 or 2) in almost all of live and healthy infants born to sexual partners of affected patients in both groups, and the number of male patients of reproductive age who did not use con- patients taking antiemetic or antinausea agents was traception. In the miltefosine group, there were 48 3 to 4 percent in both groups. One patient in the mil- live infants with no known congenital abnormalities tefosine group discontinued treatment because of gas- born to the partners of 80 such male patients (0.6 trointestinal intolerance. Ninety percent of the patients birth per patient). By comparison, in the amphotericin in the amphotericin group had rigors associated with group, there were 12 live infants with no congenital fever, whereas only one patient in the miltefosine abnormalities born to the partners of 20 such male Laboratory Variables
Serious and Other Adverse Events
The results of laboratory tests are summarized in Six patients in the miltefosine group and one patient Table 3. In the miltefosine group, the mean serum in the amphotericin group had serious adverse events.
aspartate aminotransferase concentration increased by In the miltefosine group, these events included con- 17 percent during the first week of therapy, before vulsion due to a cranial cyst (in two patients), abrupt falling to the pretreatment values during the second anemia due to bleeding hemorrhoids (in one patient), week and then decreasing further as disease resolved.
Plasmodium vivax malaria (in one patient), gram-neg- The mean serum alanine aminotransferase concentra- ative meningitis that resulted in death two days later tion increased by 12 percent during the second week (in one patient), and the Stevens–Johnson syndrome before regressing by the six-month follow-up visit.
(in one patient). Only the Stevens–Johnson syndrome There was a grade 3 elevation in the serum aspartate was thought to be attributable to drug treatment. The aminotransferase concentration in 16 patients in the patient was a 12-year-old boy who received 50 mg miltefosine group (5 percent), but therapy was not of miltefosine (2.8 mg per kilogram) daily. On day terminated prematurely in any patient because of liver- 6 of therapy, rash was seen, and treatment was stopped.
enzyme values. In the amphotericin group, 3 percent Bullae, necrosis, and peeling skin were apparent on day 7; dexamethasone therapy was started. Fever abated Mean values on renal-function tests did not change on day 8. The patient was afebrile on day 12, and le- significantly in the miltefosine group. However, 16 sions healed by approximately day 20. As noted above, percent of patients had grade 1, 2, or 3 increases in blood urea nitrogen values, serum creatinine concen-trations, or both. There were five patients in the mil- Other Discontinuations Due to Adverse Events
tefosine group (2 percent) with grade 3 elevations: in the Miltefosine Group
one patient had an elevated creatinine value of 1.63 mg The four patients in the miltefosine group (1 per- per deciliter (144 µmol per liter) before treatment, cent) who discontinued therapy because of probable which peaked at 5.00 mg per deciliter (442 µmol per drug intolerance were as follows. One patient had ar- liter) during therapy; three patients had concurrent thritis and an allergic skin rash on day 9 and stopped administration of albendazole and diclofenac, concur- taking miltefosine the next day. One patient, who was rent malaria, or concurrent meningitis. The fifth pa- receiving concomitant treatment with metronidazole tient had no explanation other than miltefosine treat- for giardia cysts, had grade 4 diarrhea requiring par- ment for a grade 2 increase in serum creatinine and a enteral fluids after two weeks of miltefosine therapy.
1744 · N Engl J Med, Vol. 347, No. 22 · November 28, 2002 · www.nejm.org
M I LT E F O S I N E F O R I N D I A N V I S C E R A L L E I S H M A N I AS I S
Miltefosine was stopped at that point. One patient had decreases in the numbers of leukocytes and platelets an increase in the bilirubin concentration on day 14 of miltefosine treatment, at which time miltefosine was For comparison with miltefosine, amphotericin B stopped. The fourth patient had grade 4 thrombocy- was tested in 99 patients in this phase 3 study. A total topenia, epistaxis, increases in aspartate aminotransfer- of 97 percent of patients who received amphotericin ase, and an increase in blood urea nitrogen. Therapy were cured, but the well-known adverse effects of fe- ver or chills and elevations on renal-function tests oc-curred in 90 percent and 60 percent of patients, re- DISCUSSION
spectively. Liposomal amphotericin B is highly effective This controlled trial shows that oral miltefosine is and well tolerated, but its cost is a barrier to wide- an effective and safe treatment for Indian visceral leish- spread use even in developed countries. Pentamidine maniasis in immunocompetent patients 12 years of age has been used in antimony-resistant cases, but toler- or older. To our knowledge, this is the largest chemo- ance is problematic, and resistance is now evident.18,19 therapy study performed according to the Good Clin- ical Practice guidelines16 for any form of leishmania- Given our demonstration of a cure rate of 94 per- sis. Of the 398 patients who presented with moderate cent in a large number of patients 12 years of age or visceral leishmaniasis (kala-azar), 299 were treated older, the efficacy of miltefosine compares well with with oral miltefosine for 28 days at a dose of approx- that of all other agents, including amphotericin B and imately 2.5 mg per kilogram per day. At the end of liposomal amphotericin B. The side effects of milte- therapy, none of the 293 patients in whom parasito- fosine are generally tolerable and compare favorably logic analysis was performed had evidence of parasites, with those of all agents other than liposomal ampho- and all were considered to be cured. At the six-month tericin B. Miltefosine has toxic effects on reproductive follow-up, 291 patients were evaluated; 9 had para- capacity in female animals, and strict contraception sites on splenic aspiration. Thus, the six-month cure must be practiced by female patients during the pe- riod of treatment and for two months after therapy.
Vomiting and diarrhea occurred in 38 percent and The risk of fetal abnormalities means that the distri- 20 percent, respectively, of patients receiving milte- bution of drugs must be carefully controlled in coun- fosine. Approximately three quarters of the gastroin- tries where leishmaniasis is endemic.
testinal events lasted one to two days per patient and The striking advantage of miltefosine is that it is ad- occurred once on each of these days. The mean serum ministered orally. Miltefosine is now registered in In- aspartate aminotransferase and alanine aminotransfer- dia (under the trade name Impavido [Zentaris]) for ase concentrations increased by approximately 15 per- patients 2 years of age or older on the basis of other cent during the first and second weeks, respectively, studies in patients in India 2 to 11 years of age that before normalizing by the end of week 2 and by the have been completed but not reported. However, be- six-month follow-up visit, respectively. The transient cause the heaviest patient in Indian studies weighed elevation in liver enzymes during treatment is attrib- only 67 kg, dose recommendations for patients with uted to a moderate effect of miltefosine on hepato- higher weights have not yet been specified. Future cytes. Mean results on renal-function tests were not trials should show whether this drug will be useful substantially altered by miltefosine, although 16 per- against visceral leishmaniasis in other regions and in cent of individual patients had mild-to-moderate ele- populations for which parenteral agents are not at- vations of serum creatinine, blood urea nitrogen, or both. Results on electrocardiography and ophthalmicexamination and male reproductive capacity were not Supported by grants from Zentaris (to Dr. Sundar) and the Special Pro- gram for Research and Training in Tropical Diseases of the United NationsDevelopment Program, the World Bank, and the World Health Organiza- Therapeutic agents may be compared with respect to efficacy, tolerance, and feasibility and cost of admin-istration. Standard therapy for visceral leishmaniasis is We are indebted to Drs. Win Gutteridge and Juntra Karbwang pentavalent antimony or, in regions with a high prev- of the Special Program for Research and Training in Tropical Diseas-es, World Health Organization; to Drs. Andreas Voss and Peter Bach- alence of antimony resistance such as the one where man of Zentaris; and to the clinicians and support staffs at the involved this study was conducted, amphotericin B. Antimoni- medical centers for their contributions. al compounds have the disadvantages of both toxicityand clinical resistance in at least 40 percent of cases in REFERENCES
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Copyright 2002 Massachusetts Medical Society.
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In 1990, the Federal Ministry of Health published the first edition of the Approved Patent Medicines List for Patent Medicines Shops in the country, and in 1994 the second edition (2nd Edition) was This is an updated list of Patent Medicines approved for stock and sale in licenced Patent Medicines Shops throughout Nigeria. It is prepared with generic names. It has been prepared in line with the

Reglamentoquesoroncal

Reglamento de la Denominación de Origen «Roncal» CAPÍTULO PRIMERO Artículo 1. De acuerdo con lo dispuesto en la Ley 25/1970, de 2 de diciembre, y en su Reglamento, aprobado por Decreto 835/1972, de 23 de marzo, en el Decreto 3711/1974, de 20 de diciembre, en el Real Decreto 728/1988, de 8 de julio y en el Real Decreto 2654/1985, de 18 de diciembre, de traspaso de funciones y servicio

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