THE EFFECT OF DIET ON THE HEMOGLOBIN, ERYTHROCYTE, AND LEUKOCYTE CONTENT OF THE BLOOD OF THE RHESUS MONKEY (MACACA MULATTA)

1. Rhesus monkeys fed purified rations supplemented with adequate amountsof the B vitamins, ascorbic acid, and whole liver substance maintained the following average blood picture:

See PDF for Table

2. Natural diets or purified rations supplemented with liver extract do not support the above blood picture. The hemoglobin is lower and there is an increase inthe range of the total leukocyte count and in the neutrophil-lymphocyte ratioto 2.0 ([unknown]). These figures are similar to the values in the literature and generallyaccepted as the normal.

3. Previous reports have shown the characteristic blood dyscrasias which develop when monkeys are fed certain B vitamin-deficient diets. These changes aresummarized graphically in this paper.

4. The importance of determining the concentration of hemoglobin and theformed elements of the blood as a diagnostic test in nutritional studies has beenshown.

Note: We wish to acknowledge our indebtedness to Merck and Co., Rahway, N. J., for some of the crystalline vitamins; to Wilson Laboratories, Chicago, Ill., for the various liver preparations; and to LederleLaboratories, Inc., Pearl River, N. Y., for synthetic folic acid.The authors are grateful to Miss Ethel Thewlis for aid in determining cellular elements and to Drs.Harry A. Waisman and James H. Shaw for assisting in early parts of the work.

     

FOLIC ACID IN THE TREATMENT OF PERNICIOUS ANEMIA

1. Folic acid in daily doses of 15 to 50 mg., orally, or 20 mg. intramuscularly,usually produced a submaximal reticulocytosis in patients with pernicious anemia.

2. In 3 patients the hemoglobin and red cells rose to a level of about 12.0 Gm.and 4.3 million respectively without further rise after 3 months of therapy.

3. Folic acid in the above doses failed to prevent the development or progressionof neurological symptoms indicative of subacute combined sclerosis.

4. In 5 patients folic acid in doses of 5 or 10 mg. orally daily combined with unit of liver extract injected intramuscularly daily produced a reticulocytosisgreater than that anticipated from adequate liver extract therapy alone.

5. With combined liver extract and folic acid therapy there was evidence ofimprovement in the symptoms and signs of subacute combined sclerosis in 3patients.

6. Folic acid, combined with unit of liver extract, was found to produce acomplete hematological remission.

7. Folic acid, alone or in combination with small doses of liver extract, producedan improvement in appetite and general well-being in patients with perniciousanemia.

8. The possible enhancing effect of liver extract when combined with folic acidcannot be due to the folic acid content of the former since 1 unit of liver extractcontains only 0.38 micrograms of folic acid.³¹

9. Folic acid administered to a patient with macrocytic anemia due to faultypostoperative intestinal digestion and absorption, produced a complete remissionin the blood picture and a marked improvement in signs and symptoms.

     

Experimental anemias in the rat; II. The effect of various sulfonamides in producing a pteroylglutamic acid deficiency and the pteroylglutamic acid activity of test substances

1. Different sulfonamides were tested to ascertain their effect in producing thecharacteristic symptoms of acute PGA deficiency in rats fed on synthetic diets.Sulfasuxidine (1 per cent) and the less soluble phthalylsulfathiazole (1 per cent)were equally effective. Sulfathiazole in 1 per cent concentration produced a hemolytic anemia not reversible by PGA or whole liver powder. In a 0.5 per cent concentration it was also effective, but in view of its toxicity, the less soluble sulfonamides were to be preferred. A mixture of 0.5 per cent sulfathiazole and 0.5 percent sulfadiazine was extremely toxic and produced a hemolytic anemia. Sulfaguanidine was toxic at 1 per cent concentration.

2. When intermittent small doses of PGA were given to PGA-deficient rats toprolong their life from 45 up to 155 days, 1 per cent sulfasuxidine or phthalylsulfathiazole, or 0.5 per cent sulfathiazole were equally efficient in producing regularlya macrocytic normochromic anemia.

3. The response of PGA-deficient rats to single doses of PGA has been studiedand an assay procedure has been suggested which uses the weight increase andduration of cure as the measure of the response. The W.B.C. and reticulocyte response can also be used as a qualitative indication of PGA activity.

4. Of the substances tested by this procedure, vitamin B₁₂, purified perniciousanemia preparations, ascorbic acid and xanthopterin showed no PGA activity. Acommercial yeast preparation and Teropterin were found to possess biologic activity comparable with that found by other workers in assays on chicks.

Note: ACKNOWLEDGMENTSWe wish to thank Dr. E. Lester-Smith, of the Glaxo Laboratories, for the generous supply of vitaminB₁₂, Dr. T. H. Jukes, of the Lederle Laboratories, for the gift of PGA and Teropterin, and Dr. W. Jacobson for the samples of purified P. A. liver preparations and xanthopterin.

     

Refractory megaloblastic anemia

1. Fifty-nine cases of megaloblastic anemia refractory partially or completelyto potent liver extracts given parenterally have been investigated in Edinburghduring the past six years. Thirty-four of these cases were associated with pregnancy, the puerperium or the sprue syndrome. No explanation of the cause of themegaloblastic anemia was discovered in the remaining 25 cases.

2. The etiology, clinical features and treatment of 25 cases of idiopathic refractory megaloblastic anemia are described. Attention is directed to the excellenttherapeutic effects produced by proteolysed liver or folic acid.

3. The mechanisms involved in refractoriness to potent parenteral liver extractsare discussed.

4. In certain cases of refractory megaloblastic anemia it is suggested that an unknown hematinic principle, in addition to the liberating factor in purified parenteral liver extract and folic acid, is required for the complete restoration of normoblastic blood formation.

Note: ACKNOWLEDGMENTSMy thanks are due to many members of my staff who have helped in theseinvestigations, particularly to Professor L. J. Davis formerly lecturer in Medicinein the University of Edinburgh, and to Dr. Girdwood. Grateful acknowledgmentmust also be made to Doctor Riding, Medical Director of Evans Medical SuppliesLtd. and his research chemists who were responsible for the preparation of proteolysed liver and the other fractions of liver mentioned above.

     

Liver extract refractory megaloblastic anemia

1 . The patient described in this report had macrocytic anemia, megaloblasticmaturation arrest in the bone marrow, glossitis, hyper-reflexia and diminished vibration perception in the feet. None of these abnormalities was improved by liverextract or vitamin B₁₂ but all responded rapidly to folic acid except the neurologicsigns.

2. This patient appears to have had a megaloblastic anemia which has been described in European clinics under the names "achrestic anemia" and "refractorymegaloblastic anemia." It appears to be similar to "Wills" factor deficiency anemia" and some cases of pernicious anemia of pregnancy.

3. This patient did not appear to have a primary deficiency of folic acid since theexcretion of this substance in the urine was within normal limits. A deficiency ofan unknown factor probably equivalent to "the Wills’ factor" is suggested.

4. It seems likely that folic acid induced a remission in this case by a "massaction" effect. The possible relationship of folic acid, vitamin B₁₂, the unknownfactor and liver extract to nucleo-protein synthesis is discussed.

Note: ACKNOWLEDGMENTWe wish to thank Doctor Charles Foertmeyer for referring this patient to us for the clinical study usedin this report.

     

The development and progression of subacute combined degeneration of the spinal cord in patients with pernicious anemia treated with synthetic pteroylglutamic (folic) acid

1. Twenty-one patients with pernicious anemia were maintained on syntheticfolic acid (pteroylglutamic acid) therapy alone for periods ranging from eight toseventeen months. Satisfactory blood levels were maintained in all cases receivingdaily oral doses of 1.25 to 15.0 mg. Severe hematologic relapse occurred withinsix months in a case treated with monthly injections of 30 mg.

2. Synthetic folic acid in oral doses of 15 mg. daily induced satisfactory hematopoietic responses in 3 patients with pernicious anemia in severe relapse, but onlyslight hematopoietic response in a fourth patient with mild pernicious anemiabut severe subacute combined degeneration of the spinal cord.

3. Ten patients showed a significant improvement in blood values for a fewmonths after substitution of folic acid for liver extract. With one exception thesesubsided after six or more months to pre-folic acid levels comparable with thosepreviously maintained with liver extract alone.

4. These observations suggest that a combination of orally administered folicacid and parenterally injected liver extract may maintain a better hematologicstatus than either substance alone.

5. A previously untreated patient with severe subacute combined degenerationof the spinal cord failed to show improvement in neural disease during twentyeight days of folic acid therapy.

6. Eleven patients developed, or showed progression of, subacute combineddegeneration of the spinal cord during folic acid treatment. Neurologic diseasedeveloped in most of these patients when the peripheral blood was normal.

7. One patient showed an extremely explosive onset and rapid progression ofneural disease. The progression of the disease was rapid in 3 other cases.

8. The institution of liver extract therapy in adddition to folic acid in 5 patientswho developed subacute combined degeneration during folic acid maintenancetherapy failed to prevent progression of the disease in 4 cases, and only partiallyarrested the disease in the fifth, in which improvement occurred more rapidlywhen folic acid was discontinued.

9. Subacute combined degeneration occurred with greater frequency in patientson large daily doses of folic acid than it did in patients with small or intermittentdoses.

10. The possibility is discussed that folic acid in large daily doses may actuallyprecipitate or aggravate neurologic disease.

11. It is suggested that folic acid may interfere with the metabolism of 1(+)glutamic acid in the central nervous system and possibly disturb the formation orfunction of acetylcholine.

     

The effects of combined folic acid and liver extract therapy

1. Folic acid, when administered alone, did not prevent the development or progression of subacute combined degeneration in 12 of 22 patients receiving this agent for from twelve to twenty-five months.

2. One patient with total gastrectomy and a macrocytic anemia developed subacute combined degeneration after five months of folic acid therapy.

3. Neurologic disease did not develop in 6 pernicious anemia patients treated with folic acid and liver extract for three and one-half to thirty-nine months.

4. In 10 pernicious anemia patients with good nutrition, neurologic relapses did not progress when liver extract or vitamin B₁₂ therapy was instituted, even though folic acid therapy was continued. In 2 patients with abnormal nutrition and complicating organic abnormalities, nervous system disease progressed after institution of liver extract therapy.

5. Our observations are best explained by the theory that the hematologic and neurologic manifestations of pernicious anemia and other macrocytic anemias associated with gastro-intestinal tract pathology and inadequate nutrition are due to a deficiency of more than one substance. The administration of folic acid may improve the hematologic status but induce a deficiency of another substance or substances, e.g., vitamin B₁₂, which are essential for the maintenance of a normal blood picture and the integrity of the central nervous system. This deficiency will eventually result in the development of a suboptimal blood picture or subacute combined degeneration of the spinal cord, or both.

6. The hematologic status of patients with pernicious anemia is not maintained in a more satisfactory state by supplementation of liver extract or vitamin B₁₂ therapy with folic acid.

7. Folic acid therapy did not produce neurologic disease in patients with iron deficiency anemia who had free gastric hydrochloric acid in their gastric secretions and presumably sufficient intrinsic factor. It did not influence response to ferrous sulfate therapy.

8. Patients with sprue, nutritional macrocytic anemia and other macrocytic anemias associated with gastro-intestinal tract pathology who are treated with folic acid should also be given supplemental liver extract or vitamin B₁₂ to insure against the development of nervous system disease.

Submitted on April 16, 1951 Accepted on July 23, 1951     

THE ERYTHROPOIETIC ACTIVITY OF CHOLINE CHLORIDE IN MEGALOBLASTIC ANEMIAS

1. The effect of the administration of choline chloride has been observed in 10cases of megaloblastic anemia of various types.

2. Choline was without effect in a case of untreated Addisonian perniciousanemia which subsequently responded to parenteral liver therapy.

3. Choline was also without effect in a case of nutritional megaloblastic anemia,in a case of megaloblastic anemia of pregnancy, and in two cases of megaloblasticanemia associated with the sprue syndrome. All these cases had proved refractoryto injections of potent liver extract before the choline was given, and all respondedto subsequent oral liver or folic acid therapy.

4. A significant erythropoietic response to choline occurred in two cases resembling Addisonian pernicious anemia which were refractory to parenteral liverextracts.

Secondary responses followed the administration of choline in two other casesof Addisonian pernicious anemia and in a case of megaloblastic anemia of pregnancy, all of which had already responded to injections of liver extract.

5. The significance of these observations is discussed. It is concluded that choline possesses no direct erythropoietic activity, but that under certain circumstances it may potentiate the effect of liver extracts.

It is suggested that refractory megaloblastic anemias may be divided into twogroups. In one, represented by well known syndromes associated with defectiveabsorption or pregnancy, the lack of response to parenteral liver extracts is notcorrected by choline. In the other, represented by two cases simulating Addisonianpernicious anemia, choline is effective in overcoming, partially or completely, therefractoriness to parenteral liver therapy. Consideration is given to the view thatthe refractoriness of this group results from hepatic dysfunction.

6. The most satisfactory method of administering choline probably consists ofintravenous injections in daily doses of 1 gram. Larger doses given intravenouslyare frequently accompanied by unpleasant side effects, while oral administrationappears to be relatively less effective.

7. It seems unlikely that choline will be of practical value in the treatment ofrefractory megaloblastic anemias, for which oral liver preparations provide themost certain and effective treatment. It is possible, however, that choline may beof use in cases complicated by severe hepatic disease.

Note: Acknowledgment: We wish to thank Dr. L. D. W. Scott for permission to include his patient (case10) in our series.

     

HEMOPOIESIS IN RIBOFLAVIN-DEFICIENT RATS

Leukopenia, granulocytopenia, and, occasionally, anemia develop in rats fed apurified diet deficient in riboflavin. Folic acid (L. casei factor) corrects the leukopenia and granulocytopenia. Riboflavin will prevent all the dyscrasias but willcorrect only the anemia.

The bone marrow in granulocytopenic rats is hypoplastic and is almost completely depleted of cells of the granulocytic series. Cells of the erythroid series aredecreased in number. The myelogram of rats made folic acid deficient by the inclusion of sulfasuxidine in a purified diet resembles this picture and in both cases theresponse of the marrow and the blood to folic acid therapy is similar.

The bone marrow in riboflavin-deficient rats having both granulocytopenia andanemia is depleted of granulocytic cells but shows an erythroid hyperplasia. Thismyelogram differs from that seen in sulfasuxidine-induced folic acid deficiencyanemia and granulocytopenia in which there is erythroid hypoplasia. The twoanemias differ further in that the folic acid deficiency anemia responds to folic acidtherapy whereas the riboflavin deficiency anemia responds to riboflavin therapybut not to folic acid therapy.

     

PERNICIOUS ANEMIA IN CHILDHOOD REPORT OF CASE IN SIX YEAR OLD GIRL RESPONDING TO REFINED LIVER EXTRACT, FOLIC ACID AND VITAMIN B12 IN SUCCESSIVE RELAPSES

A case of megaloblastic anemia without specific neurologic complications in a6 year old girl is presented as an example of pernicious anemia in childhood despitethe fact that a small amount of free hydrochloric acid was present in the gastricjuice after injection of histamine. Prompt hematologic response was obtained following administration of refined liver extract, folic acid and vitamin B₁₂ in successive relapses.

     

THE TREATMENT OF LYMPHOBLASTIC LEUKEMIA WITH CRUDE MYELOKENTRIC ACID

Eight cases of blastic lymphoid leukemia have been treated with myelokentricacid in crude form, because hypothetically in blastic lymphoid leukemia there isa deficiency of this material. The crude myelokentric acid was used because it wasmore easily obtained than partially purified material. Purification of biologicallyactive materials by methods of extraction and precipitation necessarily results in aconsiderable loss of material. Thirteen partial remissions occurred following theadministration of crude myelokentric acid. Seven of the 8 patients have died, and5 necropsies were performed.

The necropsy material adds further weight to the belief that the remissions wereinduced by the myelokentric acid in that in all 5 necropsies there was a definitealteration in the histologic morphology as contrasted with the findings in thenecropsies of the controls.

It seems inadvisable, however, to treat a large number of patients with this material because it is crude, it is relatively unavailable, and no standard dose has yetbeen devised.

Note: We wish to t hank Dr. D. L. Turner and Dr. W. A. Hause for valuable assistance in this work.

     

Transmission of antianemic principle across the placenta and its influence on embryonic erythropoiesis; II. Comparison of the effect of liver extract and pteroylglutamic acid (PGA)

1. Prehepatic embryonic erythropoiesis is influenced when normal pregnant ratsare injected with potent antianemic substances.

2. Both liver extract and PGA (folic acid) cause a reduction in mean cell diameters, but the former is slightly more effective.

3. The rate of mitosis is increased and the relative proportions of individualphases altered.

4. The distribution of light areas in the cytoplasm—negative images of organoids as seen in dry smears—is altered to a greater extent by PGA than by liverextract.

5. The in vitro and in vivo action of drugs on erythropoietic cells are discussed.

     

Refined liver extract in tropical macrocytic anemia

1. A series of 45 cases of T.M.A. treated with "refined" liver extract is reported.

2. "Refined" liver extract was found to be effective in 39 cases.

3. It was found that 2 or 3 ml. of refined liver extract (Examen N.P.) was sufficient to produce an optimum response.

4. As judged from therapeutic observations, it is suggested that in the majorityof cases of T.M.A. the deficiency is similar to that in Addisonian pernicious anemia, though the mode of production of the deficiency may not be the same.

Note: ACKNOWLEDGMENTOur thanks are due to Dr. R. Row, Hon. Director, P.G. Singhance Hindu Hospital, Bombay, whereall the cases were treated, for permission to publish these reports, and the firms concerned for the generousgift of liver extracts.

     

Response of tropical sprue to vitamin B12

These findings show that the administration of vitamin B₁₂ to patients with tropical sprue was followed by general clinical and hematologic improvement providedthe dosage was adequate. A single dose of 4 micrograms administered in case 4produced little or no change. The larger dosage of 10-25 micrograms administeredin the other cases was accompanied by striking increase in strength and vigor anda decrease in the diarrhea; however, in no instance was a maximal dose given andthese patients quickly tended to relapse clinically and hematologically. Theycould be relieved promptly again either by another injection of vitamin B₁₂ orby a compound of folic acid. (The conjugated compounds of folic acid used in thesecases were used for experimental purposes, and they produced the same hematologicresponse as that of folic acid per se.) Case 3, who had an excellent hematologicresponse after eating one serving of 400 grams of liver, is regarded as especiallysignificant in that it suggests that, as powerful as vitamin B₁₂ is as a therapeuticagent, it is more effective when given with liver. It is especially noteworthy thatcases 1 and 2, who had three injections of vitamin B₁₂, have had steady clinicaland hematologic improvement. The reader should have in mind that a singleinjection of approximately 100 micrograms of vitamin B₁₂ probably would beneeded to produce a full hematologic response in persons so ill. This tentative appraisal would suggest that this therapeutic compound, per unit of weight, is moreeffective in treating human disease than any compound that yet has been used.

Note: ACKNOWLEDGMENT We are very much indebted to others who have aided us in selecting cases and in observing results.Especially we wish to thank Dr. F. Hernandez-Morales, Dr. Hector Marchand, Miss Clemencia Benitez-Gautier, and Miss Sara Torres.

     

The effects of various sulfonamide drugs on the electrocardiogram of the dog

Experiments were performed on sixteen dogs to show the effects of various sulfonamide drugs. Sodium sulfapyridine, sodium sulfadiazine, and sodium sulfathiazole were used.Six hundred forty-two tracings (Lead II) were taken, and measured for heart rate and P-R interval. All were carefully checked for abnormalities of rhythm or conduction.No evidence of myocardial damage which could be attributed to the drug was found in this study.     

Experimental production of a nutritional macrocytic anemia in swine

1. A deficiency of pteroylglutamic acid has been produced in 32 swine fed apurified diet containing casein and supplemented with seven B vitamins, sulfasuxidine and a folic acid antagonist. The casein was fed at two levels, 10 and 26per cent. Two types of casein were used: a crude preparation possessing significant"extrinsic factor" activity and a purified casein with little activity.

2. The hematologic manifestations observed were (a) severe macrocytic anemia,(b) leukopenia, due to a proportionately greater reduction in polymorphonuclearthan in mononuclear cells, (3) slight thrombocytopenia, and (4) hyperplastic bonemarrow with an increase in immature nucleated red cells which resemble themegaloblasts seen in the bone marrow of patients with pernicious anemia.

3. The feeding of a 26 per cent rather than a 10 per cent crude casein diet did notprevent but did delay the onset of the blood changes. Anemia developed mostrapidly in the animals receiving 10 per cent purified casein.

4. The group receiving 26 per cent casein developed a greater degree of macrocytosis in the same period of time than did the group receiving 10 per cent casein.In all groups the degree of macrocytosis increased as the duration of the anemiaincreased.

5. The hematologic manifestations were not delayed nor was their developmentprevented by the intramuscular administration of 15 U.S.P. units of liver extractevery 15 days.

6. The blood and bone marrow returned rapidly to normal following the administration of pteroylglutamic acid, pteroyldiglutamic acid, pteroyltriglutamicand pteroylheptaglutamic acid. Thymine and xanthopterin had little or no activity. Tyrosine, adenine and uracil were inactive.

7. Purified liver extracts and crystalline vitamin B₁₂ were found to possess somehemopoietic activity in several animals but the activity was considerably less thanthat of the pteroylglutamic acid compounds.

8. The urinary excretion of "tyrosyl" (hydroxphenyl compounds) was notabnormal in the pteroylglutamic acid deficient pigs and was not altered by eitherpteroylglutamic acid or liver extract therapy.

9. The urinary excretion of allantoin and uric acid did not differ significantlyfrom the normal. Immediately following therapy with pteroylglutamic acid,however, in association with the reticulocytosis and lasting for the same period,there was a marked increase in the excretion of allantoin.

10. The results suggest that both pteroylglutamic acid and a factor in liverextract similar to or identical with vitamin B₁₂ are required for normal hemopoiesisin the pig.

Note: ACKNOWLEDGEMENTSThe crude methylfolic acid antagonist, xanthopterin, and the pteroylglutamic acid compounds, withthe exception of pteroylheptaglutamic acid, were kindly furnished by the Lederle Laboratories, PearlRiver, New York, through the courtesy of Dr. T. H. Jukes and Dr. S. M. Hardy.Sulfasuxidine was generously furnished by Sharp & Dohme, Inc., Philadelphia, Pa., through thecourtesy of Dr. W. A. Feirer.Pteroylheptaglutamic acid and Natola were supplied by Parke, Davis & Company, Detroit, Mich.,through the courtesy of Dr. A. E. Sharp and Dr. J. J. Pfiffner.Biotin was obtained from Hoffmann-LaRoche, Inc., Nutley, N. J., through the courtesy of Dr. E. L.Sevringhaus.The vitamins, with the exception of pteroylglutamic acid and biotin and including vitamin B₁₂ werekindly furnished by Merck and Company, Inc., Rahway, N. J., through the courtesy of Dr. A. Gibsonand the late Dr. D. F. Robertson.Experimental liver extracts (No. 1124, 1063, 1066 and 1067) were generously furnished by Armour andCompany, Chicago, Illinois through the courtesy of Dr. E. E. Hays.We are indebted to Mrs. Darlene Kehl, Mr. George Trappett, and Mr. Ocie Hadley for technicalassistance.

     

THE VALUE OF PENICILLIN IN THE TREATMENT OF AGRANULOCYTOSIS CAUSED BY THIOURACIL

Thiouracil has been found to be an effective drug in the treatment of hyperthyroidism. Agranulocytosis following its use occurred in nine cases, four of whichterminated fatally. In five others a complete and rapid recovery took place following penicillin therapy. The latter drug is believed to be ideal for all cases of agranulocytosis, and especially those in which chemotherapy has been used and mayhave been responsible for the condition. Thus far we have not seen any report ofany untoward effect on the hemopoietic system from the use of penicillin.

The use of antibacterial agents for the treatment of agranulocytosis was suggested by Dameshek and Wolfson²¹ in 1942. It was believed by these authors thatpatients with agranulocytosis died not of the leukopenia per se but of the sepsiswhich developed secondarily to the lack of granulocytes. Two very severe casesof aminopyrine agranulocytosis treated with sulfathiazole made complete recoveries. For the treatment of sulfonamide agranulocytosis, it was suggested thata preparation differing from that which had already been used be given. Withthe discovery of penicillin, and its complete lack of possible deleterious effect onthe bone marrow, its use was suggested by Dameshek¹⁷ (1944). A report on thebeneficial effects of this medication in a case of sulfonamide agranulocytosis waslater reported by Dameshek and Knowlton¹⁸ and similar cases by Sprague andFerguson¹⁹ and by Meredith and Fink.²⁰

Since sulfonamides may cause further toxic effect on the bone marrow, we feelthat their use should be avoided in the treatment of agranulocytosis, especiallywhere a history of previous use is obtained. We do not agree with others^{21, 22}who continue the use of sulfonamides in the treatment of leukopenia or agranulocytosis where these very drugs may have been responsible for the condition. Itwould seem better judgment to use penicillin, which by combating the bacterialinvasion of the body and the consequent toxemia enables the patient to surviveuntil the bone marrow cells regenerate.

     

EXPERIMENTAL LEUKOCYTOSIS. THE INEFFICACY OF P-CHLOROXYLENOL AND METHYL ACETAMIDE AS BONE MARROW STIMULANTS

1. Single and multiple injections of CXM (methyl acetamide and p-chloroxylenol) have a similar action in increasing the total number of polymorphonuclearleukocytes in the peripheral blood of a group of 32 rats. No "shift to the left"takes place.

2. There is no stimulation of the myeloid elements of the bone marrow to suggest that this leukocytosis is due to hyperplasia.

3. The evidence suggests that the mechanism for the leukocytosis produced bythe CXM consists of releasing blood cells from depots in the body. This action isselective for the granulocytes as the red cells and platelets are not affected.

4. There is progressive degeneration of the parenchymal cells of the liver aftersingle and multiple injections of these substances.

5. If less toxic combinations of methyl acetamide and para-chloro-xylenol couldbe obtained, they might be of value in the treatment of certain patients withleukopenia or agranulocytosis more particularly when the bone marrow is hyperplastic but the granulocytes are not released.

Note: The author expresses his appreciation to Dr. Oscar Riddle for the generous provision of animal andlaboratory facilities.

     

Mediterranean anemia in a Negro complicated by pernicious anemia of pregnancy: report of a case

1. A case is presented of a Negro woman with Mediterranean anemia whodeveloped megaloblastic anemia of pregnancy in each of three pregnancies.

2. The possibility that Mediterranean anemia predisposes to the developmentof pernicious anemia of pregnancy is discussed.

3. With megaloblastic erythropoiesis, anemia became more severe, but thecharacteristic red cell hypochromia of Mediterranean disease was masked.

4. Purified liver extract failed to protect against the development of megaloblastic anemia of pregnancy but folic acid produced a satisfactory therapeuticresponse.

Submitted on August 12, 1953 Accepted on November 9, 1953     

On the Etiology of "Meat Anemia" in Mice

Young mice kept on a diet consisting of meat only develop an anemiawhich is accompanied by depressed growth and high fatality.

Treatment of mice while subsisting on the meat diet with para-aminobenzoic acid, folic acid, vitamin B₁₂, liver extract, pyridoxine, iron, vitaminA, penicillin, aureomycin or a combination of some of these substancesneither prevents the anemia nor the mortality, nor does it improve growth.Some of these substances have, however, a slight effect in preventing anemia.

Replacing one of four parts of meat by beef liver or an isocaloric-isonitrogenous mixture of casein, cornstarch, salts and water almost completely prevents the anemia but does not improve, or only slightly improves, the stuntedgrowth. Dilution of meat with liver but not with the casein mixture has astriking therapeutic effect in mice rendered anemic by the meat diet.

It is assumed that the anemia is caused by the presence in meat of a hematopoiesis-inhibiting factor and/or by the lack of some unknown hematopoieticfactor(s) possibly produced by the intestinal flora and present in liver.

Submitted on September 8, 1959 Accepted on January 4, 1960