PROCAINE PENICILLIN; THERAPEUTIC El*‘l+‘IOIENUY AND A
`COMPARATIVE STUDY OF THE ABSORPTION OF SUSPENSIONS
`
`IN OIL AND IN OIL PLUS ALUMINUM MONOSTEARATE AND
`
`OF‘ AN AQUEOUS SUSPENSION CONTAINING SODIUM
`CARBOXYMETHYLCELLULOSE
`
`JAY A. ROBINSON, M.D., HAROLD L. HIRSI-I, M.D., BERNARD MHJLOFF’ M.I).,
`AND HARRY F. DOWLING, MI).
`
`WASIIINGTON, I}.
`
`(.1.
`
`NE of the greatest disadvantages of penicillin is its rapid elimination from
`the body.
`In order to decrease the frequency of injections many attempts
`have been made to delay the absorption or excretion of penicillin and tl1us'pro-
`long the action- of an injected dose. Until recently the most successful method
`of prolonging the concentrations of penicillin in the blood has been the incorpo-
`ration of penicillin in peanut oil and beeswax} With this preparation a single
`injection of 1 c.c. containing 300,000 units of penicillin was usually followed by
`assayahle blood concentrations for twenty-four hours in 90 to 92 per cent of
`patients. The introduction of a fluid preparation obviated some of the difli—
`culties inherent
`in the administration of this material.” Fluid penicillin i11
`
`peanut oil and beeswax was found to he as effective as the original viscid prepa-
`ration When 50 per cent of the total relative weight is made up of particles of
`50 p or more in length? Discomfort to the patient in the form of local pain,
`tenderness, and nodule formation at the site of injection, however, still persisted.
`For some time it has been known that a mixture of concentrated solutions of
`
`penicillin and procaine resulted in the formation of crystals which were identi-
`fied as the procaine salt of penicillin. Whereas the commercially available salts
`(sodium, potassium, and calcium) are highly soluble in aqueous solutions and
`body fluids, the procaine salt is relatively insoluble. This property forms the
`basis of a new principle of penicillin administration. As a result of the low
`solubility of procaine penicillin, a repository injection of a suspension of this
`salt in oil or water results in delayed absorption and prolonged blood concen-
`trations. This report presents the results of our studies on absorption following
`the intramuscular injection of procaine penicillin and the treatment of patients
`with various infections when procaine penicillin in oil was used.
`
`MATERIALS
`
`Crystalline procaine penicillin is usually prepared by the double decomposition of
`sodium penicillin G and procaine hydrochloride. The original commercial preparations
`were suspended in refined sesame or peanut oil so that 300,000 units were present in 1 c.c.
`as a free-flowing fluid material. Such a preparation need not be refrigerated since it will
`remain stable for at least one year at room teinpcrature. Because the procaine penicillin on
`standing separates from the oil and because of the necessity for vigorous agitation in
`
`From the George Wachineton llnivcrsity and Georgetown University Medical Divi-
`_
`sions, Gallinger Mnnicinal Hospital, and the Departments of Medicine. George Washington
`University and Georgetown University Schools of Medicine.
`Received for publication. July 7. 1948.
`
`1232
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 1
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 1
`
`

`
`1=eocAI.\u~: r-Exicinnm
`
`1233
`
`order to reestablish the suspension, detergents such as Tween 80" and Span 801' have been
`added to facilitate rcsuspension.
`These measures have been only partially successful.
`Other investigators! have added aluminum monostesrate to the mixture to maintain the
`suspension. The addition of aluminum monostearate to procaine penicillin in oil results in
`a gel formation which maintains the suspension of the penicillin in the oil.
`Peanut or sesame oil was originally employed as 3. vehicle for injecting procaine
`penicillin since it was impossible to prepare injectahle water suspensions of this peniv
`eillin salt. Recently it has been demonstrated that the addition of dried sodium carliox)’
`methylcellulose to dry crystalline procaine penicillin results in a stable suspension in
`dilnentn containing Water.-'1
`Sodium carboxymetliylcellulose in aqueous solution forms :1
`viscous gel which maintains the procaine penicillin in discrete particulate suspension.
`This has eliminated the necessity for the use of oils, which have been shown to he anti-
`genic and which may cause serious complications if they are injected accidentally into
`a blood vessel.'3
`
`All of the procaine penicillin preparations can be withdrawn from the vial and
`administered through a 19 or 20 gauge needle. For the preparations containing aluminum
`monostearatc or sodium carboxymethylcellulose, dry syringes and needles are not needed.
`When procaine penicillin in oil
`is administered, moist needles and syringes may be used
`if the injection is made immediately after the syringe is filled. Although We have given
`multiple injections of procaine penicillin in oil from a single syringe without cliflig:nlt}-
`provided the withdrawal and injections were made within a very few minutes, these pre-
`cautions are not necessary With the preparations containing aluminum inonostearatc or
`sodium carboxymethylcellulose.
`
`STUDIES ON ABSORPTION
`
`The concentrations of penicillin in the blood at various intervals were deter-
`mined according to the method of Randall and associates" following the intra-
`muscular injection of (1) procaine penicillin in oil,i,' (2) procaine penicillin in
`oil plus aluminum Inonos-tearate,§ and (3) procaine penicillin plus sodium car-
`boxymetliylcellulose in aqueous suspension." The results are expressed both as
`percentage of patients having assayable concentrations (.03 units per cubic centi-
`meter or more) and as the median concentrations at the various intervals tested.
`
`As shown in Table I, all of the patients who received a single or initial in-
`jection of 300,000 units of procaine penicillin in oil
`(1 cc.) had detectable
`levels at one, four, twelve, sixteen, and twenty hours. Only an occasional pa
`tient failed to have an assayable level at the twenty-fourth hour. About onc~l1al.t
`of the patients had measurable levels at the thirty-sixth hour, a.nd about one-third
`
`at the forty-eighth hour. The median levels at various hours are also shown
`in Table I.
`
`While this study was in progress, several of the commercially available lots
`of procaine penicillin in oil were found to be inferior in that only about one-half
`to one-third of the patients had detectable levels in the blood at the twenty-
`fourth hour following the injection of 300,000 units of procaine penicillin in
`oil (1 c.c.).3 It was found that in conversion to mass production, crystallization
`was not carefully controlled, so that large particles of procaine penicillin were
`‘Tween 80, Sorbitan mono-oleate. polypoxyalkylene derivative.
`tspan 8|]. Sorbitan mono-oleate.
`ttiunolled by Chas. Pfizer & Company,
`Indianapolis. Ind.
`§SLlDDlied by Bristol Laboratories, Inc., Syracuse, N. Y.
`|lS11DIJl1ed by Wyeth Incorporated. Philadelphia, Pa.
`
`Inc-., Brooklyn. N. 12, and Eli Lilly & Ccinoamr.
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 2
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 2
`
`

`
`1234
`
`ROBDTSON, HIRSH, MILLOFF, AND DOWLING
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 3
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 3
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`

`
`PROGAJNE PENIGILLIN
`
`1235
`
`In grinding these particles to sizes capable of passage through 19 or
`produced.
`20 gauge needles, relatively large amounts of procaine penicillin dust or flour
`were produced. The fine particles comprising this dust or flour are dissolved
`and absorbed relatively rapidly, so that prolonged blood concentrations are not
`maintained.
`(The manufacturers have taken steps to eliminate the fine par-
`ticles from their preparations.) Therefore,
`the blood concentrations obtained
`after the injection of preparations of this kind are not included in Table l.
`
`The percentage of patients and the median blood concentrations following
`the injection of 300,000 units of procaine penicillin. in oil plus 2 per cent W/V
`aluminum monostearate are also shown in Table I.
`It is apparent that the addi-
`tion of aluminum monostearate not only stabilizes the suspension of procaine
`penicillin in oil but also results in prolongation of the concentrations of
`penicillin in the blood. Preparations containing particles of penicillin less than
`5 ,u in size resulted in measurable blood concentrations in all patients at twenty-
`four, forty-eight, seventy-two, ninety-six, and one hundred twenty hours after
`injection. When large particle procaine penicillin crystals are employed in this
`mixture, the concentrations of penicillin in the blood are not so prolongrcdfi "
`
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`Fig. 1.——Cu1-ves of the concentration of pen1ci11in_i.n the blood folicrwing intramuscular injec-
`tion of 300,000 units of procaine penicillin G suspended in various vehicles.
`
`Included in Table I are the data obtained following the injection of 300,000
`units of procaine penicillin plus 3.5 Gm. of sodium carboxymethylcellulose con-
`tained in 1 c.c. of aqueous solution. All of the patients studied had measurable
`levels at sixteen,
`twenty, twenty-four, thirty-six, forty-eight, and sixty hours.
`Twenty-five per cent had assayable levels at seventy-two hours.
`
`The median concentrations at the various intervals for all three prepara-
`tions have been plotted in Fig. 1.
`
`Blood concentrations were determined in seventeen patients who were re-
`ceiving 300,000 units of -the procaine penicillin in oil preparations every
`twelve hours and in fourteen subjects who received 600,000 units (2 ac.) every
`twelve hours. Upon such regimens the blood concentrations at the twelfth hour
`were at least 0.125 unit per cubic centimeter and usually 0.25 and 0.5 unit per
`cubic centimeter. There were no significant dificrences between the two doses.
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 4
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`

`
`1236
`
`nonneson, nmsn, MILLOFF, AND DOWLING
`
`CLINICAL STUDY
`
`We have treated 251 patients with various infections with procaine peni-
`cillin in oil. All the patients received plain procaine penicillin in oil except the
`patients with gonorrhea who were treated with the material containing alumi-
`num monostcarate. The results and plans of therapy are summarized in Table II.
`
`Eighty-nine patients with pncumococcic pneumonia of known type or with
`
`findings and a course characteristic of pneumoeoccic pneumonia were treated
`
`with 600,000 units of procaine penicillin in oil (2 c.c.) every twelve hours until
`they were essentially afebrile for forty-eight to seventy-two hours. The course
`was similar to that seen with the use of other penicillin preparations, and re-
`
`covery was uneventful in all patients. These large doses were employed as a
`
`part. of a studyto evaluate the effect of massive doses in pneumonia. Other
`investigators” have found that 300,000 units a day for similar periods give
`satisfactory results.
`
`Tnnnn II. Dosscn Sonnnonns lino Rnsnurs or TREATLIENT or VARIOUS INFECTIONS Wrrn
`Pnocnrme: PFJNICILI.-IN IN OIL
`
`nrsnmsn
`
`Pneumonia
`4.1
`Typed
`48
`Untyped
`Acute bronchitis
`
`Acute sinusitis
`
`Tonsillitis
`Scarlet fever
`Vincent ’s infection
`Infectious arthritis
`Gonoeoccal
`2
`Unknown
`1
`Gonorrhesv‘
`
`Syphilis
`
`Ce-llulitis
`Typhoid fever
`
`NUMBER
`or
`PATIENTS
`
`
`
`89
`
`2
`
`3
`
`3
`1?
`1
`3
`
`5-’;
`
`75
`
`I-IE--l
`
`
`
`DOSAGE SCHEDULE
`
`COMMENT
`
`Recovered
`
`600,000 units b.i.d. until essen-
`tially afehrile for 48 to '72
`hours
`300,000 to 600,000 units b.i.d.
`for 5 days
`300,000 to 600,000 units b.i.d.
`for 5 days
`300,000 units per day for 5 days Recovered
`300,000 units per day for 5 days Recovered
`300,000 units per day for 2 days Recovered
`300,000 to 600,000 units b.i.d.
`Recovered
`for 7 to 10 days
`
`Recovered
`
`Recovered
`
`300,000 units
`
`Only 1 patient had return
`of symptoms-—possible
`reinfection
`600,000 units per day for 5 days All patients showed com-
`plete healing of lesions
`and decrease in serologic
`titers during 2- to 5- -
`month follow-up period
`600,000 units per day for 4 days Recovered
`300,000 units every 6 hours,
`No improvement
`with sulfnthiacole——6 Gm.
`initial dose and 1 Gm. every
`4 hours
`
`‘Patients treated with procaine penicillin in oil plus aluminum monosteazrate.
`
`In previous publications“ 1*‘ ” the efficacy of penicillin in. the treatment
`of scarlet fever has been reported. Procaine penicillin in oil in doses of 300,000
`units per day for five days has resulted in prompt recovery from this strepto-
`coccal
`infection without pyogenic complications in all seventeen patients
`treated.
`
`Three patients with bacterial arthritis were treated. Two were considered
`‘to have had gonococcal arthritis, since gonococci were isolated from a coexistent
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 5
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 5
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`

`
`PRDCAINE PENICILLIN
`
`I237
`
`urethral discharge. One of the patients was treated with 300,000 units of pro-
`
`caine penicillin in oil every twelve hours. Only slight improvement was noted
`after five days, at which time the dose was increased to 600,000 units every twelve
`hours and rapid improvement ensued. The second patient received 300,000 units
`
`every twelve hours for seven days with good results. These patients are included
`in a recent report.“ The third patient was a young colored woman, six months
`pregnant, who had a profuse vaginal discharge and arthritis of the wrists.
`Gonococci were not isolated from cultures of the vaginal discharge. The patient,
`was given 300,000 units of procaine penicillin in oil every twelve hours for seven
`days with rapid regression of the cervicitis and arthritis.
`Two patients with acute bacterial bronchitis and three with acute sinusitis
`have been treated successfully. One of the patients with acute sinusitis also
`had acute catarrha] otitis media, the causative organism being‘ a pneumococcus,
`Type 4. This patient was given 600,000 units (2 cc.) of procaine penicillin in
`oil. per day for four days. The temperature dropped to normal within twelve
`hours; the nasal discharge became less purulent and viscid. ind was gone at the
`time treatment was discontinued.
`
`A patient with VineeI1t’s infection of the mouth received 300,000 units per
`day for three days. Relief from soreness was reported within twelve hours and
`the gums appeared normal at the forty-eighth hour.
`Three patients with acute follicular tonsillitis were treated with 300,000
`units of procaine penicillin in oil per day for five days. Pain on swallowing and
`soreness subsided rapidly, and the exudate promptly disappeared. A beta
`hemolytic streptococcus was isolated from the throat of one patient before treat-
`ment was started and was not found thereafter.
`
`In the patient with typhoid fever, the bacteriologic diagnosis was made on
`the fourth hospital day. After several days, during which time there was no
`improvement on other therapy, it was decided to institute a, routine similar to
`that used by Comerford and coworkers“ in the treat-ment of typhoid carriers.
`
`Six grams of sulfathiazole were given initially, followed by 1 Gm. every four-
`hours.
`In addition, 300,000 units of procaine penicillin in oil were given every
`six hours. The strain of typhoid bacillus which was recovered from the blood
`cultures was found to be resistant to more than 20 units per cubic centimeter of
`penicillin, whereas the blood penicillin concentrations prior to injection at the
`twelfth hour were found to be between 1 and 2 units per cubic centimeter of
`serum. There was no improvement after five days and therapy was discontinued.
`This patient developed an abscess on the buttock from which the typhoid organ-
`ism was recovered. The source of this local infection was not established. al-
`though it
`is possible that the bacteria were carried in from the skin by the
`needles during injections of procaine penicillin. This patient later recovcrc.d on
`symptomatic treatment.
`
`W’e have treated fifty-seven patients with acute gonorrhea using a single
`injection of 300,000 units of procaine penicillin in oil plus aluminum mono-
`stearate. The patients were followed for a period of twenty-one days. All the
`patients recovered except one who suffered a possible relapse during the third
`posttreatinent week.
`It is believed, however, that this patient was re-exposed
`during the interim.
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 6
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 6
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`

`
`1238
`
`ROBINSON, HIRSH, Mitmrr, AND DOVVLING
`
`Seventy-five patients with primary and secondary syphilis were treated with
`600,000 units (2 cc.) per day for a period of five days. All the patients showed
`complete healing of lesions and a decrease in serologic titers during a follow-up
`period of two to five months.
`
`REACTIONS
`
`Four patients reported a slight degree of transitory soreness twelve to
`twenty-four hours after injection. We have given as much as 5 c.c. in a single
`injection to one patient without
`incident. A small area of induration with
`pruritis was observed in one patient at the site of injections ten days after the
`injections. Skin tests with the various ingredients of the preparation demon-
`strated sensitivity to peanut and sesame oils. We have not detected any other
`evidences of hypersensitivity to the preparation.
`It has been shown previously
`that when patients are given a second course of a drug, reactions are more likely
`to develop than during the initial course.1“v-1’ Twentyaiine patients received a
`second course of procaine penicillin in oil without any reaction.
`
`Doses of 300,000 units of procaine penicillin contain 120 mg. of procaine
`
`base per cubic centimeter. This amount of procaine base in the doses usually
`employed is not enough to produce toxic levels, particularly since the absorption
`into the circulation is slow and destruction is rapid. As much as 1 Gm. of
`procaine hydrochloride has been given iiitravenously over a period of twenty
`minutes without incident.” We have attempted to determine the procaine con-
`centration in the blood, but the amounts present, if any, were so small as to make
`accurate colorimetric estimations impossible.
`
`DISCUSSION
`
`Procaine penicillin in oil as a means of prolonging therapeutic blood con-
`centrations of penicillin appears to have certain advantages over penicillin in
`oil and wax. We have withdrawn and administered without difficulty procaine
`penicillin preparations with syringes sterilized by boiling which were damp when
`used. Procaine penicillin preparations maintain blood concentrations of peni-
`cillin which arc adequate for most purposes. The best preparations of penicillin
`in oil and wax give detectable levels in 92 per cent of the patients with 300,000
`units at the tweI1ty—fourth hour, but the average preparation produces such levels
`in only about 85 per cent of patients. Similar doses of procaine penicillin in oil
`consistently result in adequate concentrations in at least 94 per cent of the ]1a~
`tients and in 100 per cent of patients when optimal preparations are used. Not.
`only do a greater percentage of patients have detectable concentrations at the
`twenty-fourth hour, but the concentrations are usually two. to fourfold higher
`than those obtained with penicillin in oil and wax. This is undoubtedly explained
`by the fact that the release of penicillin from the procaine combination is slow,
`resulting in a flat and sustained curve, while the one produced by the oil and
`wax preparation is peaked in the early hours and is not as well sustained. The
`problem of separation of the procaine penicillin from the oil has been overcome
`by the addition of aluminum Inonostearate. With the use of carboXynicth_vl-
`cellulose the procaine penicillin can be administered in aqueous suspension.
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 7
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 7
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`

`
`PROCAINE PENICILLIN
`
`1239
`
`Another advantage of procaine penicillin preparations is the Pitucity of
`local reactions. Beeswax, which acts as a foreign substance and which may bi’
`antigenic, has been eliminated- We have not been able to demonstrate any sen-
`sitivity to procaine penicillin.
`The maintenance of continued blood concentrations makes procaine peni-»
`cillin in oil more desirable in the treatment of infections requiring short courses
`and more feasible in the cases requiring long courses. The results in the patients
`treated have been good. The only patients in whom no iinprovenient followed
`the administration of procaine penicillin were the patient with typhoid fever-
`and the one with acute gonorrhea who probably had a reinfection.
`
`SUEIMARY AND CONCLUSION
`
`A new penicillin salt, procaine penicillin, incorporated in oil, in oil and
`aluminum monostearate, and with sodium carboxymethylcellulose in an aqueous
`solution has been studied.
`
`The concentrations of penicillin in the blood at various intervals have been
`determined following intramuscular injections. The results are expressed both
`as percentage of patients having assayable levels and as the median levels at.
`the various intervals tested.
`
`reactions and no systemic reactions were observed, even
`local
`Minimal
`though twenty-nine patients received a second course.
`
`Therapeutic results in patients with various infections were similar to those
`obtained with penicillin in other dosage forms.
`It is concluded that procaine penicillin is a superior preparation for re-
`pository penicillin therapy since it does not require the use of dry syringes and
`needles,
`is followed by very few local "reactions, and results in more prolonged
`blood penicillin concentrations than any penicillin preparation yet studied.
`
`We Wish to thank Dr. Mark H. Lepper, Dr. Robert L. Brickhouse, and Dr. Thomas E.
`Stone for clinical assistance, and Mrs. Joan Broyhill, Miss Myrtle I. Meyer, Miss Helen
`Wright, and Miss 0. Barbara 0’Ncil for technical assistance.
`
`REFERENCES
`
`_L\?
`
`1. Rornansky, M. J., and Bittman, Gr. 15).: A Method of Prolonging the Action of Poni-
`cillin, Science 100: 196-198, 1944.
`Hirsh, H. L., Dowling, H. F., Vivino, J. J., and Rotman-Kavka, G.: Penicillin in Bees-
`wax and Peanut Oil,
`:1 New Preparation Which Is Fluid at Room Temperattire:
`Absorption and Therapeutic Use, J. LAB. & CLIN. MED. 32: 34-41 1947.
`3. Dowling, H. F., Romansky, M. J., Welsh, H., Robinson, J". A., Chandler, V. L., Zellcr,
`W. W., and Hirsh, H. L.:
`“Liquid” Versus “Solid” Penicillin in Oil and Wax.
`The Effect of Particle fiize and Type of Penicillin, J. A. M. A. 136: 567-589, 1947.
`4. Thomas, E. W., Lyons, R. H., Romansky, M. J ., Rein, C. R., and Kitchen, D. K.: New
`Repository Penicillin Products, J. A. M. A.
`In press.
`U!
`. Price, 0. H., Hirsh, H. L., Hildrick—Smith, G.: An Aqueous Procaine Penicillin Sus-
`pension, J. A. M. A.
`In press.
`5%.: Pulmonary Embolism Caused by
`6. Bondy, P. K., Sheldon, W. H., and Weens, H.
`Penicillin-Oil-Beeswax, Am. J. Med. 3: 34-43, 1947.
`Randall, W. A., Price, 0. W., and Welch, 1-1.: The Estimation of Penicillin in Body
`Fluids, Science 101: 365-366, 1945.
`8. Welsh, H., and Hirsh, H. L.: Pharmacology of Procaino Penicillin. Syphilis Study
`Section Meeting, Washington, D. C., April 8 and 9, 1943.
`9. Welch, H., and Chandler, V’. L.: Personal communication.
`10. Bogcr, W. P., Orett, J. E., Israel, H. L., and Flippin, H. F.: Procainc Penicillin in
`Oil.
`I. Plasma Concentrations; Preliminary Observations on Its Use in Pneu~
`monia, Am. J. M. Sc. 215: 200-256, 1948.
`
`_-1
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 8
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 8
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`

`
`1240
`
`ROBINSON, HIRSH, MILLOFF, AND DOWLING
`
`II. F., and Sweet, L. K.: Treatment of Various Infections
`11. Hirsh, H. L., Dowlin
`, With :1 Preliminary Note on the Value of Penicillin X in
`"With Penicillin
`Scarlet Fever, Ann. Int. Med. 25: 78, 1946.
`.12. Hitch, H. L., Rotman-Kavka, G., Dowling, H. F., and Sweet, L. K.: Penicillin Therapy
`of Scarlet Fever, J. A. M. A. 133: 657-661 1947.
`13. Robinson, J. A., Hirsh, H. L., and Dowling,
`F.: Oral Penicillin in the Treatment of
`Various Bacterial Infections, Am. J. Med. 4: 716, 1948.
`14. Robinson, J. A., Hitch, H. L., Zeller, W. W., and Dowling, H. F.: Gonococcal Arthritis:
`A Study of 202 Patients Treated With Penicillin, Sulfonamidca or Fever Therapy.
`To be published.
`15. Oomerford, 0. IL, Richmond, IL, and Kay, W. W.: Use of Penicillin and Sulfathiacolc
`in the Treatment of Typhoid Carriers, Lancet 2: 343-345, 1946.
`15. Dowling, H. F, and Lepper, M. 11.: “Drug Fever” Accompanying Second Courses of
`Sulfathiazole, Sulfadiazine, and Sulfapyridine, Am. J. M. Sc. 207:‘349-353, 19-14.
`.17. Dowling, H. F., Hirsh,
`II.
`I.., and Lcppcr, M. H.: Toxic Reactions Accompanying
`Second Courses of Sulfonemides in Patients Developing Toxic Reactions During :1
`Previous Course, Ann. Int. Med. 24: 629, 1946.
`18. G‘r1's.uba.rd, D. J., Robertazzi, R. W., and Peterson, M. C.: Use of Intravenous Procaine
`in Control of Pain, New York State J, Med. 47: 2187-2192, 1947.
`
`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 9
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`MYLAN PHARMS. INC. EXHIBIT 1053 PAGE 9