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BACKGROUND OF INVENTION
Throughout this application various publications are referenced by numbers
within parentheses. Full citations for these publications may be found at
the end of the specification immediately preceding the claims. The
disclosures of these publications in their entireties are hereby
incorporated by reference into this application in order to more fully
describe the state of the art to which this invention pertains.
Pneumocystis carinii pneumonia (PCP) is the most common life-threatening
opportunistic infection in patients with acquired immunodeficiency
syndrome (AIDS). There is no safe and effective prophylaxis for this
infection in patients with AIDS. Prevention of PCP would mean a reduction
in mortality, morbidity, and medical costs. Treatment of the infection is
costly, facilities for its diagnosis and treatment are scarce, and the
number of people at risk is increasing.
Pneumonia due to Pneumocystis carinii occurs in patients with AIDS and in
cancer and organ transplant patients. The infection has also been seen in
epidemics among premature and malnourished infants. The report in 1981 of
PCP in otherwise healthy male homosexuals signaled the emergence of the
AIDS epidemic (1). More than 65% of AIDS patients develop PCP (2). In many
cases the development of PCP is the first sign of immune dysfunction and
thus provides the basis for the diagnosis of AIDS.
Trimethoprim-sulfamethoxazole (SXT) is effective in the prevention and
treatment of PCP in experimental animals and in humans. Prophylaxis with
SXT has markedly decreased the incidence of PCP among patients with
leukemia or lymphoma. Unfortunately, 60-70% of patients with AIDS have
adverse reactions to SXT (3). These patients cannot receive SXT
prophylaxis and, if they develop PCP, must receive pentamidine.
Pentamidine was the first effective treatment for PCP. It is highly
effective in treatment of PCP infection in patients with AIDS. The drug is
presently administered by IV infusion or IM injection at 4 mg/kg/day for
14-21 days. Unfortunately, treatment often causes severe toxic reactions
including hypotension, renal failure, and hypoglycemia (4). Response to
therapy is slow and patients require prolonged hospitalization and
intensive, supportive care.
Pentamidine isethionate is an effective form of pentamidine. Pentamidine
isethionate has a molecular weight of 592.68 and has the following
structure:
##STR1##
Pentamidine is also sold as the naphthoate. Both forms are sold as
antiprotozals.
There are currently no methods available for prevention of PCP which have
been proven to be safe and effective among patients with AIDS. Several
methods are being investigated in clinical trials: these include
sulfamethoxazole-trimethoprim (bactrim), sulfadoxinepyrimethamine
(fansidar), dapsone, or monthly iv pentamidine. Aerosol pentamidine
appears to offer significant advantages over these methods. Because the
drug is applied topically there is efficient delivery to the target organ
and little systemic absorption. This limits toxicity and provides
increased effectiveness.
Pentamidine is effective in the chemoprophylaxis of African trypanosomiasis
(sleeping sickness) (7). Human volunteers, subjected weekly to bites from
infected tse-tse flies, resisted infection for one year or more after a
single IM dose of pentamidine (8). Twice-yearly IV or IM doses eliminated
the infection in endemic areas in subsaharn Africa. The drug has been
administered to more than ten million people in campaigns to eradicate
sleeping sickness. However, no adequate studies of prevention of PCP in
humans with IV or IM pentamidine have been reported. In fact, prophylaxis
with IV or IM pentamidine was unsuccessful in the animal model of PCP (9).
The route of administration of pentamidine profoundly affects its tissue
distribution. After IV or IM administration pentamidine is eliminated
rapidly from blood, it accumulates in tissues, and is eliminated slowly
from them. The amount of pentamidine that accumulated in the lungs of rats
or humans that received IV or IM pentamidine was a small fraction of the
amounts that accumulated in other visceral organs. An earlier study showed
that aerosol administeration of pentamidine favor its distribution to the
lung. However, the relationship between tissue levels and dosage was not
determined (10).
The aerosol route delivers pentamidine to the target organ while limiting
potentially-toxic accumulation in other organs. The drug is retained in
the lungs for many weeks after a single aerosol dose; the half-life of
elimination from the lungs in rats was 36 days. Low and infrequent
treatment with aerosol pentamidine was highly effective in prevention of
PCP in the animal model. No toxicity was seen in histopathologic sections
from the lungs of rats that received aerosol pentamidine at doses that
greatly exceeded the therapeutic dose (5).
A previous article discloses a new Bioassay for studying pentamidine
pharmacokinetics (5). In this article the authors speculate that a better
understanding of the pharmacokinetics of pentaimidine should lead to
safer, more effective use of the drug in the treatment or prevention of
PCP. Elsewhere in the paper, the authors note that aerosol administration
also deserves further study. However, there is no disclosure that
administration of pentamidine in aerosol form to subjects suseptible to
infection by Pneumocystis carinii, particularly effective in preventing
Pneumocystic carinii infection and the PCP caused thereby.
An abstract disclosing the use of pentamidine in an aerosol for prevention
of PCP was distributed on Mar. 26, 1986 to attendees at the Annual Meeting
of the American Society for Microbiology, Washington, D.C.
SUMMARY OF THE INVENTION
Pneumocystis carinii pneumonia may be prevented in a subject susceptible to
infection by Pneumocystis carinii by administering to the subject an
amount of a pentamidine in aerosol form effective to prevent infection by
Pneumocystis carinii and thus prevent Pneumocystis carinii pneumonia.
Also, this invention provides a composition for the prevention of
Pneumocystis carinii pneumonia which comprises an amount of a pentamidine
effective to prevent infection by Pneumocystis carinii and thus prevent
Pneumocystis carinii pneumonia in aerosol form and a pharmaceutically
acceptable carrier.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1. shows an apparatus used to administer aerosol pentamidine to rats.
FIG. 2. shows a semi-log plot of pentamidine concentrations in the lungs of
rats that had received a single dose of 4.0 mg/kg of pentamidine by
aerosol.
DETAILED DESCRIPTION OF THE INVENTION
Pneumocystis carinii pneumonia may be prevented in a subject susceptible to
infection by Pneumocystis carinii by administering to the subject an
amount of a pentamidine in aerosol form effective to prevent infection by
Pneumocystis carinii and thus prevent Pneumocystis carinii pneumonia.
Preferably, the subject is a human being who has been infected by the virus
which causes acquired immune deficiency syndrome (AIDS) or one who has
cancer or will receive an organ transplant or is otherwise
immunosuppressed.
The pentamidine useful in the practice of this invention may be pentamidine
isethionate or pentamidine naphthoate, particularly the former. Other
salts of pentamidine are known and would be useful in the prevention of
PCP.
The pentamidine in aerosol form may be administered by intranasal
inhalation as well as by oral inhalation. The intrasasal or oral
inhalation may be effected utilizing an ultrasonic nebulizer, metered dose
inhaler, or other such device.
For human use the amount of pentamidine in aerosol form effective to
prevent infection by Pneumocystis carinii may vary widely but is typically
between about 0.1 microgram/ml and about 200 micrograin/ml. The amount of
pentamidine contained in the aerosol is typically about 0.5 mg to about
500 mg. The prefered amount of pentamidine contained in the aerosol is
about 30 mg to about 60 mg. Pentamidine in aerosol form may be effective
to prevent infection by Pneumocystis carinii upon inital administration.
Although the pentamidine may be administered in aerosol form weekly, or
every 3 or 4 days, it is presently perferred that pentamidine in aerosol
form be administered every 3 or 4 days for about 2 weeks and thereafter
administered weekly.
This invention also provides a composition for the prevention of
Pneumocystis carinii pneumonia. This composition comprises an amount of a
pentamidine effective to prevent infection by Pneumocystis carinii and
thus prevent Pneumocystis carinii pneumonia in aerosol form and a
pharmaceutically acceptable carrier. The pharmaceutically acceptable
carrier may be any of the currently well known such carriers. An example
of such carriers is sterile, pyrogen-free water. The amount of the
pentamidine effective to prevent infection by Pneumocystis carinii may
vary widely but typically is between about 0.1 micrograin/ml and about 200
micrograin/ml and the amount of pentamidine contained in the aerosol is
typically about 0.5 mg to about 500 mg. The pentamidine may be pentamidine
isethionate or pentamidine naphthoate.
The following experimental details are set forth to aid in understanding
the invention, but are not intended to, and should not be construed so as
to limit in any way the scope of the invention as set forth in the claims
which follow.
I. Animal Studies
We compared the tissue distribution of pentamidine in experimental animals
treated with IM or aerosol pentamidine. We also tested the toxicity of
aerosol pentamidine in rats and tested its effectiveness in an
experimental model of Pneumocystis carinii pneumonia (PCP).
Measurement of Pentamidine in Tissues
All doses and concentrations of pentamidine were calculated in terms of the
di-isethionate salt: 1.74 mg of the salt equals 1.00 mg of the base.
Intramuscular (IM) doses were administered to the hindcalves of male
Sprague-Dawley rats (240-260 g, Charles River Breeding Laboratories,
Wilmington, Mass.). An agar-diffusion bioassay was used as described to
measure pentamidine concentrations in tissue (5).
Administration of Aerosol Doses
The method used to treat rats with aerosol pentamidine is illustrated in
FIG. 1. The dose was calculated from the product of the concentration of
the drug in the chamber, the minute volume of the rats (lung
vol..times.resp. rate), and the time of exposure. In all experiments
exposure time was 15 min, male Sprague-Dawley rats with an average weight
of 250 g were used, and the minute volume of the rats was assumed to be 70
ml. Rats were treated in groups of four. They were placed in the glass
chamber while it was swept with a stream of aerosolized pentamidine. The
aerosol was generated by oxygen flowing at 8 l/min through the nebulizer
(Cadema Medical Products, part no. CA 61, Middletown, N.Y.). The drug
solution was aerosolized at 0.3 ml/min with an expected mean particle
diameter of 0.5-0.8 micron. To deliver a dose of 4.0 mg/kg the neubulizer
was charged with 4.5 ml of a 25 mg/ml solution of pentamidine isethionate
in water. During the 15 min exposure time, 120 l of oxygen and 112.5 mg of
pentamidine flowed through the chamber. The concentration of pentamidine
in the atmosphere of the chamber was thus about 0.9 mcg/ml. This
concentration multiplied by the minute volume and the exposure time gives
a dose of 1.0 mg; since the rats weighed 0.25 kg, the dose was 4.0 mg/kg.
Doses in all trials were calculated as above. This estimates the amount of
pentamidine that animals inhaled, not the amount retained.
Experimental Model of PCP
Treatment regimens were tested in the standard animal model of PCP (6). To
induce infection with P. carinii, rats were immunosuppresed with steriods
for twelve weeks while restricted to a low-protein diet and tetracycline.
Administration of a test regimen was initiated early during the induction
period to determine its effectiveness in preventing PCP and was initiated
late during the induction period to determine its effectiveness in
treating PCP. Male Sprague-Dawley rats weighing 175-225 g were used. Rats
were given twice weekly subcutaneous injections of 75 mg/kg of cortisone
acetate, were maintained on an 8% protein diet, and were treated with
tetracycline via their drinking water. Rats were sacrificed after twelve
weeks of this regimen and the extent of infection was judged by counting
cysts in toluidine blue 0-stained smears of lung homogenates. Lung
homogenates were prepared by combining a weighed portion of tissue with
nine ml of 0.1N HCl per g.
Results
Table 1A shows the levels of pentamidine in different organs of rats that
were treated by IM injection with 4.0 mg/kg/day. Animals were sacrificed
at 24 h after the last dose. The drug was undetectable (0.8 mcg/g) in the
lungs after a single IM dose while the mean level in the kidneys was 26.9
mcg/g. Accumulation of pentamidine after multiple IM doses was highest in
the kidneys, liver, and spleen; levels in the kidney were about tenfold
higher than in the lung. Tissue concentrations of pentamidine in humans
after intravenous infusions of 4.0 mg/kg/day are shown in Table 1B.
Table 2 shows the levels of pentamidine in different organs of rats that
were treated with aerosol doses of 0.4 mg/kg/day. Animals were sacrificed
at 24 h after the last dose. The drug was undetectable in kidney, spleen,
and liver after eight doses of aerosol pentamidine while levels in the
lung averaged 60.5 mcg/g.
FIG. 2 shows the levels in the lungs of rats that were sacrificed at
different times after receiving a single aerosol dose of 4.0 mg/kg. Four
rats were studied at each time. There was an early phase of rapid
elimination from the lung that may reflect clearance of particles of the
drug from large airways. After this period elimination of pentamidine from
the lung was extremely slow; the half-life of elimination from days 2-42
was 36 days.
The retention factor for aerosol pentamidine can be estimated from FIG. 2.
TABLE 1A
______________________________________
Tissue Concentrations of Pentamidine in Rats
after Intramuscular Injection of 4.0 mg/kg/day
No. of
Pentamidine concentration (mcg/g)
doses Lung Kidney Liver Spleen Adrenal
______________________________________
1 NMA* 26.9.+-.4.4@
4.1.+-.0.4
4.5.+-.1.8
1.8.+-.1.2
2 3.7.+-.2.6
62.4.+-.14.8
17.2.+-.7.9
27.9.+-.2.9
3.3.+-.2.4
4 9.1.+-.6.6
83.7.+-.48.8
24.6.+-.9.2
45.0.+-.17.6
5.0.+-.2.4
______________________________________
TABLE 1B
______________________________________
Tissue Concentrations of Pentamidine in Humans
after Intravenous Infusions of 4.0 mg/kg/day
Pentamidine concentration (mcg/g)
No. of doses
Lung Kidney Liver Spleen Adrenal
______________________________________
1 NMA 8.5 35 40 19
2 NMA 13 23 40 NA#
5 42 62 112 28 NA.sup.
15 56 123 300 368 92
______________________________________
*no measurable amount
@mean .+-. SD (N = 4)
#not available
TABLE 2
______________________________________
Pentamidine concentration (microgram/g)
No. of doses
Lung Kidney Spleen
______________________________________
1 3.1 .+-. 1.9 .sup. NMA#
NMA
2 12.1 .+-. 3.0
NMA NMA
4 17.7 .+-. 5.5 NMA NMA
8 60.5 .+-. 10.2
NMA NMA
______________________________________
#no measurable amount
mean .+-. SD (N = 4)
The amount of drug retained in the lungs, by extrapolation of the
elimination curve, was about 40 mcg/g; since lung weights averaged 1.5 g,
60 mcg was retained per animal. The amount of drug inhaled by each animal
was about 1.0 mg, so about 6.0 percent was retained. Thus, with an aerosol
dose of 4.0 mg/kg, the retained dose was 0.24 mg/kg.
Results from trials in the animal model of PCP are shown in Table 3. In
Trial I, animals received no treatment or received prophylactic doses of
aerosol or IM pentamidine. Animals were treated weekly during weeks 5-11
of the induction period with aerosol pentamidine at 0.4 mg/kg or IM
pentamidine at 4.0 mg/kg. All untreated animals had severe PCP at
necropsy. Animals that had received prophylactic doses of aerosol
pentamidine had lungs that were normal in weight and appearance and cysts
of P. carinii were rare or absent in stained smears of lung homogenates.
Animals that received prophylactic doses of aerosol pentamidine had more
than a thousandfold less severe infection than was seen in control
animals. Aerosol pentamidine was more effective in prevention of PCP than
tenfold higher doses of IM pentamidine.
In trial II, animals received no treatment or received prophylaxis or
treatment with aerosol pentamidine. To test the effectiveness of aerosol
pentamidine in prophylaxis of PCP, animals were treated weekly during
weeks 7-11 of the induction period with aerosol pentamidine at 0.1 mg/kg.
To test the effectiveness of aerosol pentamidine in the treatment of PCP,
animals were treated daily for four days during week ten of the induction
period with aerosol pentamidine at 0.4 mg/kg. Both the prophylactic and
therapeutic regimens were effective.
TABLE 3
__________________________________________________________________________
no. of Pentamidine treatment Lung findings at necropsy
Trial
rats
Dose*
Route Schedule Weight (g)
Pent (ug/g)
Cysts/hpf #
__________________________________________________________________________
I 9 no treatment 3.51 .+-. 0.86@
NMA 824 .+-. 860
8 4.0 IM weekly, wk 5-11
3.28 .+-. 1.15
4.5 .+-. 1.7
102 .+-. 88
8 0.4 aerosol
weekly, wk 5-11
1.94 .+-. 0.21
29.7 .+-. 7.1
<<1
II 9 no treatment 2.57 .+-. 0.82
NMA 247 .+-. 134
9 0.2 aerosol
weekly, wk 7-11
1.43 .+-. 0.31
15.2 .+-. 5.0
10.3 .+-. 8.2
8 0.4 aerosol
daily, 4.times., wk 10
1.20 .+-. 0.20
15.8 .+-. 10.9
20.8 .+-. 30.8
III
8 no treatment 2.29 .+-. 0.66
NMA 504 .+-. 618
8 0.8 aerosol
monthly, wks 4, 8
1.26 .+-. 0.26
16.1 .+-. 3.3
4.6 .+-. 4.2
8 0.4 aerosol
biweekly, wks 7, 9, 11
1.41 .+-. 0.64
13.4 .+-. 7.9
48 .+-. 109
7 0.4 aerosol
daily, 4.times., wk 12
2.08 .+-. 0.68
8.3 .+-. 6.4
188 .+-. 255
__________________________________________________________________________
*mg/kg of pentamidine isethionate
#per high power filed (400.times.)
@mean .+-. standard deviation
In trial III, both prophylactic regimens were effective and the therapeutic
regimen was partially effective.
Within the prophylaxis and treatment groups, the lowest number of cysts
were found in animals with the highest concentrations of pentamidine in
the lung (data not shown). Retention of aerosol pentamidine was the
greater in normal animals and in animals that received early prophylactic
doses than it was in animals who were treated when they had severe
pneumonia.
Studies of the acute toxicity of aerosol pentamidine were performed in
rats. Four rats were treated with four consecutive daily doses of 3.2
mg/kg of aerosol pentamidine and were sacrificed at 24 h after the last
dose (total dose; 12.8 mg/kg). The mean concentration of pentamidine was
291 mcg/g in the lungs and 7.2 mcg/g in the kidneys. Treatments were
well-tolerated. Lungs were normal in weight and appearance. Stained
sections of the lungs were examined and no histopathologic changes were
found. There were rare foci of mild thickening of interalveolar septae
containing a few histiocytes and some congestion. Rare lymphoid aggregates
were seen in peribronchial regions. These were also seen in sections from
control animals and are common findings in normal rat lung. The presence
of high concentrations of pentamidine in the lungs appears to provoke
little or no toxicity.
II. Clinical Studies
Patient Eligibility
Patients were 18 years old or older and outpatients judged free of any
imminently-critical medical problems. All patents received a complete
physical examination and medical history evaluation. Pretreatment
laboratory studies included a CBC with differential and platelet count, a
biochemical screening profile, chest X-ray, and pulmonary function tests
including spirometry and measurement of diffusion capacity.
Patients were not receiving any other investigational agents for
chemoprophylaxis of PCP, e.g. sulfamethoxazole-trimethoprim (bactrim),
sulfadoxine-pyrimethamine (fansidar), dapsone, or IV pentamidine. They
could have been receiving investigational agents for treatment of AIDS
such as azidothymidine (AZT) or for treatment of KS or opportunistic
infections other than PCP.
All patients had:
1) AIDS or ARC as defined by the Centers for Disease Control;
2) a normal chest X-ray or minimal . abnormalities that have diminished or
stabilized over the previous month;
3) WBC 1,000/mm3 and platelets less than or equal to 60,000/mm3;
4) adequate pulmonary function (vital capacity 80% of predicted; forced
expiratory volume, 1 sec less than or equal to 65% of total FEV; and
corrected pulmonary diffusion capacity less than or equal to 60% of
predicted).
Patients who had inadequate pulmonary function according to the above
criteria were only enrolled after evaluation by the Infectious Diseases
and Pulmonary Services. These patients were enrolled if PCP could be ruled
out (e.g., by rest and exercise blood gases, gallium scan, or
bronchoscopy) and if pulmonary function is only marginally inadequate and
is considered likely to remain stable or improve. This category was
included because we expeced, based on past experience, that pretreatment
evaluation could reveal previously unsuspected pulmonary disease in a
small number of patients.
Aerosol Apparatus
A hand-held ultrasonic nebulizer (Siemens Micro-Inhalator S, model no. TV
7000) was used to administer aerosol pentamidine. Each patient was issued
a device at the start of the study. These devices were labeled with the
patient's code number. The devices are simple to operate and their
sterility was ensured as components were replaced after a single use. New
sterile plastic reservoirs for the drug solution and new sterile suction
rods were used for each treatment.
Administration of the Drag
Each aerosol treatment was given over 15-30 minutes. The nebulizer was
loaded with 3.0 ml of solution of pentamidine isethionate in sterile
water. Ampules containing pentamidine (Pentam 300, LyphoMed, Melrose Park,
Ill.) were obtained from the pharmacy by prescription. The sterile ampules
contained 300 mg of lyophilized pentamidine isethionate and were intended
as a single dose vial for IM and IV use. Using aseptic techniques, 10.0 ml
of sterile pyrogen-free water were added to an ampule to yield a solution
containing 30.0 mg/ml of pentamidine isethionate. 1.0, 1.5,or 2.0 ml
aliquots were added to the nebulizer reservoir for doses of 30, 45, or 60
mg, respectively. Sterile pyrogen-free water was added to yield a total
volume of 3.0 ml. Treatments were administered by a physician or
registered nurse.
Pharmacokinetic Studies
Pentamidine concentrations were measured in serum and urine samples
collected during the treatment period. A urine sample was obtained from
each patient before treatment numbers 1, 6, 10, 16, and 28. A serum sample
was obtained from each patient before the first treatment and at 0-15 min
after treatment numbers 1, 6, 10, 16, and 28.
Evaluation of Toxicity
General Procedure
The aim was to determine if aerosol pentamidine cause systemic or pulmonary
toxicity. The most common adverse reactions to pentamidine, when it is
given IM or IV, are hypotention, hypoglycemia, and renal failure (4). It
was not expected that these would be observed with aerosol pentamidine
because this route of administration limits delivery of the drug to the
lungs and there is little or no systemic absorption of the drug after oral
administration. None of these reactions have been seen in patients treated
with a biweekly dose of 30 mg. Signs of systemic toxicity were monitored.
To detect adverse effects on the lungs, pulmonary function was monitored.
During the study all medical problems revealed by questioning or examining
the patient were recorded. All problems were judged a concomitant illness
or adverse reaction based on the following definitions. A concomitant
illness was an experience not related to use of the study drug and
included any event attributable to enviromnmental, systemic, accidental
factors, or concomitant medication. An adverse reaction was an unwanted
experience which might be related to use of the study drug and includes
any side effect, toxicity, or sensitivity reaction to the study drug. All
adverse reactions were rated as mild, moderate, or severe.
Patients were interviewed before and after each treatment and any adverse
reactions, complaints, or comments recorded. This data and results of
physical and laboratory examinations were reviewed weekly and summary
reports prepared quarterly.
The following studies were performed on all participants before the first
treatment and at treatment numbers 6, 10, 16, and 28.
1) medical examination: included complete or interim medical history and
physical examination;
2) laboratory tests: included biochemical screening profile and complete
blood count with differnetial;
3) pulmonary function tests: included spirometry and measurement of
diffusion capacity.
Patients who in the preliminary evaluation were found to have reduced
pulmonary function (D1 CO less than 60% of predicted) also underwent all
of the examinations listed above at treatments no. 4 and 20. A chest x-ray
was obtained at entry and at treatments no. 16 and 28.
Evaluation of Effectiveness
Prophylaxis was judged effective for an individual patient if that patient
had no proven or probable episodes of PCP. Prophylaxis was considered a
proven failure if a patinet developed pneumonia and P. carinii was found
in stained preparations obtained by bronchoscopy or lung biopsy.
Prophylaxis was considered a probable failure if a patient develops
pneumonia and responded to empiric treatment with SXT the case was
considered inevaluable because a bacterial etiology for the pneumonia
could not be ruled out. If a patient died and no autopsy was perfomed, the
case was considered not evaluable unless there was evidence that the
patient had good antemortem pulmonary function and died from other causes.
If the latter conditions were met, the case was considered a probable
success.
Criteria for Discontinuing
A dose level was discontinued if a severe adverse reaction was observed in
any patient or if moderate adverse reactions were observed in more than
three patients. Administration of the drug to individual patients was
discontinued if repeated mild adverse reactions were experienced.
Treatment was discontinued if any patient had interim results from
biochemical or hematologic tests that exceeded the limits used to
established patient eligibility unless the abnormality was judged
unrelated to use of aerosol pentamidine.
Treatment was discontinued if a patient had, compared to baseline studies,
a 20% decline in vital capacity or in corrected diffusion capacity or
forced expiratory volume (1 sec).
Any patient who developed a severe opportunistic infection or other
concomitant illness necessitating hospitalization was discontinued from
the study. Unless the infection is PCP, treatment with aerosol pentamidine
was resumed when the patient was discharged from the hospital.
Any patient could elect to discontinue participation at anytime.
Summary
Trials of the safety and effectiveness of aerosol pentamidine in patients
with AIDS or ARC have been underway for one year. Initially twelve
patients were treated with biweekly doses of 30 mg of aerosol pentamidine.
The treatment period was three months; patients were examined before and
after each treatment and underwent pulmonary function testing and
biochemical and hematologic tests before treatment no. 1 and after
treatment nos. 1, 2, 4, and 6. No adverse reactions were seen, all
patients had stable or improving pulmonary function, and no patient had a
proven or possible episode of PCP.
In the next phase a total of 60 patients were enrolled; all patients
received biweekly doses of 30 mg of aerosol pentamidine. A total of 650
treatments were given. Treatment periods ranged from 1-12 months. No
proven adverse reactions have been observed. A single patient developed a
severe skin rash after his fifth dose. He had no reactions after his first
four doses and was receiving several other medications at the time the
rash developed. His rash has since disappeared and the patient is
currently receiving aerosol pentamidine elsewhere and is tolerating it
well. Five proven episodes of PCP have occurred among patients who
received biweekly doses of 30 mg; six proven episodes of PCP have occurred
among patients who were treated with this dose, but who skipped one or
more scheduled doses.
In the next phase patients were randomized to receive doses of 30, 45, or
60 mg of aerosol pentamidine. Treatments are administered weekly for the
first four weeks and then biweekly--this new schedule was designed to more
rapidly establish protective levels of pentamidine. A total of 73 patients
were enrolled over the past two months with approximately equal numbers at
each dose level. Because of evidence that the 30 mg dose was not reliably
protective and because the 45 mg and 60 mg doses appear to be well
tolerated, we have recently discontinued the 30 mg dose. Patients who were
receiving the low dose have since been randomized to receive either 45 or
60 mg. To date two patients receiving 45 mg have had proven episodes of
PCP. Both were very mild episodes.
In conclusion, a total of 960 doses of aerosol pentamidine have been
administered to a total of 116 patients. The longest period of followup
has been one year. No participant has had a significant decline in
pulmonary function, abnormalities in biochemical or hematologic tests, or
chest x-ray changes attributable to aerosol pentamidine. The treatments
appear to be well tolerated and there is preliminary evidence that they
are at least partially protective. A total of seven mild cases of PCP has
been seen. If aerosol pentamidine had been ineffective, 30-45 cases would
have been seen.
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