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Description  |
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TECHNICAL FIELD
The present invention relates to the treatment of Pneumocystis carinii
infection, particularly P. carinii pneumonia (PCP), via the aerosol
administration of the drug pentamidine to the respiratory system of a
patient suffering from such infection.
BACKGROUND
Severe Pneumocystis carinii infections of immunocompromised individuals,
such as premature infants, children with hypogammaglobulinemia or
deficiencies of cell-mediated immunity, patients receiving
immunosuppressive therapy, and patients suffering acquired
immunodeficiency syndrome (AIDS), leads to the development of Pneumocystis
carinii pneumonia (PCP). By far the most common occurrence of PCP is in
AIDS patients. More than 36,000 cases of AIDS have been reported since
1979, and 62% of these patients developed PCP ("Acquired Immunodeficiency
Syndrome (AIDS) Weekly Surveillance Report", CDC (Dec. 29, 1986)). With
current standard treatments, mortality for the first episode of PCP in
AIDS patients is approximately 20-30%. To date, over 42,000 cases of PCP
have been reported in AIDS patients (including multiple episodes), with
100,000 cases predicted to occur in the United States by 1991.
The two conventional therapies for treating PCP consist of either
trimethoprim-sulfamethoxazole (TMP-SMX) administered orally or
parenterally, or pentamidine isethionate administered parenterally: Hughes
et al, J Pediatr (1978) 92:285-291; Sattler et al, Am J Med (1981)
70:1215-1221; Navin et al, N Engl J Med (1984) 311:1701-1702.
Unfortunately, approximately 50% of patients receiving either drug
treatment develop severe toxicity, requiring discontinuation of the
therapy: e.g., K. A. Western et al, Ann Int Med (1970) 73:695; M. Wharton
et al, Ann Int Med (1985) 105:37-44; F. M. Gordin et al, Ann Intern Med
(1984) 100:495-499. Many immediate and long term side effects have been
associated with the parenteral administration of pentamidine. Pain,
swelling and sterile abscesses are observed at the site of intramuscular
injections, and thrombophlebitis and generalized or localized urticarial
eruptions are associated with intravenous administration. Severe
hypotension may also develop following a single intramuscular dose, or
after rapid intravenous infusion: Navin et al, supra. Hypoglycemia has
also been reported in patients: Walzer et al, supra; Pearson et al, Ann
Inter N Med (1985) 103:782-786. In some patients with hypoglycemia,
diabetes mellitus also develops: Osei et al, Am J Med (1984) 77:41-46.
Impaired renal function occurs in about 25% of patients receiving
pentamidine. Other common adverse reactions include elevation of liver
enzymes, hematologic disturbances with neutropenia and thrombocytopenia,
fever, hypocalcemia, and hallucinations. Less common adverse effects
include cardiac arrhythmias and pancreatitis. See, e.g., Pearson et al,
supra.
When a patient develops an adverse reaction requiring discontinuance of one
of the above standard therapies, the usual recourse is to place the
patient on the alternative standard therapy. A substantial number of
patients, however, develop an adverse reaction to both TMP-SMX therapy and
parenteral pentamidine. Thus, the art has actively pursued alternative
therapies that obviate the serious side effects associated with the above
standard therapies. For example, dapsone (diaminodiphenylsulfone) has been
tried both alone and in combination with TMP, to treat PCP. Dapsone has
been reported to be effective in a rat PCP model: Hughes et al,
Antimicrobial Agents Chemother (1984) 26:436. Dapsone alone, however, has
a failure rate for PCP of about 39%, while approximately 31% of the
patients given trimethoprim-dapsone (TMP-DPS) experienced severe toxicity:
G. S. Leoung et al, Ann Int Med (1986) 105:45-48; Mills et al, Int'l.
Conf. on AIDS, poster 297 (Paris, France, 23-25 June 1986); Medina et al,
Proceedings of the III Int'l. Conf. on AIDS, p. 208 (Washington, D.C.
1987).
Another alternative therapy is treatment with
.alpha.-difluoromethylornithine (DFMO). Although DFMO was not efficacious
in a rat model of PCP, recent clinical studies report some clinical
response for this drug: J. A. Golden et al, West J Med (1984) 141:613;
McLees et al, Am Rev Respir Dis (1987) 135:A167. Yet another potential
therapy for PCP has been suggested using the drug trimetrexate. Adverse
reactions have been reported, however, and the relapse rates within one
month appear to be high: Allegra et al, N Engl J Med (1987) 317:978-985.
The aerosolization of pentamidine has been studied in rodent models: R. H.
Waldman et al, Am Rev Respir Dis (1973) 108:1004-1006; R. J. Debs et al,
Abstracts of the 1985 ICAAC, p. 192 , (Abstract No. 550); E. H. Bernard et
al, Id. p. 193 (Abstract No. 552); R. J. Debs et al, Int'l. Conf. on AIDS,
poster 294 (Paris, France 23-25 June 1986); E. H. Bernard et al, Id.,
poster 300.
AIDS patients suffering PCP are known to have higher rates of adverse
reaction to certain therapies than other immunocompromised patients
suffering PCP: Hughes et al, supra; Gordin et al, supra. Thus, the art is
in need of a more effective therapy for PCP, particularly in AIDS
patients, and none of the known or potential routes of therapy have
demonstrated the ability to be both efficacious and free of adverse side
effects.
SUMMARY OF THE INVENTION
It has surprisingly been discovered that an aerosol of pentamidine having
particle sizes within the range of about 0.25 to about 2.5 microns (.mu.m)
delivered by inhalation to the respiratory system of a patient infected
with Pneumocystis carinii effectively inhibits the P. carinii infection
without causing systemic side effects. Furthermore, it has been discovered
that the aerosol treatment with pentamidine is even effective for
clinically manifest infections, such as PCP in AIDS patients. Thus, it has
been demonstrated that therapeutically effective amounts of aerosolized
pentamidine can be delivered by inhalation to the human lung, even
diseased lungs, while systemic levels of pentamidine remain sufficiently
low to prevent the adverse side effects associated with parenteral
pentamidine therapy. Indeed, it appears that aerosol pentamidine therapy
does not suffer any of the drawbacks associated with standard PCP
therapies, yet is highly efficacious in the treatment of at least mild to
moderate PCP. We have found that treatment using aerosolized pentamidine
is effective even in patients forced to discontinue treatment with
parenteral pentamidine due to toxicity. In view of this unexpected
combination of efficacy and safety, aerosolized pentamidine is becoming
the therapy of choice for Pneumocystis carinii infection in AIDS patients.
This treatment has been approved by the U.S. Food and Drug Administration.
In its broadest aspects, the present invention is directed to a method of
inhibiting P. carinii pulmonary infections in a human patient comprising
delivering, by inhalation to the respiratory system of a patient suffering
from Pneumocystis carinii infection, an aerosol of pentamidine having
particle sizes of which some fall within the range of about 0.25 .mu.m to
about 5.0 .mu.m, preferably within the range of about 0.5 to about 2.5
.mu.m, in an amount sufficient to effect treatment of Pneumocystis carinii
infection. The pentamidine aerosol is preferably generated and delivered
to the patient by a suitable medical nebulizer. Suitable medical
nebulizers include, but are not limited to, the Respirgard.RTM. II and the
UltraVent.RTM.. For patients with sub-clinical Pneumocystis carinii
infections, the amount of pentamidine aerosol sufficient to effect
treatment is delivered to the patient's respiratory system when about 20
mg to about 600 mg, preferably about 30 to about 300 mg, of pentamidine is
aerosolized and then administered to the patient's respiratory system by
inhalation. For treatment of subclinical infections, the drug can be
delivered intermittently, preferably by administering pentamidine aerosol
once every 2-4 weeks. For patients with clinically manifest Pneumocystis
carinii infection (e.g., with Pneumocystis carinii pneumonia), an amount
of pentamidine aerosol sufficient to effect treatment results when about
20 mg to about 600 mg pentamidine is aerosolized and administered. For
clinically manifest infections, the pentamidine aerosol is preferably
delivered repeatedly to the patient's respiratory system by having the
patient inhale the pentamidine aerosol daily for about 4 to 21 days.
In various preferred embodiments of the present invention, the particle
size of the aerosol administered to the patient is selected to minimize
deposition of pentamidine in the airways, and therefore increase the
amount of drug delivered to alveoli. The method of the present invention
is preferably employed with HIV-infected patients, particularly those
suffering from AIDS or AIDS-related complex (ARC), to prevent latent or
subclinical P. carinii infections from developing into clinically manifest
forms, as well as with HIV-positive patients to treat clinically manifest
P. carinii infections such as Pneumocystis carinii pneumonia (PCP). Other
preferred embodiments will be apparent from the detailed description and
the examples.
BRIEF DESCRIPTION OF THE FIGURE
FIG. 1 is a diagram showing a nebulizer system useful for producing and
administering pentamidine aerosol.
DETAILED DESCRIPTION
Pneumocystis carinii are organisms that invade the lungs of humans early in
childhood, and remain there throughout life. In a healthy person these
organisms are maintained at low or "subclinical" levels by the immune
system. However, if the individual's immune system is depressed, the
ability to keep Pneumocystis carinii at subclinical levels is lost.
Consequently, the number of Pneumocystis carinii present in the lung
increases, which in turn leads to pathologies or disease states that
include inflammation of lung tissue. This inflammation, among other
things, prevents the alveolar portions of the lungs from performing their
normal function of gas exchange. As the inflammation increases, patients
begin to develop symptoms such as fever and cough, and find it
increasingly difficult to breath. When the inflammation and other
pathologies become clinically manifest and reach certain clinically
defined levels, the patient is diagnosed as having Pneumocystis carinii
pneumonia, or PCP for short.
"Prophylactic" treatment for P. carinii infection as used herein refers to
treatment which prevents subclinical infection from developing into a
clinically recognizable infection such as Pneumocystis carinii pneumonia
(PCP). Such prophylactic treatment is known as post-exposure prophylaxis.
Post-exposure prophylaxis refers to administration of a drug to a patient
(1) after the patient has come in contact with the infecting organism, (2)
for the purpose of preventing the spread of the infection, i.e., the
organism. As used herein, "treatment" of P. carinii pulmonary infection
includes both treatment of clinically manifest Pneumocystis carinii
infection (such as PCP) and prevention of clinically manifest Pneumocystis
carinii infection (i.e., maintenance of Pneumocystis carinii infection at
subclinical levels).
The method of the present invention is particularly useful for treating
immunocompromised human patients. Such patients include individuals
suffering from AIDS or ARC, as well as premature infants, patients treated
with immunosuppressive drugs, and patients afflicted by other
immunocompromising diseases or defects. The present invention is
particularly useful in the treatment of AIDS and ARC patients, such
patients being defined by generally accepted clinical diagnostic criteria.
The method of the present invention is also believed to be useful for
HIV-positive individuals (patients seropositive for HIV particles,
fragments or anti-HIV antibodies) who have not yet developed AIDS or ARC,
but who are considered to be at risk for PCP. Further, in some instances
it may be desirable to treat subjects at or before the time that the
subject is immunosuppressed, for example, during or prior to scheduled
chemotherapy. A patient "at risk" for P. carinii pulmonary infection or
PCP is any patient for whom a substantial possibility exists that
clinically recognizable Pneumocystis carinii infection or PCP will
develop. For the most part, "at risk" patients are those patients who are
immunosuppressed or immunocompromised.
As used herein, "pentamidine" refers to the drug
p,p'-(pentamethylenedioxy)dibenzamidine and its pharmaceutically
acceptable salts. See, e.g., U.S. Pat. No. 2,410,769. Various salts can be
prepared by those of skill in the art by known techniques. The salt form
of the drug is particularly preferred to improve solubility in the
solution to be aerosolized. The most popular form of the drug is
pentamidine isethionate, which is the bis(.beta.-hydroxyethane sulfonate)
salt. Since sulfur oxides such as the isethionate and mesylate salts may
induce bronchoconstriction when inhaled (particularly by persons with
hyperreactive airways), it may be desirable to avoid the use of sulfur
oxide salts for certain patients. For example, pentamidine glutamate,
pentamidine lactate, and pentamidine hydrochloride may be employed as
alternatives to sulfur oxides. Pentamidine salts are available from
various commercial sources, such as Lyphomed, Melrose Park, Ill., and
Aldrich Chemical Co., Milwaukee, Wis.
Pentamidine, usually as a salt, is made into a solution or suspension for
aerosolization. The exact concentration and volume of the solution are not
critical, acceptable formulations being readily determined by those of
ordinary skill in the art. The exact concentration and volume of the
solution will generally be dictated by the particular nebulizer selected
to deliver the drug, and the intended dose. It is preferred to minimize
the total volume, however, to prevent unduly long inhalation times for the
patient.
The pentamidine solution is aerosolized by any appropriate method. Usually,
the pentamidine aerosol will be generated by a medical nebulizer system
which delivers the aerosol through a mouthpiece, facemask, etc. from which
the patient can draw the aerosol into the lungs. Various nebulizers are
known in the art and can be used in the method of the present invention.
See, e.g., Boiarski et al, U.S. Pat. No. 4,268,460; Lehmbeck et al, U.S.
Pat. No. 4,253,468; U.S. Pat. No. 4,046,146; Havstad et al, U.S. Pat. No.
3,826,255; Knight et al, U.S. Pat. No. 4,649,911; Bordoni et al, U.S. Pat.
No. 4,510,929.
In selecting a nebulizer system, it is preferred to select a system which
will effectively deliver substantial quantities of the drug to the
pulmonary alveoli. Improper technique can result in deposition only within
the airways (i.e., trachea, pharynx, bronchi, etc.), with either little or
no drug reaching the alveoli and the situs of Pneumocystis carinii
infection. A convenient way to insure effective delivery of the drug to
the alveoli is to select a nebulizer which produces sufficiently small
particles (e.g., about 0.25 to about 5.0 .mu.m, preferably about 0.5 to
about 2.5 .mu.m), since the larger particles are generally deposited in
the airway or nasopharynx. Usually, this can be accomplished by
aerosolizing the pentamidine in a manner that provides a mean maximum
particle diameter (measured as described in the Examples) of about 4-5
.mu.m or less). It is preferred to have a maximum mean particle diameter
of about 3 .mu.m or less, and most preferably about 2.5 .mu.m or less. The
preferred range of mean particle diameter is generally about 0.50 to about
2.5 .mu.m.
As an alternative to selecting small mean particle diameters to achieve
substantial alveoli deposition, it may be possible to administer a very
high dosage of pentamidine with a larger mean particle diameter. A proviso
to such an approach is that the pentamidine salt selected is not too
irritating at the required dosage and that there are a sufficient number
of particles in the total population having a diameter in the 0.5 to about
5 .mu.m range to allow for deposition in the lungs.
An example of a medical nebulizer that can be used in the practice of the
present invention is shown in FIG. 1. This nebulizer, available
commercially from Marquest Medical Products, Inc., Inglewood, Colo.
(Respirgard II.RTM. Nebulizer System, Product No. 124030), is an
inexpensive disposable nebulizer system that can aerosolize pentamidine
solutions and produce particles having a mean diameter in the range of
about 1-2 .mu.m. In the preferred mode of operation for this nebulizer,
referring to FIG. 1, oxygen flows through tube 1, usually at a rate of
about 5 to about 7 L/min, preferably about 6 L/min, into nebulizer 2,
where pentamidine solution 3 is aerosolized, generating particles in
conduit 4. When a patient draws on mouthpiece 5, air is drawn through
one-way valve 6, and the airstream entrains the pentamidine particles in
conduit 4. As the airstream containing the pentamidine aerosol passes
around the baffle of one-way valve 7, the population of large particles
(i.e., diameter greater than about 2-4 .mu.m) is substantially reduced, so
that the particles leaving the mouthpiece 5 have a mean diameter in the
range of about 1 to about 2 .mu.m. When the patient exhales through
mouthpiece 5, the vented gas containing pentamidine particles travels
through one-way valve 8 towards particle filter 9, which removes any
residual pentamidine particles from the stream. Thus, the exhaled gas
leaving the nebulizer system through particle filter 9 is free of
pentamidine, minimizing the exposure of attending personnel. Other
suitable nebulizers for use with the method of the invention include
without limitation the UltraVent.RTM. nebulizer available from
Mallinckrodt, Inc. (Maryland Heights, Mo.); the Wright nebulizer (B. M.
Wright, Lancet (1958) 3:24-25); and the DeVilbiss nebulizer (T. T. Mercer
et al, Am Ind Hyg Assoc J (1968) 29:66-78; T. T. Mercer, Chest (1981)
80:6(Sup) 813-17).
As indicated above, Pneumocystis carinii infect the alveoli. Therefore, a
key aspect of the present invention is delivering effective amounts of the
drug pentamidine to the patient's alveoli. While there is no direct method
of measuring the amount of pentamidine delivered to the alveoli,
bronchoalveolar lavage (BAL) can be used to indirectly measure alveolar
concentrations of the drug, usually 18-24 hrs after inhalation to allow
clearance of pentamidine deposited in the bronchi. It should also be
understood that the amount of pentamidine deposited in the alveoli may be
substantially less than the total amount aerosolized since a large portion
is exhaled by the patient or is trapped on the interior surfaces of the
nebulizer apparatus. For example, approximately one third of the
pentamidine dose that is placed into the nebulizer remains in the
nebulizer after inhalation is completed. This is true regardless of the
dose size, duration of inhalation, and type of nebulizer used, Respirgard
or Ultravent. Moreover, resuspension of the residue and readministration
does not significantly increase the dose delivered to the patient: about
one third remains in the nebulizer. Furthermore, even with minimization of
airway deposition, there is a portion which is still deposited in the
patient's airways.
As used herein, with reference to drug dosages and especially "effective
amounts of drug to effect treatment", "pentamidine aerosol" refers to the
amount of drug that is placed in the nebulizer and subjected to
aerosolization. The "amount nebulized" or "amount aerosolized" of the drug
means the amount that actually leaves the apparatus as an aerosol, i.e.,
the amount placed into the apparatus less the amount retained in the
reservoir and on the inner surfaces of the apparatus at the conclusion of
a treatment session. "Treatment of pentamidine delivered to the alveoli"
refers to the amount of drug that is estimated to actually reach the
alveoli. As used herein, an "effective amount" of aerosolized pentamidine
is that amount which is sufficient to effect treatment, that is, to cause
alleviation or reduction of symptoms, to inhibit the worsening of
symptoms, to prevent the onset of symptoms, and the like.
The total amount of the drug delivered to the alveoli will depend upon many
factors, including the total amount aerosolized, the type of nebulizer,
the particle size, patient breathing patterns, severity of disease,
concentration of pentamidine in the aerosolized solution, and length of
inhalation therapy. Despite these interacting factors, one of ordinary
skill in the art will be able to readily design effective protocols,
particularly if the particle size of the aerosol is minimized. Depending
on the above factors, it is believed that the efficiency of delivery by
inhalation is about 7-10%. Based on estimates of nebulizer efficiency, it
is believed that as little as about 1 mg/treatment of pentamidine actually
delivered to the alveoli will inhibit P. carinii infections. Preferably,
at least about 5 mg/treatment is delivered to the alveoli, more preferably
at least about 10 mg/treatment. An effective dose delivered to the alveoli
will probably lie in the range of about 1 mg/treatment to about 100
mg/treatment, and preferably about 20 mg/treatment to about 75
mg/treatment, although more or less may be found to be effective depending
on the patient and desired result. It is generally desirable to administer
higher doses when treating more severe infections. For severe infection,
it is preferred to adminster about one treatment per day.
Single discrete doses of aerosolized pentamidine may be administered,
usually in the lower range of the dosages described above, for treatment
of subclinical P. carinii infections to prevent PCP. Of course, higher
dosages capable of treating clinically manifest infections are also
effective against subclinical infections. The frequency of treatments
depends upon a number of factors, such as the amount of pentamidine
administered in the single dose, the health of the individual, and the
patient's history of PCP infections. In general, it is preferred that
there be at least about one week between treatments, generally about two
to about four weeks, and possibly from about two to about three months.
This extended interval between treatments is possible due to the long
halflife of pentamidine in the lungs (e.g., about 3-6 weeks).
When treating clinically manifest P. carinii infections such as PCP, it
will usually be necessary to administer at least one aerosol dose per day
to the patient for a period of about 4 to about 21 consecutive days or
longer. Despite the long halflife of pentamidine in the lungs, the
treatment is usually carried out on consecutive days because new areas of
the lungs open up to penetration and deposition of the drug with
increasing resolution of the pneumonia. It is preferred to deliver at
least about 20 mg/day to the alveoli, more preferably at least about 30
mg/day, and most preferably at least about 40 mg/day. The therapy will
usually be administered daily over a full 21 day period, unless the
treatment for PCP results in a successful response before the end of the
treatment, as judged by conventional clinical criteria; e.g., clearing of
radiographic infiltrate, improved arterial PO.sub.2 (e.g., >70 mmHg),
reduction in dyspnea, respiratory rate and/or fever.
When employing the nebulizer system depicted in FIG. 1, it is desirable to
nebulize at least about 15 mg of pentamidine, more preferably at least
about 50 mg of pentamidine, and most preferably at least about 100 mg. A
preferred amount to nebulize will be in the range of about 30 mg to about
600 mg. Higher dosages can be employed, particularly with the non-sulfur
oxide salts (to minimize irritation), due to the low toxicity of
aerosolized pentamidine. To achieve aerosolization of the above amounts
with the above device, and employing a 6 mL volume of pentamidine
solution, it will generally be necessary to place from about 30 mg to
about 600 mg of pentamidine into the solution. With other nebulizers the
amounts may vary; however, provided appropriate attention is paid to
particle size, the selection of appropriate amounts to obtain efficacious
doses is within the skill of the art in view of this disclosure. For
example, dosage levels with appropriate safety factors can be established
by comparing results from a broncho-alveolar lavage to the results
obtained from a lavage after treatment with the above nebulizer system or
effective intravenous therapy (see, e.g., Example 1).
By way of illustration with the nebulizer system shown in FIG. 1, an
effective protocol to treat PCP is to dissolve about 600 mg of pentamidine
isethionate (Pentam.RTM. 300, Product No. 113-10, LyphoMed, Melrose Park,
Ill.) in about 6 mL of sterile water or other pharmaceutically acceptable
carrier, place the solution into the nebulizer, adjust the oxygen flow to
approximately 6 L/min, have the patient breathe normally from the
nebulizer through the mouth until approximately 3-4 mL of the solution has
been nebulized. The treatment time varies, usually from about 15 to about
30 min, depending on patient tolerance, and it is estimated that the
absorbed dose from such a protocol is about 45-60 mg. Repeating this
dosage sequentially for a period of at least about 4 days to about 21 days
has been found to be an effective treatment for AIDS patients suffering
PCP. As a prophylactic for PCP, lower dosages can adequately inhibit P.
carinii infection. For example, about 50 mg to about 300 mg is dissolved
into 6 mL and aerosolized, and one treatment is administered every 2-8
weeks. Preferably, about 50 to about 300 mg is aerosolized and
administered once every 2-5 weeks, most preferably once every 4 weeks.
The only frequent adverse effect observed clinically from the
administration of aerosolized pentamidine is transient airway irritation.
Patients with hyperreactive airways, such as patients with asthma or heavy
cigarette smokers, may experience some difficulty with aerosolized
pentamidine isethionate. This irritation, manifested as coughing during
treatment and possibly chest tightness, can be relieved for some patients
by the inhalation of bronchodilatory agents. The side effect may also be
avoided by employing other salts of pentamidine, such as the glutamate,
lactate or hydrochloride, which do not contain irritating sulfur oxides.
The following examples are provided for illustrative purposes only and do
not limit the scope of the present invention.
EXAMPLE 1
(Treatment of Pneumocystis carinii Pneumonia)
A prospective, nonrandomized study was conducted using human patients
presenting mild to moderate PCP, defined as: histologic confirmation of
the diagnosis, arterial blood oxygen tension (PaP2) greater than 55 mmHg
on room air, and likely to maintain present clinical status for at least
four days, even without specific therapy. The study was approved by the
Human Research Committee at the University of California at San Francisco,
and written informed consent obtained from each patient. Patients were
excluded if they had received pentamidine therapy for PCP within the
previous three months. Patients whose condition deteriorated clinically
within four days after enrollment were placed on conventional therapy and
listed as "not evaluated."
Diagnosis of PCP was confirmed by either bronchoalveolar lavage (C.
Broaddus et al, Ann Intern Med (1985) 102:747-52; D. C. Zavala et al,
Flexible Fiberoptic Bronchoscopy, (1978, Pepco Litho Place, Cedar Rapids,
Iowa)), or by sputum induction (T. D. Bigby et al, Am Rev Respir Dis
(1986) 133:515-18). The fluid was examined with Gram's stain, uranium
stain, potassium hydroxide (E. H. Lennette et al, Manual of Clinical
Microbiology, 4th ed., (1985, Amer. Soc. for Microbiology, Washington
D.C.), and for P. carinii using the methods described by J. A. Golden et
al, Chest (1986) 90:18-22; and H. K. Kim et al, Am J Clin Pathol (1973)
6:462-66. Fluid was inoculated onto media for bacterial (including
Legionella), fungal and viral isolation.
Pulmonary function testing was performed within one week of therapy in 18
of 19 patients who were tested, using methods described in the literature
(M. M. Mitchell et al, Am Rev Respir Dis (1968) 97:571-80; R. O. Crapo et
al, Am Rev Respir Dis (1981) 123:659-64; C. H. Ogilvie et al, J Clin
Invest (1957) 36:1-17; A. F. Gelb et al, Am Rev Respir Dis (1973)
107:50-63; and H. I. Goldman et al, Am Rev Tuberc (1959) 79:457-63).
The treatment regimes were as follows:
(A) Inhaled pentamidine (N=13): 4 mg/Kg administered using a Mallinckrodt
UltraVent.RTM. nebulizer over 30-60 minutes (two consecutive 4 mL
aliquots);
(B) Intravenous pentamidine (N=9): 3 mg/Kg administered as a 2-hour
infusion, as long as clinically indicated.
Therapeutic failure was defined as clinical deterioration after four days
of treatment, or lack of improvement after one week of treatment.
For six inhalation patients (1, 4, 6, 7, 15, and 16) and five i.v. patients
(2, 3, 5, 8, and 22), plasma samples were obtained at the completion of
therapy and at 0.17, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 18
hours following initiation of therapy. For p | | |
