MATERIALS AND METHODS Study design. Patients who had been receiving ZDV for 6 weeks prior to study were enrolled. Although Pneumocystis carinii pneumonia prophylaxis was not a requirement, patients on stable regimens with aerosolized pentamidine were included. They satisfied the following inclusion-exclusion criteria: male or female, 18 years of age, laboratory evidence of HIV infection confirmed by Western blotting immunoblotting ; , clinical symptoms consistent with the diagnosis of ARC, a CD4 cell count of 500 l, an absolute neutrophil count of 1, 000 mm3, and no evidence of active pulmonary disease or significant hepatic or renal impairment. Prior to enrollment, written informed consent was obtained from each patient. Sixteen patients who were seropositive for HIV were enrolled. At the beginning of the study, ZDV was administered at a dose of 200 mg every 4 h q4h ; 100-mg capsules; Burroughs Wellcome, Research Triangle Park, N.C. ; , per the manufacturer's labelling recommendations, and RBT was administered at 450 mg once a day q.d. ; 150-mg capsules; Pharmacia, Columbus, Ohio ; per the proposed phase III clinical plans. Patients in this group are referred to as being in the high-dose group HDG ; . After the accrual of the first eight patients, dosages were amended to comply with the revised ZDV labelling and to study a lower RBT dose being used in the MAC prophylaxis studies 15 ; . Eight additional patients were enrolled and given the lower doses of ZDV 100 mg q4h ; and RBT 300 mg q.d. ; . This group is referred to as the low-dose group LDG ; . Over days 2 through 13, fasting patients received daily oral ZDV either 100 or 200 mg q4h ; and concomitant RBT 300 or 450 mg q.d. ; in the morning. ZDV was discontinued after the morning dose on day 13, while RBT dosing continued until day 16. Steady-state RBT kinetics before day 13 ; and after day 16 ; ZDV withdrawal were studied to assess the effect of ZDV. Beginning on day 17, ZDV therapy was reinitiated for all patients and they were released after being given physical examinations. This protocol design permitted pharmacological assessments in the target population exposed to combination therapy with minimal interruption or compromise of essential ZDV therapy. Adverse experiences were noted throughout the study, and patients were instructed to contact the study site at the Department of Clinical Pharmacology and Therapeutics University of Texas Southwestern Medical Center, Dallas ; by telephone while on medication on an outpatient basis. Pharmacokinetic and safety assessments. After morning dosing of ZDV and RBT on day 13, serial heparinized blood samples 10 ml ; were collected at 0, 0.33, 0.5, 0.75, and 24 h. Additional samples for determination of steady-state RBT trough levels Cminss ; were drawn on days 13, 14, and 15 to assess within- and between-patient variability. On day 16 RBT alone ; , the blood sampling schedule was similar to that of day 13. Plasma was separated from blood samples by centrifugation at 1, 000 g for 10 min and stored frozen. Twenty-four-hour urine collections were performed on days 13 and 16 over the 0- to 2-, to 4-, to 8-, to 12-, and 12- to 24-h intervals. Urine was kept refrigerated throughout the collection intervals. At the end of each interval, total urine volume and pH were measured and recorded. A 10-ml aliquot was placed in a polypropylene tube and frozen at 20 C pending analysis. Safety assessments on days 1 baseline ; , 13, and 16 included CD4 and CD8 counts, hematological analysis including differential ; , serum chemistry analysis, and urinalysis. Assay of RBT and LM 565. Concentrations of RBT and LM 565 in plasma and urine were determined by a validated high-performance liquid chromatographic assay at Harris Laboratories, Lincoln, Nebr. The assay 10 ; was developed at the Bioanalytical Research Laboratory, Pharmacia Inc., and was properly validated at the site before actual sample analysis. The system linearity of the plasma assay was established over the ranges 5 to 800 ng ml and 2.5 to 400 ng ml, for RBT and LM 565, respectively, and that of the urine assay was established over a range of 200 to 5, 000 ng ml. Quality control was routinely performed with patient sample unknowns to assess assay performance during the analysis period.

In cooperation with the Computer and Instrumentation Councils and Technologist Section, the Society of Nuclear Medi cine invites physicians, basic scientists, and technologists to attend the 3rd Conjoint Congress. Join us February 1-6, 1984 in Orlando, Florida to examine one of the most challenging developments in nuclear medicine: The Technology of NMR. Examine NMR instrumentation, imaging techniques for spacial encoding, problems of pulse sequencing, image process ing and display, spectroscopy, and system evaluation. In addition to the Councils' Program, technologists will present concurrent sessions that examine NMR, SPECT, monoclonal antibodies, and more. Section and Council members can expect their programs in November and December, respectively. For more information write: SNM Meetings Department, 475 Park Avenue South, New York, NY 10016, or call 212 ; 889-0717. Schedule Wednesday, February 1. The strains of T. brucei rhodesiense used are noteworthy in that all are clinical isolates and several were refractory to standard agents. KETRI 243 is moderately resistant to arsenical drugs and diamidines, while a clone KETRI 243 As3 ; derived from this parent is highly resistant to melarsen oxide, diminazene, and pentamidine in vivo curative dosage, 25 mg kg day for 3 days [data not shown] ; . KETRI 269 is DFMO and pentamidine refractory, while KETRI 1992 is also arsenical drug resistant 5 ; . The most active compound in vivo, CGP 40215A, appears to have a selective advantage, since although it was active against rat liver AdoMet decarboxylase IC50, 0.06 M [24] ; , it was far less effective against growth of T24 human bladder carcinoma cancer cells in vitro IC50, 100 M ; than other derivatives in the same series 27 ; . In data reported elsewhere, CGP 40215A was also a more effective inhibitor of trypanosome metabolism in vitro IC50, 0.0045 M ; than were other MGBG analogs in the series 10 ; . Used alone, CGP 40215A was curative for 15 T. brucei rhodesiense strains as laboratory infections, as well as for one T. brucei gambiense and one T. congolense isolate. The 3-day dose regimens used for most experiments proved adequate for cures; however, single doses of 20 mg kg were also curative and are of prime interest since they indicate that shorter treatment regimens are possible. In these studies, we observed no overt toxicity e.g., ruffling of hair or lethargy ; at the highest dosages utilized, 50 or 100 mg kg for 3 days for acute infections, and 25 mg kg for 7 or 14 days i.p. or 50 mg kg for 7 days administered with Alza pumps CNS infection ; . At i.p. dosages of 50 or 100 mg kg day for 14 days, deaths were observed toward the end of the dosage period data not shown ; . Although CGP 40215A was inactive when used singly against a model CNS infection, it was highly synergistic when used in combination with noncurative doses of DFMO. Threeday dosing with CGP 40215A in combination with 2 weeks of DFMO appeared to be as active as 7- or 14-day dosing if CGP 40215A was given in the middle or at the end of the DFMO regimen. The synergism appears to be unique to CNS infections, since subcurative doses of DFMO 0.25 or 0.5% for 3 days in drinking water ; and CGP 40215A 0.5, 1.0, or 2.5 mg kg daily for 3 days [data not shown] ; were not synergistic against the T. brucei brucei Lab 110 EATRO model or against four of the KETRI isolates. Strong synergism between DFMO and other trypanocides in model CNS infections has been noted in studies utilizing DFMO plus suramin 4, 6, 12 ; , DFMO plus melarsen oxide 6, 16 ; , and DFMO plus diminazene or pentamidine 17 ; . Interestingly, suramin alone or the diamidines are also inactive against laboratory CNS infections in clinical studies 4, 30 ; . CGP 40215A is a bicyclic analog of MGBG, which resembles the diamidine trypanocides diminazene and pentamidine Fig. 1 ; . The Ciba-Geigy agents were developed to take advantage of MGBG's activity as a potent AdoMet decarboxylase inhibitor while minimizing toxicity due to nonspecific antimitochondrial effects and inhibition of diamine oxidase 24, 25, 27 ; . Since the nonspecific and cytotoxic effects have been reduced, these MGBG analogs tend to have low IC50s for AdoMet decarboxylase 1.0 M ; and more specific growth inhibitory properties for tumor cells 23 ; . The strong resemblance between CGP 40215A and the diamidines led us to include the multidrug-resistant strain KETRI 243 As3 in the study. This arsenical-drug-resistant strain is also refractory to pentamidine at 50 mg kg day for 3 days, yet infections were cured by CGP 40215A dosages of 25 mg kg day for 3 days. At 10 mg of CGP 40215A per kg per day, 30% cures were also obtained with this strain data not shown ; . Since diamidines and melarsen-based.

Infection in rats and for evaluating the effects of treatment 7-9, 22, 42, ; . The present study was designed to compare pentamidine with cationic veterinary trypanocidal compounds, DFMO, and other antimicrobial drugs in the therapy of experimental P. carinii pneumonia and permax. Physical incompatibilities resulted when linezolid injection was combined with the following drugs during simulated y-site administration: amphotericin b, chlorpromazine hcl, diazepam, pentamidine isothionate, erythromycin lactobionate, phenytoin sodium, and trimethoprim-sulfamethoxazole.

Box 1: Current guidelines on anti-infective prophylaxis P. jiroveci Cotrimoxazole or double strength trimethoprim sulphamethoxazole In cases of cytopenia or toxicity caused by cotrimoxazole, inhaled pentamidine is appropriate Antiviral Antifungal Valaciclovir, famciclovir, aciclovir Not routinely recommended potential to induce resistant strains and perphenazine.
Study 3013: extension of Study 3003, uncontrolled long-term follow-up study of 143 patients who were well-controlled on LANTUS from 3003, for 201-1159 days. The most common adverse events were upper respiratory infections, infection, and rhinitis. Note that when comparing safety findings between studies, the difference in length of exposure needs to be kept in mind. Study 4005: controlled, randomized, double-cross-over: 26 subjects age range 12 - 20 ; , regimen of LANTUS + lispro vs. human NPH + human regular. Adverse events were equally distributed between the two treatment regimens. The most common adverse events were upper respiratory tract infection and gastroenteritis. Patients in the pediatric clinical trials of LANTUS were treated with a human NPH-based regimen pre-study, and patients assigned to receive human NPH during the study began study treatment on the same human NPH regimen they had taken pre-study. This may have been a factor in the increased incidence of hypoglycemia seen in LANTUS -treated patients during but not following ; initial titration in these trials, as an increase in hypoglycemia may be expected when switching from one insulin to another and titrating the dose of the new insulin. DRUG INTERACTIONS A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. Drug-Drug Interactions Substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia, for example: oral antidiabetic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAO inhibitors, pentoxifylline, propoxyphene, salicylates, somatostatin analog e.g. octreotide ; , sulfonamide antibiotics. Substances that may reduce the blood-glucose-lowering effect, for example: corticosteroids, danazol, diazoxide, diuretics, sympathomimetic agents e.g., epinephrine, salbutamol, terbutaline ; , glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens e.g., in oral contraceptives ; , protease inhibitors and atypical antipsychotic medications e.g., olanzapine and clozapine ; . Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the bloodglucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. In addition, under the influence of sympatholytic medicinal products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent and pentasa.

Pentamidine administration safety

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Pentamidine side effects

Pentamidine pharmacokinetics

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