This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, that can be given safely over one week. The investigators plan to infuse low doses of intravenous PTHrP to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrp on markers of bone turnover, and plasma 1,25 (OH)2 vitamin D regulation in healthy human volunteers.
During this research the investigators administer PTHrP to healthy young volunteers in a controlled, continuous intravenous manner. As research subjects complete the week-long study without adverse effects, the dose of PThrP will be increased in later subjects. In the event of a significant adverse effect, immediate action will be taken to reverse it. The investigators want to estimate the effect of a sustainable level of mild hypercalcemia achieved by a week-long intravenous infusion of PTHrP has on vitamin D metabolism, markers of bone turnover and fractional excretion of calcium.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Masking
SINGLE
Enrollment
14
IND # 49,175
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Dose Limiting Toxicity (DLT)
DLT was defined as achieving one major criterion or two minor criteria rated at ≥ 2 on a scale of 0-5. The major criteria were defined as symptomatic orthostatic hypotension (systolic BP fall \>30 mm/hg), tachycardia (pulse \> 120), hypertension (systolic BP \>160 mm/hg on 2 occasions), hypercalcemia (serum calcium ≥ 12 mg/dl), and hypophosphatemia (serum phosphorous \< 1.5 mg/dl). Minor criteria included symptoms such as flushing, nausea, abdominal or muscle cramps, dizziness, lightheadedness, palpitations, etc.
Time frame: 12 hours after the infusion was started then q 8 hours for 7 days
Total Serum Calcium
mg/dl
Time frame: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
Ionized Serum Calcium
mg/dl
Time frame: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
Serum Phosphorous
mg/dl
Time frame: 12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete
1,25 Vitamin D
pg/ml
Time frame: Baseline and Daily through day 8 then at follow-up visit
24 Hour Urine Calcium
mg/gm creatinine collected on day 7 of PTHrP infusion
Time frame: 24 hours
Tubular Maximum of Phosphorous (TmP/GFR)
mg/dl calculated from daily second morning void
Time frame: daily
Serum Amino-terminal Telopeptide of Collagen -1 (sNTX)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Amino-terminal Peptides of Procollagen 1 (P1NP)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Bone Specific Alkaline Phosphatase (BSAP)
% change from baseline
Time frame: Baseline, Daily, and 1 week follow-up
Parathyroid Hormone (1-84)
pg/ml
Time frame: Baseline and Daily
Fractional Excretion of Calcium
% calculated from daily second morning void
Time frame: daily
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