PMPA 9 2 Rphosphonomethoxypropyladenine Acyclic Nucleoside Phosphonate ANP
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PMPA 9 -[2 -(R)-(phosphonomethoxy)propyl]adenine Acyclic Nucleoside Phosphonate (ANP) analogue Antiretroviral activity Chain terminator of reverse transcriptase reaction Tenofovir
PMPA Strategies Maternal Immediately post-inoculation Acute Infection Chronic Infection
Fanconi’s Syndrome Global proximal tubular dysfunction Diminished proximal tubular transport capacity All transport linked to Na+ is affected Excessive urinary loss of phosphorus, potassium, bicarbonate, glucose, and amino acids
Fanconi’s Syndrome Clinical Signs & Sequelae Hypophosphatemia Rickets, osteomalacia, growth failure Hypokalemia Muscle weakness, ileus, constipation, arrhythmias Hyperbicarbonaturia Acidosis
Fanconi’s Syndrome Clinical Signs & Sequelae (cont’d) Glycosuria w/o hyperglycemia No sequelae Generalized aminoaciduria No sequelae Solute wasting PU/PD Dehydration
Fanconi’s Syndrome - Causes Inherited Cystinosis Intoxications Heavy metals Pharmaceuticals Tetracycline Streptozotocin Disorders of protein metabolism Amyloidosis Multiple Myeloma
M 6697 - PMPA Tx
M 6797 - PMPA Tx
M 8297 - PMPA Tx
M 6897 - PMPA Tx
Generalized Aminoaciduria Values are expressed in m. M/g Creatinine
Urinalysis All values are expressed in mg/d. L except K+ which Is m. Eq/L
PMPA Alone Tx Group Mild anorexia Weight plateau
Fanconi’s Syndrome - Etiology PMPA toxicity Formulation error Genetic component
Fanconi’s Syndrome - Treatment Identify underlying etiology Phosphate (60 mg/kg/d - divide TID or QID) Vitamin D - 1, 25 (OH)D 3 Potassium (divide TID or QID) Alkali (3 to 5 m. Eq/kg/d) Fluid therapy (correct dehydration) Glycosuria & aminoaciduria insignificant
PMPA Phase II Dose = 20 mg/kg, SQ for ? No initial intervention Monitor weight, chem panels, physical conditions Initial drop in serum phosphorus, increase in creatinine as expected Weights remained stable or increased
PMPA Phase II - Treatment Neutra. Phos K in oral solution Formulated tablets ($$) Formulated gelatin treats ($ and time) Chewable vitamins!
Fanconi’s Syndrome Ultimate Diagnostic Plan Radiographs Chemistry panels Blood gases Urinalyses and fractional excretion of selected solutes Urine amino acid profiles Kidney and bone biopsies Circulating vitamin D and PTH levels Appetite, weight, and activity level
Acknowledgments CRPRC Koen Van Rompay Marta Marthas Jeff Roberts Celia Valverde Therapeutics staff Univ. of Pittsburgh Mickey Murphey-Corb Melanie Osborn Shawn Bengtson T. Eric Stewart Dawn Mc. Clemens David Fineman Edwin Klein Norbert Bischofberger
Rickets & Osteomalacia Rickets (children) Inadequate mineralization of osteoid Inadequate provisional mineralization of epiphyseal cartilage Deformation of skeleton due to loss of structural rigidity Osteomalacia (children and adults) Inadequate mineralization - osteopenia
Rickets Differential Diagnoses Nutritional Vitamin D Calcium Phosphorus Hyperparathyroidism 1° 2° Renal osteodystrophy Inborn errors of metabolism
Synergistic Action of SIV DNA Immunization and PMPA Therapy PMPA (30 mg/kg) SQ IV Challenge SID SIV/∆B 670 Immunizations 1 3 6 9 Months 12 21 24 + 5 wks 28 Days
- Conteúdo local anp
- Phosphoanhydride bond
- Anp
- Anp
- Anp
- Anp
- Nucleoside monophosphate
- Nucleoside reverse transcriptase inhibitors
- Inhibition of nucleic acid synthesis
- Pentose sugar structure in dna
- Anp 101
- Nucleoside triphosphate in dna replication
- Local markov assumption
- A vertex is if its indgree(v)=1 and outdegree(v)=0.
- Connected acyclic graph
- Stable abstractions principle