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1.
Int Urol Nephrol ; 51(10): 1823-1829, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31368056

ABSTRACT

PURPOSE: The recent observation that urinary calcium excretion (UCE) drops considerably with CKD and that this effect may occur beyond compensation for reduced intestinal calcium absorption suggests that CKD per se is a state of sustained positive calcium balance, a mechanism likely to contribute to vascular calcification and CVD in CKD. However, the determinants of UCE reduction in CKD are not well understood and there is a lack of clinical studies, particularly in the CKD population. Therefore, in this study, we aimed to evaluate variables associated with UCE in a CKD cohort. METHODS: Baseline data on 356 participants of the Progredir Study, Sao Paulo, Brazil, essentially composed of CKD G3a-G4, were analyzed according to UCE (24 h urine collection). RESULTS: Median 24 h UCE was 38 mg/day (IQR 21-68 mg/day) and 0.48 mg/kg/day (IQR 0.28-0.82 mg/kg/day). In univariate analysis, UCE was inversely related to age, phosphorus, 1-84 PTH, FGF-23 and sclerostin, and positively associated with eGFR, DBP, 1,25(OH)2-vitamin D, calcium, bicarbonate, total calorie intake and spironolactone use. After adjustments for age, sex and eGFR, only 1,25(OH)2-vitamin D, calcium, FGF-23, bicarbonate and total calorie intake remained associated with it, but not PTH nor sclerostin. Lastly, in a multivariable model, eGFR, serum 1,25(OH)2-vitamin D, calcium, and FGF-23 remained associated with UCE. Similar results were observed when calcium fractional excretion was used instead of UCE, with eGFR, 1-25-vitamin D and FGF-23 remaining as independent associations. CONCLUSION: Our results showed that CKD is associated with very low levels of UCE and that 1,25(OH)2-vitamin D, serum calcium and FGF-23 were independently associated with UCE in this population, raising the question whether these factors are modulators of the tubular handling of calcium in CKD.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Calcitriol/physiology , Fibroblast Growth Factors/physiology , Hypercalciuria/etiology , Parathyroid Hormone/physiology , Renal Insufficiency, Chronic/complications , Aged , Cross-Sectional Studies , Female , Fibroblast Growth Factor-23 , Humans , Male
2.
Biologicals ; 39(2): 73-80, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21353597

ABSTRACT

We evaluated growth factor contents and clinical efficacy of allogeneic platelet gel (PG) prepared with standard blood banking procedures from routine platelet concentrates (PCs) obtained from buffy coats. The PGs were used to treat 11 hypomobile very elderly patients unable to undergo autologous blood processing and previously ineffectively treated with expensive advanced medications for 8-275 weeks. PGs were prepared by platelet activation with human thrombin or commercial batroxobin. Median and range growth factor contents (ng/mL) were: platelet derived growth factor (PDGF-AB/-BB) 112 (31-157) and 20 (3.8-34); transforming growth factor (TGF-ß1/-ß2) 214 (48-289) and 0.087 (0.03-0.28); basic-fibroblast growth factor (b-FGF) 0.03 (0.006-0.214); vascular endothelial growth factor (VEGF) 1.15 (0.18-2.46); epidermal growth factor (EGF) 4.50 (0.87-6.64); insulin-like growth factor (IGF-l) 116 (72-156). In the clinical study, 222 PGs were used within 2 h of activation to treat 14 chronic skin ulcers in the 11 patients. No improvement was seen in 3 patients with 24, 27 and 30 cm(3) ulcers who could be treated for no more than 4, 7 and 8 weeks due to progressively worsening clinical conditions, while 11 ulcers with 3.2 cm(3) median size (range 0.2-3.6) in the remaining 8 patients showed 91 ± 14 % reduction after a median of 12 weeks (range 1-20). Cost of PG treatment (19,976 euro) amounted to about 10% of the ineffective advanced medication hospital reimbursement fees (191,236 euro). This study supports efficacy and feasibility of allogeneic PG to treat recalcitrant ulcers in very elderly hypomobile patients for whom autologous blood processing may be difficult.


Subject(s)
Blood Platelets/cytology , Gels/therapeutic use , Mobility Limitation , Platelet Transfusion/methods , Skin Ulcer/therapy , Aged, 80 and over , Algorithms , Blood Platelets/physiology , Cost-Benefit Analysis , Feasibility Studies , Female , Humans , Male , Platelet Transfusion/economics , Plateletpheresis/economics , Plateletpheresis/methods , Salvage Therapy , Skin Ulcer/complications , Skin Ulcer/surgery , Transplantation, Homologous , Treatment Failure , Treatment Outcome
4.
J Med Chem ; 38(22): 4557-69, 1995 Oct 27.
Article in English | MEDLINE | ID: mdl-7473584

ABSTRACT

The design and application of alpha-hydroxy phosphonates, a new class of transition state analogs, toward the discovery of novel and potent inhibitors of the aspartyl protease renin is described. Tripeptidic alpha-hydroxy diethyl phosphonate 3, the first example in this series, was found to be a good inhibitor of human renin (IC50 = 29 nM), and preliminary studies led to the choice of alpha-hydroxy dimethyl phosphonate 15 (IC50 = 16 nM) as a base-line compound for further structure-activity relationship study. Corresponding phosphinate (28-30) and phosphine oxide (23 and 24) analogs of 15 were prepared to assess the steric and electronic requirements around the phosphorus center. Evaluation of these analogs suggested that the presence of at least one alkoxy group on phosphorus was a critical requirement for good activity. Inhibitors with leucine at P2 possessed better in vitro activity than the corresponding P2 histidine analogs (15, IC50 = 16 nM vs 37, IC50 = 220 nM; 33, IC50 = 8.5 nM vs 40, IC50 = 41 nM). Compound 34 (IC50 = 31 nM), the P3 aminocaproic analog of 15, showed complete and long-lasting inhibition of plasma renin activity while eliciting a 10-15 mmHg drop in mean arterial pressure when administered intravenously at 1 mumol/kg in conscious, sodium-depleted, cynomolgus monkeys. In summary, the alpha-hydroxy phosphonates represent a promising and structurally novel class of transition state analog inhibitors of human renin.


Subject(s)
Organophosphonates/pharmacology , Protease Inhibitors/pharmacology , Renin/antagonists & inhibitors , Angiotensinogen/analogs & derivatives , Angiotensinogen/metabolism , Animals , Blood Pressure/drug effects , Haplorhini , Humans , Magnetic Resonance Spectroscopy , Organophosphonates/chemical synthesis , Protease Inhibitors/chemical synthesis , Renin/blood , Structure-Activity Relationship
5.
J Med Chem ; 36(17): 2431-47, 1993 Aug 20.
Article in English | MEDLINE | ID: mdl-8355245

ABSTRACT

Application of the concept of activated ketones to the design of novel and potent transition-state analog inhibitors of the aspartyl protease renin is described. Three different classes of peptidic activated ketones were synthesized: 1,1,1-trifluoromethyl ketones, alpha-keto esters, and alpha-diketones. The corresponding alcohols were also evaluated as renin inhibitors in each series. While the trifluoromethyl alcohol 12 (I50 = 4000 nM) was equipotent to the simple methyl alcohol 7 (I50 = 3200 nM), the structurally similar alpha-hydroxy esters (32 and 30, I50's = 5.3 and 4.7 nM, respectively) and alpha-hydroxy ketones (41 and 42, I50 = 23 and 15 nM, respectively) were 150-300-fold more active. The hydrating capability of the activated ketone functionality was important for intrinsic potency in the case of trifluoromethyl ketones, as illustrated by the significantly better activity of trifluoromethyl ketone 13 (I50 = 250 nM) compared to its alcohol analog 12 (I50 = 4000 nM). It was however unimportant for the alpha-keto ester (20 and 31, I50 = 15 and 4.1 nM, respectively) and alpha-diketone (43 and 44, I50 = 52 and 28 nM, respectively) based inhibitors, since their activity was essentially similar to that of the corresponding alcohols. These results collectively suggest that, whereas the trifluoromethyl ketones derive their renin inhibitory potency primarily from their ability to become hydrated, this is not a critical feature for the activity of alpha-dicarbonyl-based inhibitors. The alpha-keto ester and alpha-diketone based renin inhibitors benefit predominantly from the hydrophobic and/or H-bonding type binding interactions of the neighboring ester or acyl group itself, rather than the ability of this group to deactivate the adjacent ketone group and thereby make it susceptible to hydration.


Subject(s)
Ketones/chemical synthesis , Ketones/pharmacology , Renin/antagonists & inhibitors , Humans , Stereoisomerism , Structure-Activity Relationship
6.
J Nucl Med ; 32(9): 1730-7, 1991 Sep.
Article in English | MEDLINE | ID: mdl-1880575

ABSTRACT

To evaluate the feasibility of probing the distribution of angiotensin-converting enzyme (ACE) in vivo using positron emission tomography (PET), 4-cis-[18F]fluorocaptopril (18FCAP) was prepared by the reaction of the triflate 2 with K18F/Kryptofix 222 in MeCN followed by hydrolysis (2 N NaOH). The synthesis time was 1 hr with an average radiochemical yield (EOS) of 12% and a specific activity of greater than 300 Ci/mmol. In vivo biodistribution in rats at 30 min after administration showed high uptakes into organs known to have high ACE concentration (lung, kidney and aorta) and faster clearance of 18FCAP for lung and kidney, compared to the clearance from the aorta. When different amounts of unlabeled 4-cis-fluorocaptopril (SQ 25750) were coinjected in rats, a dose of greater than 5 micrograms/kg decreased the lung uptake by one-half while only 1 microgram/kg decreased the kidney uptake by one-half. In general, the binding in the four tissues studied was saturable with the expected capacity. 18FCAP was administered to a human and displaceable uptake observed in the lung and kidney. The results demonstrate the feasibility of probing ACE in vivo using PET.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Captopril/analogs & derivatives , Tomography, Emission-Computed , Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Animals , Captopril/chemical synthesis , Captopril/pharmacokinetics , Female , Fluorine Radioisotopes , Humans , Kidney/diagnostic imaging , Lung/diagnostic imaging , Male , Rats , Rats, Inbred Strains , Tissue Distribution
7.
J Med Chem ; 33(5): 1459-69, 1990 May.
Article in English | MEDLINE | ID: mdl-2329568

ABSTRACT

Analogues of (S)-1-[6-amino-2[[hydroxy(4-phenylbutyl)phosphinyl] oxy]-1-oxohexyl]-L-proline (1, SQ 29,852) in which the terminal proline residue has been replaced by a variety of substituted and heteroatom-substituted prolines, N-arylglycines, N-cycloalkylglycines, and bicyclic amino acids have been synthesized and evaluated as inhibitors of angiotensin converting enzyme in vitro and in vivo. In general, the addition of lipophilic substituents to the 4-position of proline of the parent phosphonate 1 resulted in substantial increases in in vitro activity. The largest improvements were observed in the case of cis-benzyl (36-fold) and dithioketal (24-fold) analogues 2r and 2x, respectively. These enhancements of in vitro activity were accompanied by modest increases (2-3.5-fold) in in vivo (iv) activity. Among the various terminal amino acid replacements examined in this study, the indoline-based analogue 2i was by far the most potent compound on iv administration in the normotensive rat.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Indoles/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Chemical Phenomena , Chemistry , Indoles/pharmacology , Male , Organophosphorus Compounds/pharmacology , Proline/analogs & derivatives , Proline/pharmacology , Rabbits , Rats , Rats, Inbred Strains , Stereoisomerism , Structure-Activity Relationship
8.
J Cardiovasc Pharmacol ; 14(5): 730-6, 1989 Nov.
Article in English | MEDLINE | ID: mdl-2481187

ABSTRACT

Fosinopril is the first member of a new chemical class of angiotensin I (AI) converting enzyme (ACE) inhibitors, the phosphinic acids. In vitro, SQ 27,519, the active moiety of the prodrug fosinopril, was a more potent inhibitor of purified rabbit lung ACE- (IC50 = 11 vs. 23 nM) and bradykinin-induced contractions of guinea pig ileum than captopril. In vivo, SQ 27,519 was equipotent to captopril as an inhibitor of an AI pressor response after intravenous (i.v.) administration to conscious rats and monkeys but appeared to be less potent in conscious dogs. After oral administration, fosinopril again was equipotent to captopril as an inhibitor of an AI pressor response in rats and monkeys and slightly less potent in dogs. However, both SQ 27,519 (i.v. studies) and fosinopril (oral studies) had a longer effect than captopril in all three species. When fosinopril was administered orally for 5 days, its effects on an AI pressor response were the same on days 1 and 5, suggesting lack of tolerance to the compound. The ACE inhibitory effect of captopril, but not fosinopril, was prolonged in conscious rats with glycerol-induced acute renal failure, suggesting that fosinopril is excreted by an extrarenal route. Finally, fosinopril had no effect on the pressor or chronotropic effects of norepinephrine (NE) or 1,1-dimethyl-4-phenylpiperinium (DMPP) or electrical stimulation of the sympathetic ganglia of pithed rats. Fosinopril attenuated the pressor, but not the chronotropic effects of tyramine. We conclude that fosinopril is a potent and long-lasting inhibitor of ACE in conscious animal models that does not impair adrenergic function or reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Captopril/pharmacology , Organophosphorus Compounds/pharmacology , Proline/analogs & derivatives , Acute Kidney Injury/physiopathology , Administration, Oral , Animals , Blood Pressure/drug effects , Bradykinin/blood , Dogs , Fosinopril , Heart Rate/drug effects , Injections, Intravenous , Macaca fascicularis , Male , Proline/pharmacology , Rats , Rats, Inbred Strains , Sympathetic Nervous System/drug effects , Time Factors
9.
J Cardiovasc Pharmacol ; 13(6): 887-94, 1989 Jun.
Article in English | MEDLINE | ID: mdl-2484083

ABSTRACT

Zofenopril calcium (one-half calcium salt) is a prodrug ester analog of captopril whose biological effects are manifested by its active component, SQ 26,333. Because of the relative insolubilities of both zofenopril calcium and SQ 26,333, zofenopril potassium salt and SQ 26,703, the arginine salt of the active ACE (angiotensin I converting enzyme) inhibitory moiety of zofenopril, were employed in many of the following studies. The in vitro and in vivo pharmacological effects of zofenopril have been evaluated and comparisons have been made to captopril. In vitro, SQ 26,703 was more potent than captopril as an inhibitor of rabbit lung ACE (IC50 = 8 vs. 23 nM). SQ 26,703 was also a potent inhibitor of angiotensin I (AI)-induced contractions (EC50 = 3 nM) and a potentiator of bradykinin-induced contractions (EC50 = 1 nM) of isolated guinea pig ileum, while it had no effect on the inotropic effects of angiotensin II, BaCl2, PGE1, histamine, serotonin, or acetycholine in the same tissue, signifying that zofenopril is a specific inhibitor of ACE. In vivo, the potency of SQ 26,703 was equal to or greater than that of captopril as an inhibitor of an AI pressor response when given intravenously to rats, dogs, and monkeys. After oral administration of equimolar doses, zofenopril was the more effective and longer lasting ACE inhibitor in all three species. In SHR, doses of 6.6 and 22.0 mg/kg, p.o. lowered pressure by 20 and 33 mm Hg, respectively, while 30 mg/kg of captopril lowered pressure by 25 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/metabolism , Captopril/analogs & derivatives , Animals , Biological Availability , Blood Pressure/drug effects , Captopril/pharmacokinetics , Captopril/pharmacology , Dogs , Female , Ileum , In Vitro Techniques , Macaca fascicularis , Male , Muscle Contraction/drug effects , Rats
10.
J Med Chem ; 31(1): 204-12, 1988 Jan.
Article in English | MEDLINE | ID: mdl-3336020

ABSTRACT

The synthesis of a series of orally active, phosphinyloxyacyl proline inhibitors of angiotensin converting enzyme (ACE) is described. The in vitro and in vivo ACE inhibitory activities are reported for each compound. The structure-activity relationship for this series of compounds in relation to the carboxyalkyl dipeptide ACE inhibitors as well as other types of hydroxyphosphinyl-containing ACE inhibitors (e.g., the corresponding nitrogen and carbon isosteres) is discussed. Within an isosteric series of phosphorus-containing inhibitors based on the lysylproline terminal dipeptide sequence, only the phosphonates (oxygen isosteres) show a high level of oral activity. Optimum potency and oral activity in the phosphonate series occurs with the (phenylbutyl)- and n-hexylphosphonate side chains. An aminobutyl side chain in the P1' residue is an absolute requirement for full expression of oral activity. The most potent of these compounds, 8b (SQ 29,852), has intravenous and oral activities superior in potency to those of captopril in the normotensive rat.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Organophosphorus Compounds/chemical synthesis , Proline/analogs & derivatives , Administration, Oral , Animals , Blood Pressure/drug effects , Indicators and Reagents , Lung/enzymology , Magnetic Resonance Spectroscopy , Male , Optical Rotation , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/pharmacology , Proline/administration & dosage , Proline/chemical synthesis , Proline/pharmacology , Rabbits , Rats , Rats, Inbred Strains , Structure-Activity Relationship
11.
J Cardiovasc Pharmacol ; 10 Suppl 7: S17-30, 1987.
Article in English | MEDLINE | ID: mdl-2485059

ABSTRACT

Angiotensin-converting enzyme (ACE), the receptor for an important new class of antihypertensive drugs, is now one of the better studied zinc metallopeptidases. The development of several classes of tightly binding competitive inhibitors of ACE has led to increased understanding of the structure and function of this enzyme while also yielding important new drugs for the diagnosis and treatment of hypertensive disease. Peptides from snake venom provided the first proof of the therapeutic utility of ACE inhibitors, and a tripeptide sequence, Phe-Ala-Pro, was used as a model for sidechain interactions with ACE in the rational design of simpler nonpeptidic inhibitors such as captopril and enalapril. These and more recently developed ACE inhibitors can be classified according to their structural analogy to dipeptides or tripeptides and according to the nature of their zinc-binding ligands, such as sulfhydryl, ketone, carboxylate, or hydroxyphosphinyl, that contribute greatly to their binding to ACE. Several newer ACE inhibitors have increased potency and/or improved pharmacokinetic properties due to modifications such as substitution of the proline ring or replacement of the methyl side chain analogous to Ala by an aminobutyl residue analogous to Lys. The availability of structurally diverse ACE inhibitors with great potency and specificity provides a powerful biochemical tool for purification, localization, and characterization of ACE in different tissues, and for distinguishing related zinc metallopeptidases with similar properties.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Dipeptides/pharmacology , Drug Design , Humans , Peptides/pharmacology , Peptidyl-Dipeptidase A/isolation & purification , Proline/chemistry , Snake Venoms/pharmacology
13.
J Med Chem ; 25(3): 250-8, 1982 Mar.
Article in English | MEDLINE | ID: mdl-6279843

ABSTRACT

A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) in order to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). It was concluded that the interaction involves a hydrogen bond from a donor site on ACE to the oxygen of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a hydrogen bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.


Subject(s)
Amino Acids, Sulfur/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors , Amino Acids, Sulfur/pharmacology , Animals , Chemical Phenomena , Chemistry, Physical , Hydrogen Bonding , In Vitro Techniques , Lung/enzymology , Molecular Conformation , Rabbits , Structure-Activity Relationship
14.
Med Res Rev ; 2(1): 1-41, 1982.
Article in English | MEDLINE | ID: mdl-6287131

ABSTRACT

A decade of experimentation, with work in the last four years greatly accelerated by the availability of captopril, favors the conclusion that angiotensin-converting enzyme inhibitors exert their antihypertensive effect by blocking the formation of angiotensin II. The apparently anomalous efficacy of ACE inhibitors in hypertension characterized by low circulating renin levels may point to the importance of the vascular renin-angiotensin system in controlling blood pressure. Neither kinin potentiation nor blockade of the CNS renin-angiotensin system appear to play a significant role in the antihypertensive effect of captopril. Pharmacological and clinical studies on ACE inhibitors of novel chemical structure will establish their utility as antihypertensive agents and may lead to greater understanding of the mechanism of action of all ACE inhibitors.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Animals , Chemical Phenomena , Chemistry , Dipeptides/pharmacology , Humans , Hypertension/physiopathology , Hypertension, Renal/drug therapy , Kallikreins/physiology , Kinins/physiology , Zinc/physiology
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