ABSTRACT
Fragility fractures associated with glucocorticoid-induced osteoporosis (GIO) can markedly impair quality of life. However, only 20% of patients are treated in compliance with the relevant management guidelines, and bone mineral density analysis with dual-energy X-ray absorptiometry (DXA) is only rarely performed. We report the intervention methods suggested by pharmacists and describe their efficacy. Patients who visited the outpatient clinic of the General Medicine Department of Ogaki Municipal Hospital and received steroids were enrolled. The rates of DXA implementation and compliance with GIO pharmacotherapy guidelines before and after pharmacist to physician-suggested interventions were compared. Guideline compliance was defined as prescription of osteoporosis drugs to patients with a score of ≥3. Administered prophylaxes and bone mineral density were subsequently assessed. The before and after intervention DXA rates were 1% (1/100 patients) and 96.0% (96/100 patients; P<0.01), respectively. Overall, 96.9% (93/96) of the patients met the GIO criteria for pharmacotherapy initiation (score ≥3), and the guideline compliance rates before and after the intervention were 39.8% (37/93) and 93.5% (87/93; P<0.01), respectively. Of the 56 patients who did not receive prophylaxis, 52 were recommended treatment, yielding an acceptance rate of 82.7% (43/52). Among the 37 patients receiving prophylaxis, 20 (54.1%) had a DXA-related young adult mean of ≤70%, of whom 11 (55.0%) agreed to drug therapy. The acceptance rate of pharmacotherapy recommendations for patients not receiving prophylaxis was higher than that for those receiving prophylaxis (P=0.03). Pharmacist-initiated interventions for GIO facilitates the administration of appropriate pharmacotherapy.
Subject(s)
Absorptiometry, Photon , Bone Density Conservation Agents , Bone Density , Glucocorticoids , Guideline Adherence , Osteoporosis , Pharmacists , Humans , Bone Density/drug effects , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Female , Male , Aged , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Middle Aged , Bone Density Conservation Agents/administration & dosage , Aged, 80 and over , AdultABSTRACT
BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).
Subject(s)
Colorectal Neoplasms , Neutropenia , Colorectal Neoplasms/drug therapy , Drug Combinations , Humans , Japan , Pyrrolidines , Thymine , Trifluridine/adverse effects , Uracil/adverse effectsABSTRACT
Eight carbohydrate-pendant platinum(II) complexes have been synthesized from carbohydrate-diamine conjugates. D-Glucose, D-mannose, D-galactose, D-xylose, and L-glucose are attached to the dichloroplatinum(II) moiety by 1,3- or 1,2-diaminopropane chelates through with an O-glycoside bond. All the carbohydrate moieties reduced the toxicity inherent with platinum(II) complexes.
Subject(s)
Antineoplastic Agents/pharmacology , Carbohydrate Metabolism , Carbohydrates/pharmacology , Cisplatin/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Carbohydrates/chemistry , Cisplatin/chemistry , Drug Screening Assays, Antitumor , Lethal Dose 50 , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred Strains , Molecular StructureABSTRACT
Reactions of MCl(2).nH(2)O with N,N'-bis(D-glucopyranosyl)-1,4,7-triazacyclononane ((D-Glc)(2)-tacn), which was formed from D-glucose and 1,4,7-triazacyclononane (tacn) in situ, afforded a series of mononuclear divalent metal complexes with two beta-D-glucopyranosyl moieties, [M((D-Glc)(2)-tacn)Cl]Cl (M = Zn (11), Cu (12), Ni (13), Co (14)). Complexes 11-14 were characterized by analytical and spectroscopic measurements and X-ray crystallography and were found to have a distorted octahedral M(II) center ligated by the pentacoordinate N-glycoside ligand, (beta-D-glucopyranosyl)(2)-tacn, and a chloride anion. Each D-glucose moiety is tethered to the metal center through the beta-N-glycosidic bond with tacn and additionally coordinated via the C-2 hydroxyl group, resulting in a lambda-gauche five-membered chelate ring. When L-rhamnose (6-deoxy-L-mannose) was used instead of D-glucose, the nickel(II) complex with two beta-L-rhamnopyranosyl moieties, [Ni((D-Man)(2)-tacn)(MeOH)]Cl(2) (15), was obtained and characterized by an X-ray analysis. Reactions of 11 (M = Zn) with [Zn(XDK)(H(2)O)] (21) or [Cu(XDK)(py)(2)] (22) (H(2)XDK = m-xylylenediamine bis(Kemp's triacid imide)) yielded homo and heterotrimetallic complexes formulated as [Zn(2)M'((D-Glc)(2)-tacn)(2)(XDK)]Cl(2) (M' = Zn (31), Cu (32)). The similar reactions of 12 (M = Cu) with complex 21 or 22 afforded [Cu(2)M'((D-Glc)(2)-tacn)(2)(XDK)]Cl(2) (M' = Cu (33), Zn (34)). An X-ray crystallographic study revealed that complexes 31 and 34 have either Zn(II)(3) or Cu(II)Zn(II)Cu(II) trimetallic centers bridged by two carboxylate groups of XDK and two D-glucopyranosyl residues. The M...M' separations are 3.418(3)-3.462(3) A (31) and 3.414(1)-3.460(1) A (34), and the M...M'...M angles are 155.18(8) degrees (31) and 161.56(6) degrees (34). The terminal metal ions are octahedrally coordinated by the (D-Glc)(2)-tacn ligand through three nitrogen atoms of tacn, two oxygen atoms of the C-2 hydroxyl groups of the carbohydrates, and a carboxylate oxygen atom of XDK ligand. The central metal ions sit in a distorted octahedral environment ligated by four oxygen atoms of the carbohydrate residues in the (D-Glc)(2)-tacn ligands and two carboxylate oxygen atoms of XDK. The deprotonated beta-D-glucopyranosyl unit at the C-2 hydroxyl group bridges the terminal and central ions with the C-2 mu-alkoxo group, with the C-1 N-glycosidic amino and the C-3 hydroxyl groups coordinating to each metal center. Complexes 31-34 are the first examples of metal complexes in which D-glucose units act as bridging ligands. These structures could be very useful substrate binding models of xylose or glucose isomerases, which promote D-glucose D-fructose isomerization by using divalent dimetallic centers bridged by a glutamate residue.
Subject(s)
Aldose-Ketose Isomerases/chemistry , Carboxylic Acids/chemistry , Copper/chemistry , Glucose/chemistry , Organometallic Compounds/chemistry , Zinc/chemistry , Aldose-Ketose Isomerases/metabolism , Algorithms , Catalysis , Crystallography, X-Ray , Fourier Analysis , Glutamic Acid/chemistry , Models, Chemical , Molecular Structure , Monosaccharides/chemistry , Substrate SpecificityABSTRACT
Epimerization of aldoses at C-2 has been extensively investigated by using various metal ions in conjunction with diamines, monoamines, and aminoalcohols. Aldoses are epimerized at C-2 by a combination of alkaline-earth or rare-earth metal ions (Ca(2+), Sr(2+), Pr(3+), or Ce(3+)) and such monoamines as triethylamine. In particular, the Ca(2+)-triethylamine system proved effective in promoting aldose-ketose isomerization as well as C-2 epimerization of aldoses. 13C NMR studies using D-(1-(13)C)glucose and D-(1-(13)C)galactose with the CaCl(2) system in CD(3)OD revealed that the C-2 epimerization proceeds via stereospecific rearrangement of the carbon skeleton, or 1,2-carbon shift, and ketose formation proceeds partially through an intramolecular hydrogen migration or 1,2-hydride shift and, in part, via an enediol intermediate. These simultaneous aldose-aldose and aldose-ketose isomerizations showed interesting substrate-dependent chemoselectivity. Whereas the mannose-type aldoses having 2,3-erythro configuration (D-mannose, D-lyxose, and D-ribose) showed considerable resistance to both the C-2 epimerization and the aldose-ketose isomerization, the glucose-type sugars having 2,3-threo and 3,4-threo configurations, D-glucose and D-xylose, are mainly epimerized at C-2 and those having the 2,3-threo and 3,4-erythro configurations, D-galactose and D-arabinose, were mostly isomerized into 2-ketoses. These features are of potential interest in relevance to biomimic sugar transformations by metal ions.
Subject(s)
Aldose-Ketose Isomerases/chemistry , Amines/pharmacology , Calcium/pharmacology , Carbohydrates/chemistry , Ethylamines/pharmacology , Isomerism , Metals, Heavy/pharmacology , Molecular Mimicry , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Organometallic Compounds/pharmacology , Substrate SpecificityABSTRACT
A 58-year-old man developed proteinuria and renal dysfunction following pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin was administered, and prednisolone pulse therapy and plasmapheresis were performed. Subsequently, serum creatinine was decreased. Eight months later, creatinine and CRP were again elevated, and MRSA was detected. Vancomycin was again administered and plasmapheresis was performed. However, renal function was not improved and continuous hemodialysis was initiated. This case indicates that complete eradication of MRSA is necessary to treat MRSA-associated glomerulonephritis, and if this is not attained, a permanent loss of renal function occurs.
Subject(s)
Glomerulonephritis/complications , Glomerulonephritis/microbiology , Kidney Failure, Chronic/etiology , Methicillin/therapeutic use , Penicillin Resistance , Penicillins/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcus aureus/physiology , Anti-Bacterial Agents/therapeutic use , Glucocorticoids/therapeutic use , Humans , Male , Middle Aged , Plasmapheresis , Prednisolone/therapeutic use , Staphylococcal Infections/therapy , Vancomycin/therapeutic useABSTRACT
A set of 1,3-propanediamine derivatives connected to carbohydrates (5) has been prepared in four steps from peracetylated sugar and 1,3-dibromo-2-propanol in 60-73% yields. D-Glucose, D-mannose, D-galactose, D-xylose, D-ribose, and maltose are utilized as sugar molecules in this work. The diamine moiety was connected to the C1 carbon of the glycopyranose ring via an O-glycoside bond. All of the anomeric configurations and sugar puckering conformations, except in the D-maltose derivative, were determined by X-ray crystallography of the diazido or dibromo precursors. While glycosidation of peracetylated galactopyranose with 1,3-dibromo-2-propanol in the presence of boron trifluoride afforded both anomers, the neighboring group participation of the 2-acetoxy group yielded a single anomer for the other substrates. This method has been used to synthesize a library of sugar-pendant diamines including an OH-protected derivative (6), and an N,N'-diisopropyl-substituted derivative (7). A similar series of reactions using 2,3-dibromo-1-propanol gave ethylenediamine-type derivatives (11), and bis(bromomethyl)bis(hydroxymethyl)methane (12) gave bisglucose-pendant derivatives (16).
Subject(s)
Diamines/chemical synthesis , Oligosaccharides/chemical synthesis , Carbohydrate Sequence , Indicators and Reagents , Molecular Conformation , Molecular Sequence Data , X-Ray DiffractionABSTRACT
7 cases, considered as being true etiological exceptions selected from 756 upper gastrointestinal bleeding, are presented. The causes of bleeding were: pancreatic pseudocyst with intracystic hemorrhage broken into duodenum (2 cases), the nonepithelial gastroduodenal tumor (3 cases), the aneurysm of gastroduodenal artery broken into duodenum (1 case) and the aortoduodenal fistula in one patient with a bilateral aorto-iliac by-pass (1 case). The etiological diagnosis could not be established in any cases before the operations. All the cases were operated on, the operation being imposed by the severity of bleeding and having the haemostasis as a main purpose.
Subject(s)
Gastrointestinal Diseases/complications , Gastrointestinal Hemorrhage/etiology , Adult , Aged , Aneurysm/complications , Duodenal Neoplasms/complications , Fatal Outcome , Female , Gastrointestinal Diseases/surgery , Humans , Leiomyoma, Epithelioid/complications , Male , Middle Aged , Neurilemmoma/complications , Pancreatic Pseudocyst/complications , Stomach Neoplasms/complicationsABSTRACT
Reactions of MnX2.nH2O with tris(N-(D-mannosyl)-2-aminoethyl)amine ((D-Man)3-tren), which was formed from D-mannose and tris(2-aminoethyl)amine (tren) in situ, afforded colorless crystals of [Mn((D-Man)3-tren)]X2 (3a, X = Cl; 3b, X = Br; 3c, X = NO3; 3d, X = 1/2SO4). The similar reaction of MnSO4.5H2O with tris(N-(L-rhamnosyl)-2-aminoethyl)amine ((L-Rha)3-tren) gave [Mn((L-Rha)3-tren)]SO4 (4d), where L-rhamnose is 6-deoxy-L-mannose. The structures of 3b and 4d were determined by X-ray crystallography to have a seven-coordinate Mn(II) center ligated by the N-glycoside ligand, (aldose)3-tren, with a C3 helical structure. Three D-mannosyl residues of 3b are arranged in a delta(ob3) configuration around the metal, leading to formation of a cage-type sugar domain in which a water molecule is trapped. In 4d, three L-rhamnosyl moieties are in a delta(lel3) configuration to form a facially opened sugar domain on which a sulfate anion is capping through hydrogen bonding. These structures demonstrated that a configurational switch around the seven-coordinate manganese(II) center occurs depending on its counteranion. Reactions of 3a, 3b, and 4d with 0.5 equiv of Mn(II) salt in the presence of triethylamine yielded reddish orange crystals formulated as [[Mn((aldose)3-tren)]2Mn(H2O)X3.nH2O (5a, aldose = D-Man, X = Cl; 5b, aldose = D-Man, X = Br; 6d, aldose = L-Rha, X = 1/2SO4). The analogous trinuclear complexes 6a (aldose = L-Rha, X = Cl), 6b (aldose = L-Rha, X = Br), and 6c (aldose = L-Rha, X = NO3) were prepared by the one-pot reaction of Mn(II) salts with (L-Rha)3-tren without isolation of the intermediate Mn(II) complexes. X-ray crystallographic studies revealed that 5a, 5b, 6c, and 6d have a linearly ordered trimanganese core, Mn(II)Mn(III)Mn(II), bridged by two carbohydrate residues with Mn-Mn separations of 3.845(2)-3.919(4) A and Mn-Mn-Mn angles of 170.7(1)-173.81(7) degrees. The terminal Mn(II) atoms are seven-coordinate with a distorted mono-face-capped octahedral geometry ligated by the (aldose)3-tren ligand through three oxygen atoms of C-2 hydroxyl groups, three N-glycosidic nitrogen atoms, and a tertiary amino group. The central Mn(III) atoms are five-coordinate ligated by four oxygen atoms of carbohydrate residues in the (aldose)3-tren ligands and one water molecule, resulting in a square-pyramidal geometry. In the bridging part, a beta-aldopyranosyl unit with a chair conformation bridges the two Mn(II)Mn(III) ions with the C-2 mu-alkoxo group and with the C-1 N-glycosidic amino and the C-3 alkoxo groups coordinating to each metal center. These structures could be very useful information in relation to xylose isomerases which promote aldose-ketose isomerization by using divalent dimetal centers such as Mn2+, Mg2+, and Co2+.
Subject(s)
Carbohydrates/chemistry , Glycosides/chemical synthesis , Manganese/chemistry , Crystallography, X-Ray , Indicators and Reagents , Molecular Conformation , Spectrophotometry, UltravioletABSTRACT
Nickel(II) complexes containing N-glycosides derived from D-glucosamine (D-GlcN) and ethylenediamine (en) and trimethylenediamine (tn), [Ni(D-GlcN-en)2]Cl2.H2O (1) (D-GlcN-en = 1-¿(2-aminoethyl)amino¿-2-amino-1,2-dideoxy-D-glucose) and [Ni(D-GlcN-tn)2]Cl2.4H2O (2) (D-GlcN-tn = 1-¿(3-aminopropyl)amino¿-2-amino-1,2-dideoxy-D-glucose), are fairly stable in water at room temperature and showed effective antifungal activity against pathogenic yeast, Candida albicans, with the MIC (minimal concentration of inhibition) values of the complexes being 0.25 mM. The results obtained enzyme assays by using preparations of C. albicans chitinase fraction suggested that the sugar complexes 1 and 2 played a role of novel chitinase (chitin-degradation enzyme) inhibitor, where the modes of inhibition were competitive (Ki = 1.3 mM for 1, Ki = 1.8 mM for 2). The newly prepared nickel(II) complex 2 was characterized by elemental analysis, magnetic susceptibility, electronic absorption and circular dichroism spectroscopies, and an X-ray crystallographic analysis.
Subject(s)
Antifungal Agents/pharmacology , Candida albicans/drug effects , Glucosamine , Nickel , Organometallic Compounds/pharmacology , Antifungal Agents/chemical synthesis , Circular Dichroism , Crystallography, X-Ray , Diamines , Ethylenediamines , Kinetics , Microscopy, Phase-Contrast , Models, Molecular , Spectrophotometry, InfraredABSTRACT
Elevation of intracellular sodium ion concentration in human erythrocyte induced by the cardiac glycoside, proscillaridin, and its four derivatives was measured using 23Na NMR spectrometry. In this examination, there was a significant correlation between the time to half maximum inotropic effect and the time to maximum of Na+ concentrations in human erythrocyte, determined by 23Na NMR.
Subject(s)
Cardiac Glycosides/pharmacology , Erythrocytes/metabolism , Sodium/blood , Animals , Erythrocytes/drug effects , Guinea Pigs , Humans , In Vitro Techniques , Magnetic Resonance Spectroscopy , Papillary Muscles/drug effects , Proscillaridin/analogs & derivatives , Proscillaridin/pharmacology , Sodium Isotopes , ThermodynamicsABSTRACT
To reduce the vascular contracting effect of the hydrogenated cardiac glycosides, 20-(R)- and 20-(S)-tetrahydroproscillaridins (THPs, 1a, 1b), and to extend the concentration-dependent range, mono- and dinitrates of THPs were prepared. The pharmacological activities of the nitrates of THP were evaluated by use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase preparations from dog kidney. Furthermore, the effect for smooth muscle was examined using the helical strips isolated from 13-week-old spontaneously hypertensive rat. The positive inotropic effects of mononitrates (11a, 11b, 2a, 2b, 8a, and 8b) were more potent than those of THPs. Nitration of the sugar moiety in THPs resulted in a vascular relaxing effect unobserved in the case of THPs.
Subject(s)
Cardiac Glycosides/chemical synthesis , Myocardial Contraction/drug effects , Nitrates , Proscillaridin/analogs & derivatives , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Animals , Cardiac Glycosides/pharmacology , Dogs , Dose-Response Relationship, Drug , Esterification , Guinea Pigs , In Vitro Techniques , Proscillaridin/chemical synthesis , Proscillaridin/pharmacology , Stimulation, Chemical , Structure-Activity RelationshipABSTRACT
Three aromatic compounds (2-4) possessing a carbomethoxyl group or a dimethoxyphthaloyl group, prepared by the Diels-Alder reaction of the cardiac glycoside, proscillaridin (1), with dimethyl acetylenedicarboxylate and methyl propiolate, were transformed into alcohols, carboxylic acids and amides. The biological activities of the resulting derivatives were evaluated by the use of Na+, K(+)-adenosine triphosphatase (Na+,K(+)-ATPase) from dog kidney and isolated guinea-pig papillary muscle. Although the biological activities of the resulting derivatives were less potent than that of 1, a para-substituted benzylalcohol (5), methylbenzamides (9a and 10a), and ethylbenzamides (9b and 10b) inhibited the activity of Na+,K(+)-ATPase almost as potently as naturally occurring cardiac glycosides such as digoxin and digitoxin.
Subject(s)
Proscillaridin/analogs & derivatives , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Animals , Dogs , Guinea Pigs , Kidney/enzymology , Magnetic Resonance Spectroscopy , Papillary Muscles/enzymology , Proscillaridin/chemistry , Proscillaridin/pharmacology , Spectrophotometry, UltravioletABSTRACT
The Diels-Alder reactions of a cardiac glycoside, proscillaridin (1), with some dienophiles were investigated. The reaction of 1 with alkenes such as methyl vinyl ketone and methyl acrylate afforded 3-oxo-2-oxabicyclo[2.2.2]oct-7-enes (2-5) and para-substituted benzene derivatives (6 and 7), while 1 reacted with alkynes (3-butyn-2-one, methyl propiolate) to yield para- or meta-substituted benzene derivatives (6-9). The biological activities of the resulting derivatives were evaluated by the use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase (ATPase) preparation from dog kidney. Among the proscillaridin derivatives, compounds 4 and 7 moderately inhibited Na+,K(+)-ATPase activity. Furthermore, the concentration range of 7 over which its positive inotropic effect on guinea-pig papillary muscle preparations, increased from 5% to 95% of maximum was broader than that of 1, i.e., concentration dependency was maintained over a greater range of concentration.
Subject(s)
Proscillaridin/chemistry , Adenosine Triphosphatases/antagonists & inhibitors , Animals , Dogs , Guinea Pigs , In Vitro Techniques , Muscle Contraction/drug effects , Proscillaridin/analogs & derivatives , Proscillaridin/pharmacologyABSTRACT
To reduce the vascular contracting effect of the cardiac glycoside, proscillaridin (1), all kinds of its nitrates were prepared by utilizing effectively an isopropylidene function as a protective group. The pharmacological activities of proscillaridin nitrates were evaluated by the use of isolated guinea-pig papillary muscle preparations and Na+,K(+)-adenosine triphosphatase preparations from the dog kidney. Furthermore, the effect for smooth muscle using the helical strips isolated from 13-week old spontaneously hypertensive rat was examined. The positive inotropic effects and Na+, K(+)-adenosine triphosphatase inhibition activities of mononitrates (6, 9, 15) and dinitrates (3, 4, 5) were a little less potent than 1, but those of trinitrate (2) were much reduced. Every nitrate did not exhibited a vascular contracting effect but a relaxing effect. Among them, the vascular relaxing effects of 2',3'-dinitrate (3) and 2',4'-dinitrate (4) were more potent than those of the other nitrates.
Subject(s)
Digitalis Glycosides/chemical synthesis , Nitrates/chemical synthesis , Proscillaridin/chemical synthesis , Animals , Digitalis Glycosides/pharmacology , Dogs , Dose-Response Relationship, Drug , Guinea Pigs , In Vitro Techniques , Myocardial Contraction/drug effects , Nitrates/pharmacology , Proscillaridin/pharmacology , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Stimulation, Chemical , Structure-Activity RelationshipABSTRACT
Non-obese diabetic mice aged 30 to 60 days were treated orally with Cyclosporin at doses of 25, 15 and 2.5 mg/kg every 2 days until 160 days of age. Diabetes developed in 12 out of 18 oil-treated mice (67%), with partial to complete Langerhans' islet destruction associated with lymphocytic infiltration. The non-obese diabetic mice showed a plasma glucose concentration of 6.62 +/- 0.92 mmol/l (mean +/- SD) at 50 days of age. The plasma glucose level of oil-treated non-obese diabetic mice gradually increased after 130 days of age and reached 14.0 to 19.0 mmol/l at 160 days of age, while Cyclosporin-treated non-obese diabetic mice showed neither clear increase of plasma glucose levels nor development of insulitis. The cumulative incidence of diabetes in Cyclosporin-treated mice was significantly lower than that in oil-treated mice (p less than 0.01). Subsequently, Cyclosporin treatment was started after development of glucose intolerance. Twenty-five mg/kg of Cyclosporin was administered every 2 days for 35 days. Cyclosporin appeared to have little therapeutic effect on diabetes in non-obese diabetic mice.