Neuroprotection from focal ischemia by 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is dependent on treatment duration in rats

OBJECTIVES: We sought to determine whether treatment with high dose verapamil prevents restenosis in patients at high risk for reoccurrence after successful percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Restenosis is the major limitation of PTCA. Calcium antagonists have demonstrated some potential as inhibitors of this process. METHODS: A total of 98 patients with peripheral occlusive arterial disease (POAD), stable angina pectoris, mild hypertension and at least one additional risk factor increasing the likelihood of restenosis after angioplasty were selected for this placebo-controlled, double-blind, randomized trial. Verapamil (240 mg twice daily) or placebo was taken for 6 months. Efficacy variables assessed before and after angioplasty and at 6 weeks and 6 months after PTCA included thickness of the intima/media complex degree of stenosis, interventricular septal thickness, crurobrachial pressure ratios of dorsalis pedis and posterior tibial arteries, distance to claudication and total vessel diameter. RESULTS: No significant intergroup differences emerged before or immediately after PTCA. Six weeks after angioplasty, a significant thickening of the intima/media complex in the treated vascular segment of 14.3% occurred in the placebo group versus 0% among verapamil patients (p < 0.01). At 6 months, the intima/media thickness was 35.7% greater in the placebo group but had decreased by 14.3% in the verapamil group (p < 0.001). At 6 months, a marked reduction in septal thickness was observed in the verapamil group versus that in the placebo group (p < 0.001). The rate of restenosis was also significantly lower in the verapamil group (p < 0.001). Few minor side effects were reported. CONCLUSIONS: In patients with POAD at increased risk for restenosis, the administration of high dose verapamil prevented recurrent stenosis for 6 months after successful peripheral angioplasty and was well tolerated.     

Immunopharmacologic properties of 1,6-bis[2-(diethylamino)ethoxy]xanthen-9-one dihydrochloride (Wy-15297)

When tested in a series of immunopharmacologic assays, the interferon inducer, WY-15297, was shown to lack activity in early vascular and humoral phases of the inflammatory response, while it was quite effective against the immunologic phase. The profile of activity of Wy-15927 was, however, unlike those previously described for reference antiinflammatory and immunosuppressive drugs and this may represent one of a new class of immunopharmacologic agents capable of selectively modulating the lymphoreticular system.     

Prolongation of anesthetic action by BNPP (bis-[p-nitrophenyl] phosphate)

Bis-[p-nitrophenyl] phosphate, BNPP, an enzyme inhibitor of the organophosphate class, has been used to inhibit the enzyme, carboxylic ester hydrolase EC 3.1.1.1. Esterases play a major role in the rapid metabolism of propanidid in vivo; in fact, the short duration of action of this intravenous anesthetic agent is due to this rapid hydrolysis. The duration of anesthesia with propanidid alone in healthy mongrel dogs was 10.1 +/- 2.1 (SEM) minutes. When the dogs were pretreated with BNPP, propanidid anesthesia time was prolonged to 38.2 +/- 7.9 (SEM) minutes. Measurements of serum propanidid concentration demonstrated that prolonged high levels of propanidid were associated with the extended anesthesia time. Therefore, BNPP can significantly alter the anesthetic action of propanidid by inhibition of the enzyme system responsible for the rapid hydrolysis of the agent. The experimental model used in the present study provides a means for investigation of effects of certain drugs when their metabolism is impaired.     

Investigations on the synthesis and properties of 4-aminosubstituted 2,6,7-trimethyl-1,5-dioxo-1,2,5,6-tetrahydropyrido[3,4-d]pyridazines

Synthesis of 4-aminosubstituted 2,6,7-trimethyl-1,5-dioxo-1,2,5,6-tetrahydropyrido[3,4-d]pyridazin es 2-11 and the results of the preliminary pharmacological screening of the selected compounds 2, 4, 5, 10, 11 are described in this paper.     

Synthesis and trazodone-like analgesic activity of 4-phenyl-6-aryl-2-[3-(4-arylpiperazin-1-yl)propyl]pyridazin -3-ones

A series of 4,6-diaryl pyridazinones, chemically related to trazodone, ws synthesized and evaluated for analgesic activity. With ED50 values ranging from 8.4 to 46.7 mg kg(-1) i.p. in the phenylbenzoquinone-induced writhing test (PBQ test), most compounds were several times more potent than acetaminophen (ED50 = 231.3 mg kg(-1) i.p.) and noramidopyrine (ED50 = 68.5 mg kg(-1) i.p.). A multiple linear regression analysis demonstrated a correlation between antinociceptive activity and lipophilicity, as well as electronic and steric factors. The most active pyridazinones 2c and 2j exhibited minimal sedative and neurotoxic effects at the dose of 25 mg kg(-1) i.p. They were devoid of activity in the hot plate test and their analgesic activity was not significantly reversed by naloxone in the PBQ test. The antinociceptive response induced by morphine (0.15 mg kg(-1) s.c.) in the PBQ test was greatly potentiated by 2c and 2j administered at the low doses of 1 and 2.5 mg kg(-1) i.p., respectively. On the other hand, their analgesic effects were enhanced synergistically by 5-hydroxytryptophan combined with carbidopa. All these data imply that a significant part of the antinociceptive effect induced by 2c and 2j may involve both opioid and serotonergic pathways. In addition, these two pyridazinones did not exhibit any antidepressant properties in the forced swimming test, nor did they potentiate yohimbine-induced toxicity.     

Synthesis and antitumor activity of 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates

Ten 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates were synthesized and evaluated for antitumor activity. The 2-phenoxyethyl ester exhibited activity against P-388 lymphocytic leukemia, and the n-butyl and n-pentyl esters exhibited activity against L-1210 lymphoid leukemia in initial screening tests.     

Pharmacological and histopathological aspects of 1-methyl-4-phenyl-4-hydroxy-piperidine (MPIP)

The inhibitory effects of Radix Astragali (RA) on hypoxic structural remodeling of intra-acinar pulmonary arteries (IAPA) and pulmonary hypertension (PHT) were studied in rats, which were fed in hypoxic environment under normal atmospheric pressure (10% O2 10 hours/day). 60 rats were divided into 3 groups; hypoxia group, hypoxia+RA group and control group. On the 15th and 30th day of hypoxia, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) were measured and pulmonary vessel changes were studies under light and electronic microscopes and morphometric analysis. Compared with the hypoxia+RA group, RA could prevent IAPA wall cell damage and dilate the constricted IPIA induced by hypoxia. RA could also inhibit hypertrophic changes in the tunica media and proliferation of adventitial cells of the IAPA and muscularization of non-muscular arteries. Therefore, preserving the IAPA wall cells and dilating IAPA by RA may play an important role in inhibiting structural remodeling of IAPA and pulmonary hypertension.     

Synthesis and Characterization of Some Lanthanide（Ⅲ） Complexes with 4- [N-（2-methoxy benzylinine）formy1]-2, 3-dimethyl-1-phenyl-3-pyazolin-5-one

A series of seven novel lanthanide（Ⅲ ） nitrato complexes with 4-[ N-（2-methoxybenzylimine）formyl] 1-2, 3- dimethyl-1-phenyl-3-pyazolin-5-one （2mbfa）, were synthesized. These complexes were characterized by elemental analysis, molecular mass determination, conductance and magnetic moment measurements, IR, UV-visible, and ^13CNMR spectral studies, In these complexes, the Schiff base, 2mbfa, acts as neutral bidentate ligand by utilizing the carbonyl oxygen and azomethine nitrogen as donor sites. All the three nitrate ions are also coordinated unidentately with 7 coordination for the lanthanide（Ⅲ） ions with a tentative monocapped octahedral geometry for the complexes. All the seven lanthanide（Ⅲ） complexes have a general formula, [ Ln（2mbfa）：（NO3）3 ].     

S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride

The novel benzoindane S 18126 possessed > 100-fold higher affinity at cloned, human (h) D4 (Ki = 2.4 nM) vs. hD2 (738 nM), hD3 (2840 nM), hD1 (> 3000 nM) and hD5 (> 3000 nM) receptors and about 50 other sites, except sigma1 receptors (1.6 nM). L 745,870 similarly showed selectivity for hD4 (2.5 nM) vs. hD2 (905 nM) and hD3 (> 3000 nM) receptors. In contrast, raclopride displayed low affinity at hD4 (> 3000 nM) vs. hD2 (1.1 nM) and hD3 receptors (1.4 nM). Stimulation of [35S]-GTPgammaS binding at hD4 receptors by dopamine (DA) was blocked by S 18126 and L 745,870 with Kb values of 2.2 and 1.0 nM, respectively, whereas raclopride (> 1000 nM) was inactive. In contrast, raclopride inhibited stimulation of [35S]-GTPgammaS binding at hD2 sites by DA with a Kb of 1.4 nM, whereas S 18126 (> 1000 nM) and L 745,870 (> 1000 nM) were inactive. As concerns presynaptic dopaminergic receptors, raclopride (0.01-0.05 mg/kg s.c. ) markedly enhanced DA synthesis in mesocortical, mesolimbic and nigrostriatal dopaminergic pathways. In contrast, even high doses (2. 5-40.0 mg/kg s.c.) of S 18126 and L 745,870 were only weakly active. Similarly, raclopride (0.016 mg/kg i.v.) abolished inhibition of the firing rate of ventrotegmental dopaminergic neurons by apomorphine, whereas even high doses (0.5 mg/kg i.v.) of S 18126 and L 745,870 were only weakly active. As regards postsynaptic dopaminergic receptors, raclopride potently (0.01-0.3 mg/kg s.c.) reduced rotation elicited by quinpirole in rats with unilateral lesions of the substantia nigra, antagonized induction of hypothermia by PD 128, 907, blocked amphetamine-induced hyperlocomotion and was effective in six further models of potential antipsychotic activity. In contrast, S 18126 and L 745,870 were only weakly active in these models (5.0-> 40.0 mg/kg s.c.). In six models of extrapyramidal and motor symptoms, such as induction of catalepsy, raclopride was likewise potently active (0.01-2.0 mg/kg s.c.) whereas S 18126 and L 745,870 were only weakly active (10.0-80.0 mg/kg s.c.). In freely moving rats, raclopride (0.16 mg/kg s.c.) increased levels of DA by + 55% in dialysates of the frontal cortex. However, it also increased levels of DA in the accumbens and striatum by 70% and 75%, respectively. In contrast to raclopride, at a dose of 0.16 mg/kg s.c. , neither S 18126 nor L 745,870 modified frontal cortex levels of DA. However, at a high dose (40.0 mg/kg s.c.), S 18126 increased dialysate levels of DA (+ 85%) and noradrenaline (+ 100%), but not serotonin (+ 10%), in frontal cortex without affecting DA levels in accumbens (+ 10%) and striatum (+ 10%). In conclusion, S 18126 and L 745,870 behave as potent and selective antagonists of cloned, hD4 vs. other dopaminergic receptor types in vitro. However, their in vivo effects at high doses probably reflect residual antagonist actions at D2 (or D3) receptors. Selective blockade of D4 receptors was thus associated neither with a modification of dopaminergic transmission nor with antipsychotic (antiproductive) or extrapyramidal properties. The functional effects of selective D4 receptor blockade remain to be established.     

Evidence for the sequential formation of two complexes between an uptake inhibitor, GBR 12783 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-2-propenyl)piperazine], and the neuronal transporter of dopamine

Incubation of a crude synaptosomal fraction from rat striatum with GBR 12783 at 37 degrees C produced an inhibition of the specific uptake of [3H]dopamine that increased with time. The inhibition increased when GBR 12783 was present during preincubation and incubation (IC50 = 1.85+/-0.1 nM) instead of incubation alone (IC50 = 25+/-3.5 nM). Time-course studies of uptake inhibition demonstrated that a first collision transporter-inhibitor complex (TI) was formed immediately after addition of GBR 12783 so that the initial uptake velocity (V0) decreased for increasing concentrations of inhibitor (Ki > or = 20 nM). TI slowly isomerized to a more stable complex TI* (Ki* < or = 5 nM) with a value of t1/2 = 20-270 s. Fits of data to model 2 in which the steady-state uptake (VS) is set to zero were generally preferred, suggesting that formation of TI* could tend to irreversibility, as a consequence of a very low reverse isomerization. As expected, k, V0, and VS tended to steady-state values in an asymptotic manner for high concentrations of GBR 12783. GBR 12783 at 2.5 nM produced a mixed inhibition of the uptake, with an increase in KM and a decrease in Vmax; these effects were improved for 10 nM GBR 12783 and at 20 degrees C. These results are discussed in relation to previous data concerning [3H]GBR 12783 binding. The present work gives the first experimental demonstration that dopamine uptake blockers can act according to a two-step mechanism of inhibition; this is of great interest, because these inhibitors can oppose the effects of cocaine or amphetamine on the transporter according to a reaction that is partly nondependent on the concentration of the abused agent.     

Preparation of 8-[3-(4-fluorobenzoyl)-propyl]-1-(4-[123I] iodobenzoyl)-1,3,8-triazaspiro[4,5]decan-4-one: a novel selective serotonin 5-HT2 receptor agent

OBJECTIVE: to evaluate the effectiveness of a reduced-frequency prenatal visit schedule by comparing perinatal outcomes, anxiety and maternal satisfaction with prenatal care. METHODS: pregnancy outcomes of infant and maternal morbidity and mortality, anxiety and satisfaction for 81 women receiving prenatal care at a free-standing birthing center according to either an alternative prenatal care visit schedule (APCVS) (n = 43) or the traditional prenatal care visit schedule (TPCVS) (n = 38) were examined in this prospective randomized study. Upon entry into prenatal care, all women were of low obstetrical risk status. RESULTS: major findings revealed no significant differences in selected perinatal outcomes between the two study groups. Women in the APCVS group reported significantly higher levels of satisfaction than women in the TPCVS group on both the satisfaction with provider subscale (F = 5.74, P = .02) and the satisfaction with the prenatal care system subscale (F = 2.01, P = .04). There were no statistically significant differences found in anxiety scores between women in the two study groups. CONCLUSIONS: low-risk women who followed the reduced-frequency visit schedule experienced no difference in perinatal outcomes or anxiety. Women in the reduced-frequency (APCVS) group reported an increased level of satisfaction with both provider and the prenatal care system.     

Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors

A new series of heteroaromatic GBR 12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine] (I) and GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine] (2) analogs was synthesized and evaluated as dopamine transporter (DAT) ligands. Analogs 5-16, in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound 2. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing (6 and 8) and pyridine-containing (14 and 16) derivatives displayed potency comparable to 2 in decreasing the cocaine-maintained responding at the doses tested (0.8, 1.7, and 3 mg/kg). However, these compounds did not produce the degree of separation between food- and cocaine-maintained responding that was seen with 2. Among the bicyclic fused-ring congeners 17-38, the indole-containing analog of 2, 22, showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, whereas the corresponding indole-containing derivative of 1, 21, displayed the highest selectivity (over 600-fold) at this site vs the SERT site.     

Studies of the antagonist actions of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl] propionic acid (ATPO) on non-NMDA receptors in cultured rat neurones

Whole-cell patch-clamp recordings from single cultured cortical neurones have been used to study the action of (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl+ ++]propionic acid (ATPO), which has previously been proposed to be a potent selective antagonist of 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors. ATPO competitively reduced peak responses evoked by semi-rapid applications of AMPA (Ki = 16 microM) but had variable effects on plateau responses, which were on average unchanged. Following blockade of AMPA receptor desensitization by cyclothiazide (CTZ, 100 microM), the plateau responses were reduced by ATPO to a similar extent as the peak responses, indicating that ATPO reduces desensitization of AMPA receptors. Semi-rapid application of kainic acid (KA) and the KA receptor-selective agonist, (2S,4R)-4-methylglutamic acid (MeGlu) evoked non-desensitizing responses which were competitively antagonized by ATPO (Ki values: 27 and 23 microM, respectively). Responses to MeGlu were unaffected by CTZ (100 microM), but potentiated 3 fold following blockade of KA receptor desensitization by concanavalin A (Con A, 300 microg ml(-1)). Responses of spinal cord neurones to MeGlu were blocked by ATPO to a similar extent before and after blockade of KA receptor desensitization by Con A. Although selectively potentiated by Con A, plateau responses to MeGlu were reduced by 69.6% by the AMPA selective antagonist, GYKI 53655 (10 microM). The remaining component was further reduced by ATPO with a Ki of 36 microM, which was not significantly different from that in the absence of GYKI 53655, but was greater than that on responses to AMPA. It is concluded that ATPO is a moderate-potency competitive inhibitor of naturally expressed non-NMDA receptors.     

N-[4-(1,1''-biphenyl)methyl]-4-(4-thiomorpholinylmethyl) benzenamines as non-oxazolidinone analogues of antimycobacterial U-100480

Twenty-three patients underwent conventional arteriography and 3D contrast enhanced magnetic resonance angiography explorations. The study was limited to the iliofemoral arteries (13 segments for each patient). Each segment was classified as having 0-49%, 50-99% or 100% stenosis. Overall results were excellent with K = 0.822, sensitivity 92% and specificity 93%. Segment by segment analysis corroborated the overall results except for the internal iliac arteries and the deep femoral arteries, demonstrating the limitations of this technique in this series.     

YM022 [(R)-1-[2,3-dihydro-1-(2''-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea]: an irreversible cholecystokinin type-B receptor antagonist

It is controversial whether osteopontin (OP) is expressed in glomeruli and involved in glomerular diseases. We examined whether the OP expression is present at gene and protein levels in cultured rat mesangial cells (MCs). Northern blotting revealed a 1.7 kb OP-mRNA expression in MCs. Fetal calf serum (FCS) and TNF-alpha increased OP gene expression in serum-starved MCs by 2.7- and 1.8-fold over 24- and 12-hour periods, respectively. PDGF, IL-1beta, and TGF-beta had little effect on OP gene expression. Western blotting detected the OP protein expression (69 kDa). FCS and TNF-alpha increased OP protein expression in serum-starved MCs over 48- and 24-hour periods, respectively. The present study clearly demonstrated the expression of OP gene and protein in cultured rat MCs. Increased OP production under serum or TNF-alpha stimulation suggests that intraglomerular OP may contribute to the development of glomerular diseases.