The Promise of Cilnidipine in Hypertension with Comorbidities: National Consensus Statement: National Consensus Group Comprises Cardiologists, Nephrologists, and Diabetologists from India in a National Meet at New Delhi held on 22nd May 2022.

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.

Angiotensin Receptor-Neprilysin Inhibitor Therapy and Cardiac Remodeling in Heart Failure: Consensus Statement from India.

Adverse cardiac remodeling refers to progressive structural and functional modifications in the heart because of increased wall stress in the myocardium, loss of viable myocardium, and neurohormonal stimulation. The guideline-directed medical therapy for Heart failure (HF) includes Angiotensin receptor-neprilysin inhibitor (ARNI) (sacubitril/valsartan), ß-blockers, sodium-glucose co-transporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRA). ARNI is under-prescribed in India despite its attractive safety and efficacy profile. Therefore, the consensus discusses objectives and topics related to ARNI in the management of cardiac remodeling, and experts shared their views on the early timely intervention of effective dosage of ARNI to improve the diagnosis and enhance mortality and morbidity benefits in cardiac reverse remodeling (CRR).

Role of Iron Therapy in Heart Failure: A Consensus Statement from India.

Iron deficiency (ID) with or without anemia is frequently observed in patients with heart failure (HF). Uncorrected ID is associated with higher hospitalization and mortality in patients with acute HF (AHF) and chronic HF (CHF). Hence, in addition to chronic renal insufficiency, anemia, and diabetes, ID appears as a novel comorbidity and a treatment target of CHF. Intravenous (IV) ferric carboxymaltose (FCM) reduces the hospitalization risk due to HF worsening and improves functional capacity and quality of life (QOL) in HF patients. The current consensus document provides criteria, an expert opinion on the diagnosis of ID in HF, patient profiles for IV FCM, and correct administration and monitoring of such patients.

Roxithromycin potency quantification in pharmaceutical preparation by applying a validated bioassay method and comparison with HPLC analysis.

Roxithromycin (RXM) is used to treat bacterial infections. An alternative bioassay for the assessment of the potency of this drug in pharmaceutical formulations has not been reported earlier. This study reports the development and validation of cost-effective, simple, sensitive, precise, accurate and reproducible one-level agar diffusion (5+1) bioassay for estimation of potency and bioactivity of RXM in tablet. Among six tested microbial strains, Streptococcus pneumoniae (MTCC-1935) was used as the most susceptible strain against RXM. Bioassay was optimized by investigating buffer pH, inoculums and reference standard concentration. The results of proposed bioassay displayed high linearity, precision, accuracy, robustness and specificity. All potency results were statistically analyzed and found to be linear (R(2)=0.9957) in between 2.0 and 6.0µg/mL, precise with relative standard deviation (RSD) of repeatability intra-assay below 1.5%, and intermediate precision between day RSD 0.39% and accurate (100.68%). The bioassay and previously validated HPLC methods were compared, which indicated that there was no significant difference between these two methods. The results demonstrated the validity of the proposed microbial assay, which allows reliable quantitation of RXM in pharmaceutical samples and therefore can be used as a substitute alternative methodology for the routine quality control of this medicine, in situation when HPLC is not affordable in the laboratory.

Role of omega-3 ethyl ester concentrate in reducing sudden cardiac death following myocardial infarction and in management of hypertriglyceridemia: an Indian consensus statement.

INTRODUCTION: Sudden cardiac death (SCD) is the most lethal manifestation of heart disease. In an Indian study the SCDs contribute about 10% of the total mortality and SCD post ST elevation myocardial infarction (MI) constitutes for about half of total deaths. OBJECTIVE: Given the limitations of existing therapy there is a need for an effective, easy to use, broadly applicable and affordable intervention to prevent SCD post MI. Leading cardiologists from all over India came together to discuss the potential role of n-3 acid ethyl esters (90%) of eicosapentaenoic acid (EPA) 460 mg & docosahexaenoic acid (DHA) 380 mg in the management of post MI patients and those with hypertriglyceridemia. RECOMMENDATIONS: Highly purified & concentrated omega-3 ethyl esters (90%) of EPA (460 mg) & DHA (380 mg) has clinically proven benefits in improving post MI outcomes (significant 15% risk reduction for all-cause mortality, 20% risk reduction for CVD and 45% risk reduction in SCD in GISSI-Prevenzione trial) and in reducing hypertriglyceridemia, and hence, represent an interesting option adding to the treatment armamentarium in the secondary prevention after MI based on its anti-arrhythmogenic effects and also in reducing hypertriglyceridemia.

Enhanced external counterpulsation and CVD protection: 3D echo validation: a promising approach.

UNLABELLED: AIMS & OBJECTIVE: To evaluate the impact of enhanced external counterpulsation (EECP) on various echo variables by 3D-Echocardiography. MATERIALS AND METHODS: 60 adult patients from indoor and outdoor patient department; consisting of 16 patients with heart failure (HF) with left ventricular systolic dysfunction, 20 patients with heart failure with normal ejection fraction (HFNEF), 4 patients with prior percutaneous coronary intervention (PCI), 3 patients with prior coronary artery bypass grafting (CABG) and 17 patients with syndrome X; were subjected to Echocardiographic evaluation. The various echo variables included were left ventricular myocardial performance index (LVMPI), left ventricular mass index (LVMi), left ventricular diastolic dysfunction (LVDD), left ventricular systolic function (LVEF) and left atrial volume index (LAVi). Once randomized, patients underwent 35 hrs EECP treatment sessions, each lasting 1 hour, could be given once or twice per day. RESULTS: There was a significant reduction in the overall prolonged mean LVMPI from baseline (0.54 +/- 0.2) to post ECP treatment (0.43 +/- 0.1) in the total study population (p < 0.001). EECP treatment significantly reduced baseline grade II or grade III diastolic dysfunction and E/E' ratio > 12, but not in patients with baseline E/E' < 12, baseline normal diastolic function or grade I diastolic dysfunction. Similiarly the mean LVEF in the subset of patients with HF treatment was 30.7 +/- 3.1; post ECP the mean LVEF was increased to 36.9 +/- 3.2 which was statistically significant (p < 0.001). In the remaining patients, who had mean LVEF within normal range, there was no significant difference pre and post EECP (p value- NS). Pre EECP the mean LAVi in the total population was increased up to 33.4 +/- 5.6 ml/m2. Post EECP the mean LAVi reduced to 24.8 +/- 4.2 ml/m2, which was also statistically significant (p < 0.001). Regarding mean LVMi as well as in the patterns of LVH, there were no significant changes seen as compared to baseline. CONCLUSION: Enhanced External counterpulsation is noninvasive, non-surgical method of choice for CVD & heart failure protection. It is very useful in Single vessel or multivessel disease, heart failure, HFNEF, Post PCI or post CABG and syndrome X. It reduces LVMPI and improves global cardiac function, increases LVEF in patients with ejection fraction of less than 50%, reduces grade II or grade III diastolic dysfunction and E/E' ratio more than 12, decreases LAVi by 25.7%; thereby reducing adverse clinical events in CAD and heart failure.

Clinical outcomes of submassive pulmonary embolism thrombolysis-an Indian experience.

BACKGROUND: Acute pulmonary thromboembolism is the most dangerous presentation of venous thromboembolic disease. The role of thrombolysis in massive pulmonary embolism has been studied extensively, but the same is not there for submassive pulmonary embolism. This study is aimed at evaluating the effects of thrombolysis in acute submassive pulmonary embolism. This was a prospective, case-control, observational study. Patients presenting with acute submassive pulmonary embolism were divided into thrombolysis group and control group depending on whether they received thrombolysis plus anticoagulation or anticoagulation only, respectively. RESULTS: A total of 86 patients were included in the study. Forty-two patients were in the thrombolysis group, and 44 patients were in the control group. The mean ± SD age in the control and thrombolysis groups was 63.3 ± 14.7 and 56.4 ± 13.8 years, respectively. The two groups were well matched in sex distribution and associated comorbidities like COPD, active surgery, major trauma, and immobilization. On echocardiography, dilated RA/RV in pre-treatment vs. post-treatment was seen in 20 (45.5%) vs. 20 (45.5%) in the control group and 26 (61.9%) vs. 11 (26.2%) in the thrombolysis group. Similarly, RV systolic dysfunction in pre-treatment vs. post-treatment was seen in 24 (54.5%) vs. 21 (47.7%) in the control group and 22 (52.4%) vs. 8 (19.0%) in the thrombolysis group. Pulmonary artery pressure in pre-treatment vs. post-treatment was 64.4 ± 15.0 vs. 45.9 ± 9.9 mmHg in the control group and 68.3 ± 17.4 vs. 31.4 ± 6.9 mmHg in the thrombolysis group. In control vs. thrombolysis group, there were 5 vs. 1 death, 6 vs. 1 hemodynamic decompensation, and 6 vs. 1 patient needing mechanical ventilation. CONCLUSION: Thrombolysis in submassive pulmonary embolism is associated with better right ventricular functions, lower pulmonary artery pressures, and comparable mortality rates.

Cardiological society of India document on safety measure during echo evaluation of cardiovascular disease in the time of COVID-19.

An echocardiographic investigation is one of the key modalities of diagnosis in cardiology. There has been a rising presence of cardiological comorbidities in patients positive for COVID-19. Hence, it is becoming extremely essential to look into the correct safety precautions, healthcare professionals must take while conducting an echo investigation. The decision matrix formulated for conducting an echocardiographic evaluation is based on presence or absence of cardiological comorbidity vis-à-vis positive, suspected or negative for COVID-19. The safety measures have been constructed keeping in mind the current safety precautions by WHO, CDC and MoHFW, India.

3D echocardiography: "The most powerful predictor of masked CVD in metabolic syndrome".

UNLABELLED: AIMS & OBJECTIVE: To evaluate the impact of the Metabolic Syndrome (MetS) on various echo variables by 3D Echocardiography. MATERIALS AND METHODS: 100 patients of MetS from indoor and outdoor patient departments were subjected to Echocardiographic and Carotid Doppler evaluation. They were divided into three groups: Group A, Group B and Group C on the basis of age <40 yrs, 40-60 yrs and >60 yrs respectively. The echo variables included left ventricular myocardial performance index (LVMPI), left ventricular mass index (LVMi), left ventricular diastolic dysfunction (LVDD), systolic function (LVEF), left atrial volume index (LAVi) and composite common carotid intima media thickness (CCIMT). RESULTS: The mean LVMPI was abnormal in all the groups and showed an increasing trend with prolonged LVMPI (> 0.4) in 74% of the total population. Prolonged LVMPI in Group A, Group B and Group C were 12.1%, 52.7% and 35.1% respectively. There was also a strong correlation between LVMPI & LVDD (p-value < 0.0001). Only 9% had systolic dysfunction (LVEF < 50%), but 68% of patients had abnormal diastolic function, of which 53% had grade I LVDD, 12% had grade II LVDD and 3% had grade III diastolic dysfunction. None of our patients had grade IV diastolic dysfunction. The mean LA Vi was normal in all the groups, but LAVi increased with worsening LVDD. The mean LVMi indexed to Body Surface Area (BSA) was normal in all the groups, but showed a statistically significant increasing trend from Group A to Group C (p-value < 0.05). Statistically significant higher LVMi values were observed for males as compared to females (p-value < 0.0001). On analysis of patients having left ventricular hypertrophy (LVH), 76% had concentric remodeling; only 11 % had concentric hypertrophy, but none had eccentric hypertrophy. Most of our patients in Group B & Group C had higher mean Composite CCIMT (0.73 +/- 0.33 & 0.84 +/- 0.42 respectively) which was statistically very significant (p-value < 0.001) CONCLUSION: Metabolic Syndrome is associated with masked cardiovascular disease (CVD) as evident by 3D Echo in this series of patients. LVMPI was an early indicator and the most robust marker of early LVDD. Impaired relaxation was highly prevalent; while LAVi was less robust predictor of LVDD in this series of patients. Concentric left ventricular remodeling was the most common pattern of LVH. Most of our series of patients had increased Composite CCIMT. Thus 3D Echocardiography has great potential and is very useful for early detection and timely therapeutic interventions in patients with subclinical CVD in MetS.

Low Framingham risk score despite high prevalence of metabolic syndrome in asymptomatic North-Indian population.

BACKGROUND: Conflicting data exists regarding relationship between the Framingham risk score (FRS) and presence of metabolic syndrome (MS). Strong influence of age on FRS may further modify this relationship as prevalence of MS at younger age increases in South-Asian countries including India. However, only limited information is available about the prevalence of MS and its relationship with FRS in such populations at present. METHODS: Clinical examination and biochemical investigations were performed in 1905 asymptomatic office executives who underwent routine health check-up at a tertiary care centre in India during the year 2005. Diagnosis of MS and FRS were based on the modified National Cholesterol Education Program-Adult Treatment Panel III guidelines. RESULTS: Mean age of the subjects was 45.2 +/- 10.3 years and 71.8% were males. MS was present in 47.5% (905 of 1905) subjects. Overall, 76.8% patients with MS had 10-year cardiovascular (CV) risk < 10%, 20.6% had 10-20% risk and only 2.7% had > 20% risk according to FRS. In the lowest age-quartile, 95.9% patients had 10-year risk < 10%, 4.1% patients had 10-20% risk and none had > 20% risk. In contrast, in the highest age-quartile, less than half of the patients had 10-year risk <10% and nearly half had 10-20% risk of CV events. CONCLUSIONS: Although the prevalence of MS is markedly high in young asymptomatic Indians, majority have low 10-year risk of CV events as estimated by FRS. These findings necessitate continued emphasis on detection of MS in these populations as reliance on FRS alone may result in underestimation of CV risk in them.

Prevalence of cardiovascular risk factors in Indian patients undergoing coronary artery bypass surgery.

BACKGROUND: Conventional cardiovascular risk factors (CVRFs) are known to influence short-term and long-term outcome following coronary artery bypass graft surgery (CABG). There has been recent increase in prevalence of CVRFs in general population in India. However no information is available regarding the prevalence of same in patients undergoing CABG. METHODS AND RESULTS: In this cross-sectional study, one thousand consecutive patients undergoing elective CABG were included and data on major CVRFs was obtained in them. Mean age of the patients was 59.73 +/- 9.5 years and 884/1000 (88.4%) patients were males. 505/994 (50.8%) patients had BMI > or = 25.0 kg/m2 and 747/994 (75.2%) had BMI > or = 23.0 kg/m2. Diabetes mellitus was present in 475/1000 (47.5%) patients (46.5% men and 55.2% women), hypertension in 709/1000 (70.9% overall; 70.8% men and 71.6% women) and dyslipidemia in 781/913 patients (85.6% overall; 84.5% men and 93.9% women). 213/913 (23.3%) patients had LDL > or = 100mg/dl, 662/913 (72.5%) patients had low HDL and 338/913 (37.0%) patients had elevated triglycerides. 199/1000 (19.9%) patients (18.7% men and 29.3% women) had family history of premature CAD and 545/1000 (54.5%) patients (53.4% men and 62.9% women) had at least one family member having CAD (irrespective of the age of onset). 94/1000 (9.4%) patients (10.4% men and 1.7% women) were current smokers and another 302/1000 (30.2% overall; 33.7% men and 3.4% women) had history of smoking in the preceding one year. 876/913 (95.9%) of all the patients had at least one of the five major CVRFs and only 37/ 913 (4.1%) patients (4.1% men and 4.3% women) were free of all these risk factors. Sixty-one of the 1000 patients (6.1%) were younger than 45.0 years of age. As compared to older patients, dyslipidemia, family history of premature CAD and smoking were commoner in patients less than 45 years of age. In contrast, diabetes and hypertension were more prevalent in the older individuals. CONCLUSIONS: The present study showed high prevalence of most of the conventional CVRFs, esp. diabetes, hypertension and dyslipidemia in Indian population undergoing CABG.

Pharmacokinetics, biodistribution, and gamma camera imaging of 111In-KC-4G3 murine monoclonal antibody in athymic nude mice with or without human tumor xenografts.

The pharmacokinetics and tissue distribution of the monoclonal antibody radioconjugate 111In-diethylenetriaminepentaacetic acid-KC-4G3, which is directed against a high molecular weight mucin(s) antigen expressed on the human milk fat globule and many epithelial cell membranes, were examined in BALB/c nude mice with and without xenografts of the human tumor lines ZR-75 (mammary adenocarcinoma, KC-4G3 antigen positive) and BALL-1 (B-cell lymphoma, KC-4G3 antigen negative). Plasma of ZR-75 and BALL-1 tumor-bearing nude mice inoculated with 111In-KC-4G3 had a higher initial volume of distribution (V1), steady state volume of distribution (Vss), and plasma clearance and a lower initial half-life (t1/2 alpha) than non-tumor-bearing nude mice. There were no significant differences in biological half-life (t1/2 beta) in tumor- and non-tumor-bearing nude mice. Urinary and fecal excretion of radioactivity by ZR-75 tumor-bearing mice was greater than that of BALL-1 and non-tumor-bearing mice. Localization of 111In-KC-4G3 in mice bearing xenografts of ZR-75 was significantly greater than in mice with BALL-1 tumors. Uptake of 111In-KC-4G3 by ZR-75 tumors averaged 14% of injected dose/g at 72 h after inoculation and was unaffected by antibody dose. Significantly, the radioconjugate concentration in ZR-75 tumors remained relatively constant from 72 to 336 h post-inoculation, while that in normal tissues declined considerably over this period. Nonspecific reticuloendothelial tissue uptake of 111In-KC-4G3 was only moderately affected by pretreatment with a large excess of unlabeled normal mouse immunoglobulin and was not changed by treatment with asialofetuin. Further enhancement of specific localization of 111In-KC-4G3 was obtained by subtraction of the blood pool identified by co-inoculation of 131I-labeled, isotype-identical, normal mouse immunoglobulin. Gamma camera images of 111In-KC-4G3-inoculated ZR-75 tumor-bearing mice showed enhanced tumor localization compared to mice with BALL-1 tumors. The results of this study suggest that 111In-KC-4G3 may prove useful for imaging and possibly therapy of human malignancies expressing the high molecular weight epithelial mucin(s).

Imaging of non-small cell lung cancers with a monoclonal antibody, KC-4G3, which recognizes a human milk fat globule antigen.

To determine the role of lung cancer tumor imaging with monoclonal antibodies directed against high molecular weight human milk fat globule antigens, we administered i.v. 111In-KC-4G3 to 24 patients with advanced non-small cell lung cancer. One mg of 111In-KC-4G3 was mixed with 0, 9, 49, 99, or 499 mg of unlabeled KC-4G3 and infused i.v. over 1 to 5 h. The mean 111In-KC-4G3 radiochemical purity was greater than 97% and the resultant immunoreactivity averaged 62%. Successful imaging of cancer sites was accomplished in 92% of 24 patients, and 57% of 91 total lesions were visualized. Successful localization of tumor sites related to size (P less than 0.001), with 81% of lesions greater than 3.0 cm in diameter, 50% of lesions 1.5 to 3 cm, and 6% of lesions less than 1.5 cm successfully imaging, and to location (P less than 0.05), with 69% of pulmonary lesions, 80% of soft tissue lesions, and only 32% of bone metastases being visualized. Nonspecific reticulo-endothelial uptake of radioactivity was a major problem. Approximately 35% of 111In was chelated to serum transferrin by 24 and 48 h after infusion. The mean t 1/2 beta for plasma radioisotope and immunoreactive KC-4G3 was 29 and 27 h, respectively. There was no correlation between total infused antibody dose and imaging success or between total dose and effect on 111In and KC-4G3 kinetics. Circulating free KC-4 antigen was measurable in all but one patient before study. Tumor biopsy following infusion could demonstrate antibody presence but not saturable antigen binding. We conclude that (a) 111In-KC-4G3 demonstrates successful tumor localization in non-small cell lung cancers bearing generally high expression of its antigen and (b) further investigations to diminish nonspecific radioactivity for imaging and utilization of high dose radiolabeled antibody for therapeutic intent are warranted.

High-dose 90Y Mx-diethylenetriaminepentaacetic acid (DTPA)-BrE-3 and autologous hematopoietic stem cell support (AHSCS) for the treatment of advanced breast cancer: a phase I trial.

This Phase I trial explores the use of high-dose 90Y conjugated to the antibreast cancer monoclonal antibody BrE-3 and autologous hematologic cell support in the treatment of women with stage four breast cancer. Nine women with heavily pretreated disease were enrolled. All of the patients had BrE-3-positive tumors by immunostaining and were treated with increasing doses of 90Y (15 mCi/m2, 3 patients), 20 mCi/M2 (six patients), and a fixed (50 mg) dose of BrE-3. 111In-labeled BrE-3 (5 mCi) was given simultaneously for scanning purposes. The only toxicity noted was hematological. Grade 4 platelet toxicity requiring transfusion support occurred in four patients. Grade 4 WBC toxicity was seen in two patients that resolved in 3-9 days. All hematological nadirs occurred approximately 25 days after treatment. Objective partial responses were noted in 4 of 8 (50%) patients with measurable tumors. Dose escalation is ongoing.

Utility of three-dimensional echocardiography during balloon mitral valvuloplasty.

OBJECTIVES: We investigated the role of three-dimensional echocardiography in assessing mitral valve anatomy in greater detail in patients immediately before and after balloon mitral valvuloplasty (BMV). BACKGROUND: Three-dimensional echocardiography is a recently developed, evolving imaging technique that allows visualization of intracardiac structures from any perspective. METHODS: We studied 19 patients undergoing BMV using transesophageal echocardiography (TEE) (Chicago, Illinois) to image the mitral valve. The TEE was interfaced to a TomTec three-dimensional workstation that allows electrocardiographic and respiratory cycle gated image acquisition. The acquired images are digitized, and after postprocessing a three-dimensional image is reconstructed. The mitral valve was viewed "en-face" as if looking up from the left ventricle. RESULTS: The mean mitral valve area (by pressure half-time from the Doppler of the two-dimensional echocardiogram) increased after BMV from 0.86+/-0.06 cm2 to 2.07+/-0.10 cm2, p < 0.0001. This was similar to the mitral valve areas obtained by planimetry from the three-dimensional images. The three-dimensional reconstructions showed a complete commissural split in 10 patients and partial splitting in 9 patients. In three of the eight patients who had an increase in the amount of mitral regurgitation secondary to BMV, the three-dimensional reconstructions were able to detect tears within the valve leaflet. One leaflet tear actually extended up to the mitral valve annulus and was associated with the only case of severe mitral regurgitation. CONCLUSIONS: The three-dimensional echocardiographic reconstruction enabled visualization of the mitral valve so that commissural splitting and leaflet tears not seen on the two-dimensional echocardiogram became visible.

Autoradiographic measurement of cerebral lactate transport rate constants in normal and activated conditions.

We used quantitative autoradiography to measure the regional rate constants of blood-to-brain transport of lactate in normal rats and rats treated with kainic acid. Mean cerebral values of lactate transport rate constants were not significantly different between the normal and treated rats, being 0.13 and 0.14 min-1 (ml/g), respectively. Regional values were also generally similar between the groups, but structures that are known to be activated by kainic acid showed increased values in the treated rats compared with rates in the controls. Our measured values of lactate transport rate constants are approximately 50% as great as those published for glucose, indicating that blood-brain transfer of lactate can be significant. This observation supports the hypothesis that radiolabel derived from glucose can leave the brain as radiolabeled lactate in conditions in which intracerebral lactate concentration rises, a hypothesis that has previously been presented to explain differences between rates of accumulation of radiolabel derived from deoxyglucose and glucose in such conditions.

Synthesis, antitumor activity, and chemical properties of silaplatin and related platinum (II) and platinum (IV) complexes derived from beta-silyl amines.

Platinum (II) and platinum (IV) coordination complexes derived from beta-silyl-substituted amines were prepared. The solubility of selected complexes in water and physiological saline was measured, and the effect of the beta-silicon on the reactivity of the complex in aqueous solution was determined by HPLC. The stabilities of selected silyl complexes were compared to the carbon analogues. The cyclic complexes 2a ("silaplatin") and its Pt(IV) analogue, 2b, were very active against L1210 leukemia in vivo. Both the platinum (II) complex 2a and the platinum (IV) complex 2b produced a significant number of cures over the dose range 10-40 mg/kg. The platinum (II) complex 2a, silaplatin, was very active in vivo against an L1210 leukemia subline that was resistant to cisplatin; 2a was also active, when given ip, against ic implanted L1210. The cyclobutanedicarboxylic acid complex 3c was synthesized; this complex was active against both cisplatin sensitive and resistant L1210 leukemia but was less potent than the analogous dichloro compound 2a. The acyclic platinum (II) and platinum (IV) complexes 1a,b were synthesized and unexpectedly found to be inactive in vivo against L1210 leukemia. More lipophilic silaplatin analogues were prepared--Pt(II) complex 2c and Pt(IV) complex 2d have one additional methylene carbon compared to 2a,b, whereas Pt(II) complex 2e and Pt(IV) complex 2f have two additional methylene carbons. Cyclization of the alkyl groups attached to the silicon gave the spiro bicyclic Pt(II) complexes 10a and 11a and the Pt(IV) complexes 10b and 11b.

Dopamine D-2 receptor imaging radiopharmaceuticals: synthesis, radiolabeling, and in vitro binding of (R)-(+)- and (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N- [(1-ethyl-2-pyrrolidinyl)methyl]benzamide.

In developing central nervous system (CNS) dopamine D-2 receptor imaging agents, enantiomers, R-(+) and S-(-) isomers, of 3-[125I]iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamide, [125I]IBZM, were synthesized, and their in vitro binding characteristics were evaluated in rat striatum tissue preparation. The (S)-(-)-[125I]IBZM showed high specific dopamine D-2 receptor binding (Kd = 0.43 nM, Bmax = 0.48 pmol/mg of protein). Competition data of various ligands for IBZM binding displayed the following rank order of potency: spiperone greater than (S)-(-)-IBZM greater than (+)-butaclamol much greater than (R)-(+)-IBZM greater than (S)-(-)-BZM greater than dopamine greater than ketanserin greater than SCH23390 much greater than propanolol. The results indicate that [125I]IBZM binds specifically to the dopamine D-2-receptor with stereospecificity. The [123I]IBZM is potentially useful as an imaging agent for the investigation of dopamine D-2 receptors in humans.

In vitro and in vivo evaluation of [123I]IBZM: a potential CNS D-2 dopamine receptor imaging agent.

In vitro binding characteristics of a CNS dopamine D-2 receptor imaging agent, (S)-N-[(1-ethyl-2-pyrrolidinyl)] methyl-2-hydroxy-3-iodo-6-methoxybenzamide [( 125I]IBZM), was carried out in rats. Also brain images, as well as organ biodistribution were determined in a monkey following the administration of 123I-labeled compound. The S-(-)-I[125I]IBZM showed high specific dopamine D-2 receptor binding in rat striatum (Kd = 0.426 +/- 0.082 nM, Bmax = 480 +/- 22 fmol/mg of protein). Competition of various ligands for the IBZM binding displayed the following rank order of potency: spiperone greater than S(-)IBZM much greater than R(+)IBZM greater than or equal to S(-)BZM greater than dopamine greater than ketanserin greater than SCH-23390 much greater than propranolol, norepinephrine, serotonin. In vivo planar images of a monkey injected with [123I]IBZM demonstrated a high concentration in basal ganglia of brain. The ratios of activity in the basal ganglia to cerebellum and the cortex to cerebellum in monkey brain were 4.93 and 1.44, respectively, at 120 min postinjection. These preliminary results indicate that [123I]IBZM is a potentially promising imaging agent for the investigation of dopamine D-2 receptors in humans.