Selective Imidazoline Receptor Agonists: redefining the role of centrally acting agents in management of hypertension

Hypertension, often referred to as ‘The silent killer’, is christened so, as it is seldom preceded by any warning signs or symptoms. With the new ACC/AHA guidelines lowering the Blood Pressure (BP) threshold values, it has resulted in a 140% relative increase in the hypertension prevalence in India, which is 3 times higher than that of in United States. Imidazoline receptor agonists control BP effectively with minimal adverse effects of sedation and mental depression that are usually associated with centrally acting antihypertensives. While having a low affinity to the α2-adrenergic receptors, these new generation centrally acting antihypertensive agents are highly selective for imidazoline receptor. Moxonidine, a second-generation centrally acting antihypertensive drug having selective agonist activity on imidazoline I1 receptors and minor activity on imidazoline α2 adrenoceptors, reduces the activity of Sympathetic Nervous System (SNS) by activating I1 imidazoline receptors in Rostral Ventrolateral Medulla (RVLM). Studies of moxonidine have shown equal effectiveness in lowering BP like other well-established antihypertensive drugs such as nifedipine, atenolol or angiotensin-converting enzyme inhibitors, with minimal adverse events. At doses of 0.2-0.6 mg, moxonidine induces satisfactory BP reduction in patients with mild-to-moderate essential hypertension. In patients with mild-to-moderate hypertension, moxonidine (0.2-0.4 mg o.d.) significantly decreased Systolic Blood Pressure/Diastolic Blood Pressure (SBP/DBP), respectively, by 19.5/11.6 mmHg. In obese, non-controlled hypertensive patients, there is a 14% and 13.5% reduction in the mean SBP and DBP, respectively, from the baseline value after moxonidine treatment and during the follow-up with an additional reduction in body weight, plasma leptin levels and Body Mass Index (BMI) (p<0.01). Thus, moxonidine could be considered as a therapeutic option in obese patients with metabolic syndrome.

Cutaneous T-cell lymphomas and their management strategies.

Cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of lymphoproliferative disorders characterized by the proliferation of skin-homing post-thymic T-cells. It is the second most common extranodal non-Hodgekin's lymphoma. Many variants of mycosis fungoides and CTCLs are known to date, differing in clinical, histological, and immunophenotypic characteristics. Oral involvement has also been reported rarely in CTCLs. Treatment depends on the disease stage or the type of variant. New insights into the disease and the number of emerging novel therapeutic options have made it an interesting area for dermatologists and medical oncologists.

Study to assess the pathophysiological role of VEGF in patients with chronic myeloid leukemia(CML) .

Background: VEGF play a significant role in the pathogenesis of chronic myeloid leukemia. Aims & Objective: (1) Assess the pathophysiological role of VEGF in patients with chronic myeloid leukemia (CML). (2) Study the effect of Hydroxyurea and Imatinib on serum VEGF level. Material and Methods: A total of 40 cases of chronic myeloid leukemia (CML) and 20 age and sex matched healthy controls were included in this study. The patients were divided into 3 subcategories: Untreated cases (which did not receive any treatment); patients who were treated with Hydroxyurea and patients who were treated with Imatinib Mesylate. 5 ml of blood was collected, were centrifuged at 5000 rpm for 10 minutes and stored at - 20°C until assay. Results: On comparing the various subgroups with control, the value was 726.61 ± 199.67 pg/ml in untreated group. It was 573.53 ± 213.423 pg/ml in Hydroxyurea group and 530.00±180.96 pg/ml in Imatinib group. Fresh cases had significantly elevated VEGF value (P value < 0.001). VEGF level significantly elevated in Untreated cases when compared to treated groups either hydroxyurea (p=0.02) or Imatinib (p=0.019). There was no significant difference between Hydroxyurea and Imatinib groups. Conclusion: This study suggests that VEGF play a significant role in the pathogenesis of chronic myeloid leukemia. Understanding this may help in designing new therapeutic strategies (antiangiogenic agents) for this dreaded disease.

Acanthamoebae presenting as primary meningoencephalitis in AIDS.

A rare case of Acanthamoebae meningoencephalitis is diagnosed in cerebrospinal fluid (CSF) of a 24 years old male suffering from acquired immunodeficiency syndrome (AIDS) patient on the basis of bright field microscopy and culture growth on non-nutrient agar with Escherichia coli. This case illustrates that Acanthamoebae should be considered in the differential diagnosis of meningoencephalitis in AIDS in addition to tuberculosis and cryptococcus infection in tropical areas.

Primary amyloidosis presenting with predominant lymphnodal masses.

A 50 year young farmer presented with clinical features of bilateral carpal tunnel syndrome and generalized lymphadenopathy including paratracheal and retroperitoneal lymphodes. The histological diagnosis confirmed primary amyloidosis of lymphnodes. Presentation of primary amyloidosis as lymphnodal mass with deposition of amyloid in carpal tunnel is extremely rare and can only be diagnosed by histochemistry. The clinical response to drugs is variable and needs surgical intervention for decompressive therapy which can improve the symptoms of carpal tunnel syndrome.

Efficacy & tolerability of ondansetron compared to metoclopramide in dose dependent cisplatin-induced delayed emesis.

BACKGROUND & OBJECTIVES: Delayed emesis with cisplatin is a significant problem, which is often poorly controlled with conventional antiemetics. There is a relative paucity of data on the control of delayed emesis and rather inconsistent results have been reported. The present study aimed to compare the efficacy and tolerability of ondansetron versus metoclopramide in dose related grades of cisplatin-induced delayed emesis. METHODS: A total of 80 chemotherapy naive patients with malignancy were randomized to receive cisplatin 60 mg/m2 intravenously (iv) either as a single dose on day 1 (high dose regimen) or split into three doses of 20 mg/m2 each on 3 days (low dose regimen) along with bleomycin +5- fluorouracil in 40 patients each. Patients were further randomized in each cisplatin regimen to receive either 20 mg metoclopramide (20 patients) or 8 mg ondansetron (20 patients) iv 30 min prior to cisplatin administration followed by the respective antiemetic orally 8 hourly for five days after the last cisplatin administration. Ten patients receiving high dose cisplatin in each group were also given dexamethasone 8 mg iv with the primary antiemetic. The assessment period started 24 h after last cisplatin infusion and ended at midnight on day 5. RESULTS: In low dose cisplatin regimen, complete suppression of delayed emesis occurred in 55 per cent patients receiving ondansetron and in 30 per cent patients receiving metoclopramide. Neither ondansetron nor metoclopramide could completely suppress delayed emesis in high dose cisplatin regimen. Protection from nausea in the delayed phase was seen in 85 per cent patients receiving ondansetron and in 70 per cent patients receiving metoclopramide in low dose regimen, while nausea protection rates were 70 vs 0 per cent respectively in the high dose regimen. Addition of dexamethasone to metoclopramide significantly augmented its antiemetic efficacy (P<0.02) and the combination of metoclopramide + dexamethasone was found to be as efficacious as ondansetron monotherapy. Twenty out of 80 patients reported 39 adverse events of mild intensity. No significant effects on QOL (quality of life) parameters were observed in any group over the 5-day period. INTERPRETATION & CONCLUSION: The results demonstrate that delayed emesis due to cisplatin is also dose related, and superior antiemetic efficacy of ondansetron compared to metoclopramide is maintained, though its superiority is less marked than against acute emesis. Metoclopramide and dexamethasone combination matched the antiemetic efficacy of ondansetron monotherapy.

Spectrum of renal disease in malaria.

Between January 2000 and December 2001, renal involvement in 81 cases of malaria was studied. Their age ranged between 05 and 66 (mean 35.5) years. Distribution of malarial parasite was P falciparum (75), mixed infection (4) and P vivax (2). The evidence of clinical renal disease in the form of acute renal failure, electrolyte abnormality, abnormal urinary sediment and increased urinary protein excretion (>500 mg/24 hours) was found in 100%, 91.3%, 46.9% and 18.5% respectively. Probable aetiopathogenesis of acute renal failure (ARF) was multifactorial. Volume depletion (72.8%) was the dominant cause of ARF in these patients. In addition, hyperbilirubinaemia, intravascular haemolysis and sepsis were responsible for ARF in 64.2%, 70.3% and 25.9% cases respectively. All the patients were managed with anti-malarial drugs and dialysis support was needed in 35 patients (43.2%). Prognosis of malarial acute renal failure is favourable with mortality rate of 18.5%. Multi-organ failure was the commonest cause (33.3%) of death.

Evaluation of efficacy and tolerability of Losartan and Ramipril combination in the management of hypertensive patients with associated diabetes mellitus in India (LORD Trial).

AIM: The study was conducted to evaluate efficacy and tolerability of fixed dose combination (FDC) of Losartan and Ramipril in the management of mild to moderate hypertensive Native Asian Indian patients with associated diabetes mellitus. The secondary objective was to evaluate the efficacy of the combination in reducing microalbuminuria. MATERIAL AND METHODS: The study was an open, non-comparative, multicentric clinical trial conducted in seven Indian centres in 315 eligible patients. All the patients were treated with Losartan 50 mg + Ramipril 2.5 mg or Losartan 50 mg + Ramipril 5 mg once a day in 12 weeks and consisted of a total of eight visits. RESULTS: The mean age of patients was 52.93 years (range 45 - 60 years). Of the total patients, 62.86% were males and 37.14% were females. The mean prestudy systolic blood pressure was 160.56 +/- 14.44 which was significantly reduced to 126.85 +/- 9.78 at the end of 12 weeks (P < 0.001). Similarly the mean diastolic blood pressure was 98.91 +/- 8.33 at baseline (stage I) which was significantly reduced to 79.82 +/- 5.42 at the end of 12 weeks (P < 0.001). A mean fall of 33.72 mmHg in systolic blood pressure and the mean fall of 19.10 mmHg was observed in systolic and diastolic blood pressure respectively at the end of the treatment which was statistically highly significant (P < 0.001). The JNC-VII goal of blood pressure < 130/80 was achieved in 79.05% patients after the treatment which losartan and ramipril combination only. Microalbuminuria (urinary albumin excretion > 30 but < 300 mg/day) was seen in 83/250 (33.2%) patients and 135 (54%) patients had clinical proteinuria (albuminuria) at baseline. At the end of the therapy 20.8% patients achieved normoalbuminuria. Good to excellent efficacy response was reported in 98.09% patients and 98.41% patients reported good to excellent tolerability to the treatment. CONCLUSION: The fixed dose combination of Losartan and Ramipril showed good to excellent efficacy response in 98.10% patients and achieved a target blood pressure of 130/80 mmHg in 79.05% patients in 12 weeks. The combination reduced the urinary albumin excretion in majority of the patients with microalbuminuria and proteinuria (the major marker of nephropathy).

Comparison of ondansetron with metoclopramide in prevention of acute emesis associated with low dose & high dose cisplatin chemotherapy.

BACKGROUND & OBJECTIVES: Nausea and vomiting remain the most distressing side effects of cancer chemotherapy. The present study aimed to study the efficacy and tolerability of ondansetron versus (vs) metoclopramide in different dose related grades of cisplatin induced acute emesis. METHODS: A total of 137 patients were enrolled and 80 completed the study. Cisplatin 60 mg/m2 was given intravenously (iv) either as a single dose on day 1 (high dose regimen) or in three doses of 20 mg/m2 each on days 1-3 (low dose regimen) along with bleomycin +5-flurouracil in 40 patients each. Patients were randomized in each cisplatin regimen to receive either 20 mg metoclopramide (20 patients) or 8 mg ondansetron (20 patients) iv 30 min prior to cisplatin administration followed by 20 mg metoclopramide or 8 mg ondansetron orally 8 h respectively for 24 h after the last cisplatin administration. Ten patients receiving high dose cisplatin in each group were also given dexamethasone 8 mg iv with the primary antiemetic. Patients were assessed for 24 h after the last cisplatin injection. RESULTS: In low dose cisplatin regimen, complete suppression of acute emesis occurred in 65 per cent patients receiving ondansetron versus 30 per cent receiving metoclopramide, while in high dose regimen, complete response rate was 20 per cent with ondansetron versus 0 per cent with metoclopramide. Dexamethasone significantly augmented the antiemetic efficacy of metoclopramide but not that of ondansetron. Protection from nausea in the acute phase was seen in 95 per cent patients receiving ondansetron vs 70 per cent receiving metoclopramide in low dose regimen. With high dose the protection rates were 90 vs 0 per cent respectively. Combination of dexamethasone + metoclopramide achieved 70 per cent protection while dexamethasone + ondansetron was effective in 90 per cent. Dropouts and withdrawals were more among patients receiving high dose cisplatin and antiemetic regimens without dexamethasone. Thirty nine adverse events were reported by 20 out of 80 patients. All adverse events were mild. INTERPRETATION & CONCLUSION: The results demonstrate dose related emetogenicity of cisplatin and superior antiemetic efficacy of ondansetron, especially against high dose cisplatin regimen. Dexamethasone potentiated efficacy of metoclopramide but not that of ondansetron. The combination of metoclopramide plus dexamethasone was found to be as efficacious as ondansetron monotherapy.

Role of kidney in hypertension.

Renin angiotensin system in the genesis of hypertension was established long after Goldblatt's belief that the minute capillaries of the kidney regulate blood pressure and he also suggested kidney released a pressure substance which lead to rise of blood pressure. Guyton provided experimental and analytical data supporting the role of renal pressure natriuresis in the regulation of normal circulation and its function resulting in the pathogenesis of hypertension. Hady and Overbeck proposed that the blood pressure of volume expanded hypertension was raised by a circulating inhibitor of the Na+/K+ ATPase pump. Brenner et al proposed that hypertension may arise from a congenital reduction in the number of nephrons or in the filtration surface area per glomerulus, thereby limiting ability to excrete sodium, raising blood pressure. Renin angiotensin system can be interrupted at four sites by adrenergic blocker, renin inhibitor, angiotensin converting enzyme inhibitor and angiotensin receptor blocker. Non-modulation in the face of relatively high dietary sodium could explain the pathogenesis of sodium sensitive hypertension and provide a more targeted, rational therapy for its correction.

Correlation of serum and salivary carbamazepine concentration in epileptic patients: implications for therapeutic drug monitoring.

Therapeutic drug monitoring (TDM) of carbamazepine (CBZ) in saliva is an attractive alternative, because its collection is painless, non-invasive and simpler than drawing blood. Salivary drug levels, also closely reflect the free drug concentration. The aim of the study was to evaluate the suitability of saliva in routine TDM of CBZ in adult epileptic patients. Blood and saliva samples were taken simultaneously at 0 hours and 24 hours of CBZ dosing from 31 epileptic patients, receiving CBZ monotherapy for three or more months. Levels of CBZ in both these fluids were measured by high performance liquid chromatography. Strong and highly significant correlation was found between serum and salivary CBZ concentration (r = 0.659, p<0.001). Estimation of CBZ level in saliva is thus a practicable, valid and convenient method of TDM in epileptic patients.

An experimental study of some indigenous drugs with special reference to hydraulic permeability.

The effect of commonly used indigenous drugs for hepatic disorders i.e. Tinospora cordifolia, (Guduchi/Amrita), Andrographis paniculata (Kalmegha), Picrorhiza kurroa (Kutki), Phyllantnus niruri (Bhoomyamalaki) and Berberis aristata (Daruharidra) was tested on the hydraulic permeability of water in the presence of bile salt through a transport cell model. The data on hydraulic permeability were calculated as t (time). JV = Lp x AP, where Lp = hydraulic conductivity and AP is the pressure difference. It was observed that the value of controlled hydraulic permeability (0.49 x 10(-8) M3 S(-1) N(-1)) decreased in the presence of indigenous drugs and bile salt. The results suggest that these drugs might have the cell membrane stabilizing property which may lead to prevention of the toxic effect of bile salts in various hepatic disorders.

Association of drug levels & pharmacokinetics of carbamazepine with seizure control.

BACKGROUND & OBJECTIVES: A sizeable number of epilepsy patients remain uncontrolled with carbamazepine (CBZ) monotherapy. While the therapeutic plasma concentration range of CBZ is only vaguely defined, pharmacokinetic differences in the disposition of CBZ among subjects could be responsible for the inadequate control of seizures in some. This study was aimed at associating serum CBZ levels with seizure control and elucidating any pharmacokinetic differences between patients with controlled and uncontrolled epilepsy. METHODS: The study was conducted in 16 controlled and 15 uncontrolled adult epileptic patients receiving CBZ monotherapy for the previous 3 or more months, without any dosage change. Blood samples were drawn from the patients before and 0.5, 1, 2, 3, 4, 8, 12 and 24 h after ingestion of their total daily dose of CBZ. Serum CBZ levels were measured by HPLC and the pharmacokinetic parameters were calculated. RESULTS: The uncontrolled epileptic patients were receiving a higher daily dose of CBZ (difference not significant). The trough and peak serum CBZ levels were relatively higher in the uncontrolled group, and at no time point were the drug levels lower in these patients compared to the controlled group. The absorption kinetics, volume of distribution and plasma half life of CBZ were similar in the two groups. Thus, non-attainment or non-maintenance of therapeutic CBZ level or other pharmacokinetic difference was not responsible for occurrence of seizures in the uncontrolled patients. A high percentage of patients with generalised tonic clonic seizures (73%) and simple partial seizures (SPS) with generalisation (66%) were controlled by CBZ, while SPS and complex partial seizures (CPS) were largely uncontrolled. INTERPRETATION & CONCLUSIONS: It appears that pharmacodynamic resistance of the seizure to CBZ rather than pharmacokinetic factors is responsible for lack of efficacy of CBZ in nonresponding epileptic patients.

Assessment of carbonic anhydrase activity in blood by alteration in pH.

Carbonic anhydrase enzyme activity could be measured by manometeric and colorimetric techniques. A simpler and modified method of carbonic anhydrase enzyme activity assessment in blood is proposed. In the present method differences in pH by hydration of CO2 in absence and presence of carbonic anhydrase inhibitor have been used to measure the carbonic anhydrase activity in the blood.

Renal cortical necrosis in pregnancy-related acute renal failure.

Of 63 patients of obstetrical acute renal failure, 15 cases (23.8%) had biopsy proven bilateral renal cortical necrosis. Remaining 48 patients (76.2%) had acute tubular necrosis. Eight of 39 cases in early pregnancy had cortical necrosis (postabortum) and 7 of 24 patients in late pregnancy revealed cortical necrosis. Diffuse and patchy cortical necroses were seen in 12 and 3 patients respectively. The incidence of cortical necrosis was almost equal in both early as well as late pregnancies. The high incidence (20.5%) of cortical necrosis following septic abortion remains the interesting feature of the present study in contrast to very low incidence (1.5%) of cortical necrosis in postabortum group in developed countries. The death occurred in most patients (14 ie, 93.3%) of cortical necrosis because of uraemic complications and sepsis.

Complications of percutaneous renal biopsy.

Three hundred twenty renal biopsies were done in 305 patients over a period of 5 years. Adequate tissue for pathologic diagnosis was obtained in about 79% of biopsy attempts. The overall morbidity of procedure was 6.8%. Haematuria in 11.8% cases was the commonest complication. Haematuria resolved spontaneously in 63.8% of patients within 4-12 hours. Hypotension due to blood loss occurred in 3 patients (0.98%) who required blood transfusion. Five patients (1.6%) developed perirenal haematoma. Urinary retention requiring single catheterisation was seen in 12 cases (3.9%). Perirenal abscess occurred in one case. Minor complications improving with symptomatic medication included vomiting, abdominal pain and vasovagal attack in 3.6%, 2.6% and 1.6% cases respectively.

Curative efficacy of norfloxacin in falciparum malaria.

Fifteen patients of uncomplicated falciparum malaria from Delhi were treated with norfloxacin (10 with 400 mg, 5 with 800 mg, both twice daily) for 3 days and the response was measured according to the WHO extended in vivo test criteria. The lower dose produced S response in two, RII response in five and RIII response in three patients, while the higher dose produced S response in four and RI response in one patient. In patients with S or RI response, the parasite clearance time was 68.6 +/- 9.1 h the defervescence time being 48 h. Thus, norfloxacin did reveal in vivo activity in falciparum malaria, but a dose of 400 mg twice daily proved to be curative only in a small percentage of cases and not consistently. Nausea and bitter taste were the only side effects noted in two patients.