1. INTRODUCTION:

Nanotechnology-based antihypertensive treatment has not been investigated in patients with uncontrolled hypertension,

i.e., those with systolic blood pressure (SBP) ≥ 140 or diastolic blood pressure (DBP) ≥ 90 at baseline without any medications. One of the reasons behind the lack of nanotechnology-based research in these patients is that, despite decades of investigations, including genetics and epigenetic studies, the exact origins of human hypertension remain unclear. The treatments for uncontrolled hypertension of many patients are unsatisfactory, and the cost of the medical care for these patients is significantly higher than that for hypertensive patients with acceptable blood pressure (SBP < 140 and DBP<90).^1-5. Hypertension may develop without underlying causes (primary-essential hypertension) or with elevated blood pressure caused by different organic or functional diseases, classified by the World Health Organization (WHO) as secondary hypertension. Nowadays, we are far from deciphering the etiology and major pathogenic mechanisms of essential hypertension. In recent years, many research has confirmed the fact that the use of ACE inhibitors contributes to managing essential hypertension more profoundly compared to the effect of diuretics. Treatment with the centrally acting alpha2-adrenergic receptor agonists results in a significant reduction in the activity of the central sympathetic nervous system in essential hypertension. Administering diazoxide to patients with inoperable pheochromocytoma contributes to the normalization of blood pressure values without the use of significant blockers of adrenergic receptors. It can be suggested that in the treatment of essential hypertension, the best and most sustainable effect on blood pressure values can be achieved by increasing the inhibiting impact on the adrenergic neurons by using drugs acting on them or reducing their activity. These facts lay the ground for the reasoning of our assumptions and the development of the present research^6-10.

It should be noted that adrenergic innervation significantly contributes to the regulation of blood pressure values. In addition to its significant role in essential hypertension, its activity is intensified, contributing to the development of cerebrovascular diseases, hyperlipidemia, obesity, diabetes mellitus, as well as acute and chronic heart failure and chronic nephritis. These data allow laying forth the assumptions that the increase of sodium blood in the kidneys caused by the adrenal nerves hyperactivity under the conditions of NaCl-loading may contribute to the development of hypertension. It is suggested that in this case, an optimal measure for the hypertension treatment would rely on both the use of diuretics that effectively remove sodium and reducing the activity of the adrenergic neurons. A comprehensive approach to such patients requires our assessment of the possible implications of the drugs reducing adrenergic stimulations - to what extent they are able to compensate for the hypotensive lack of control, and tolerance to such drugs. The issue of reliable control of the BP deserves wide research of the prescription of the adrenergic neurons inhibitors in the dose sufficient for suppressing the hyperactivation allowed for by the numerous compensatory responses to the depletion of norepinephrine. It is a common fact that reducing the influence of adrenergic drive on the cardiovascular system produces serious "counteraction" to an increased vascular tone and volemic milieu. The discovery of a clear antihypertensive potential in the property of receptors of the carotid sinus baroreceptors' potential capability of producing the effect of BR, in its part, was the ground for developing stimulating devices and their clinical application. Treatment of such patients with the help of the BR stent in a sleeve shape is a procedure with high efficacy evidenced from a double-blind research and reduced rate of complicacy conditioned by failure of the identification of the role of the relevant sympathetic regulatory structures^10,11.

Treatment of patients with uncontrolled arterial hypertension is an urgent issue, just like the identification of a reliable guidance for managing these patients. Adequate blood pressure (BP) control is vitally important for patients with hypertension, and those patients' quality of life largely depends not only on the level of the BP, but also on any comorbid pathologies available. Sedative drugs and even a limited area of surgical procedures are the tools we use less frequently in patients left without control of their BP. At the same time, why not using neurodestruction giving our knowledge of the pathogenesis of essential hypertension (EH)^12-15.

However, it is very probable that, as in any other chronic disease, primary hypertension is multifactorial and polyetiological in character, with the development of permanent and unstable pathogenetic constructions due to the influence of many integral factors. It is essential that the search for causes of essential hypertension be made in the framework of anonymous, blind, strictly monitored, longitudinal monitoring of the state of integrated defense and adaptive mechanisms^16-20.

The primary etiological factor in essential generalized (systemic) hypertension is the increased impact of local vasoconstrictor systems, the adrenergic neurons, and endothelial (tissue hormone), manifested in disorders in the functioning of the links of physiological regulation of cardiovascular functions. The choice of treatment depends on the degree and stage of the disease, the urgency of the risk factors (complications), and failure of the regulatory-reparative mechanisms of the defensive and adaptive systems. These particularities accompany the characteristic reduction in the sick patient correction of the hypotensive therapy. Accordingly, personalized therapy of hypertensive patients should be subjected to the development and recommendation of certain tactics of balancing therapy, taking into account the comprehensive form of the disease. In this case, it is appropriate to develop and apply functional, first functional-metabolic, criteria for balancing the integrated correction of therapy (ICT) of essential hypertension^21,22.

1.2. Nanotechnology in Medicine:

The limitations of current pharmacological management options suggest the need for new and more effective therapeutic avenues. A new technology that allows precise and controllable inhibition of the sympathetic neurons located upstream of the stellate ganglion has been developed and evaluated in three animal models, and adrenergic neurotransmission and blood pressure have also been evaluated. Based on these preliminary data, the translation of the target vascular control reported to human subjects with uncontrolled hypertension has been performed. The scientific hypothesis is mainly to determine the safety of sympathetic neurons' regulation performed on patients' pectoralis before implanting a permanent stimulator. There is also a broader scientific hypothesis that the sympathetic neurons' inhibition technique can be rapidly translated in patients with uncontrolled hypertension, hold a good safety profile and improve blood pressure control^24,25.

The structures of nanosized small molecules, nanoparticles, and nanocomposites infused with metallic and nonmetallic elements lead to manipulatable behaviors that enable their use in the guided repair and improvement of patients with nerve disorders such as migraine condition, diabetes, kidney disease, hypertension, and controlled drug release. The engineered ion channels in the case of pain and arrhythmia have the capacity to influence muscle mechanical function, extend the longevity, and, most important of all, plug determined molecular signaling pathways that manage chronic diseases. Given the diversity of the chemical and physical properties that originate from the properties exhibited by small molecules and the various nanoparticles and nanocomposites presented in the following sections, we highlight here the importance of ion and molecular transport due to selective permeability and the change in mechanical properties. For therapeutic applications of nanomedicine in the form of either CNTs or fullerenes, the use of beneficial/benign chaperon-like molecules is considerable for ensuring the activity of various anion and cation channels in excitable cells, increasing the nanomedicine opportunities for both compact and elongated nanocomposites^26,27.

1.3. Research Objectives:

In the world, about 5% of patients admitted to hospital are treated for hypertensive crisis, which is more often associated with a hypertensive crisis in the form of a neurological deficit. For the complex treatment of RRD, adrenergic blockers of sympathomimetic nervous system activity are used. Adrenergic neurons control the function of almost all systems of our body. The effectiveness of signal transmission induces alpha-1-adrenergic, among other things are located on the smooth muscles of blood vessels, which ensures their tone, blood pressure and determines the intensity of the blood flow. Artectics selectively inhibit and block this type of receptor. The selective blocking of alpha-1-adrenergic is one of the principles of action of blood pressure regulators called adrenergic that selectively affect alpha-1-adrenergic. With a blocking action, artectics further regulate alpha-2-adrenergic receptors, which are fewer in number, contributing to the lowering of blood pressure as a whole^28-30.

One of the methods is to inhibit or activate adrenergic mechanisms of regulation, which makes it possible to give a differentiated assessment of the degree of the regulatory role of these mechanisms. Adrenergic blockers are currently among the most universally used groups of antihypertensive drugs. In addition to blocking the excitation effect of catecholamines on alpha receptors in peripheral blood vessels, alpha-adrenergic blockers weaken adrenergic constriction of the smooth muscle layer of the urethra, which is the basis for their use in the treatment of benign prostatic hyperplasia. The effect is explained by the lengthening of the downgoing tract of the urine stream. Therefore, the entire group of alpha 1-blockers is combined into a separate group of drugs called adrenoblockers³¹.

As a result of performing a wide range of treatment and diagnostic procedures in patients with a long-term history of arterial hypertension on the background of medication therapy, it was found that patients had undiagnosed ORH, approximately 35-40%. The decrease in the level of BP in these patients in the treatment process was insufficient, despite the maximum dosage of antihypertensive drugs. In this regard, the search for novel and pathogenetically substantiated arterial pressure (AP) reducing strategies remains relevant³².

2. Physiology of Adrenergic Neurons:

From the first experiments with electrical stimulation, it has been shown that activation of the central and peripheral sites of the sympathetic nervous system, including the brain, spinal cord, and peripheral adrenergic neurons, produces intense pressor and metabolic responses. The first step of this reflex arc is the activation of the sympatho-excitatory neurons located in the medulla oblongata. Their projections descend into the intermediolateral cell columns of the spinal cord, where they form synapses with the pre-ganglionic sympathetic neurons. Their axons exit the central nervous system, traveling within the sympathetic trunks to reach the sympathetic ganglia. Here, the excitatory fibers form chemical synapses with the adrenergic neurons. These post-ganglionic neurons are smaller compared to most of the pre-ganglionic neurons but show a quite long and complex internal-external chemical and electrical organization. Indeed, the cell bodies, i.e., the central chunk of the neuron, are located inside these ganglia, while the long axon is directed toward the target organs. These post-ganglionic neurons contain an impressive amount of acetylcholine, the classical cholinergic neurotransmitter. These neurons are organized in a unique way compared to any other cholinergic neuron. The axons form many varicosities, and these release the ultra-fast acetylcholine, following the dense stimulation. The fast acetylcholine stimulates the adrenergic receptors localized in the adrenergic effector cells. These, following the slow action, increase the intracellular calcium ion concentration, responsible for the well-known final cell effects, which, starting from the heart to the microcirculation and the adipose tissue, are characteristic of the adrenergic excitation³³.

2.1. Role in Blood Pressure Regulation:

The main player in the regulation of blood pressure in response to a reduction of the circulating blood volume and, subsequently, cardiac filling, is a volume control system or, as it is often called, volume receptor system. The concept of volume receptors came into existence based on the results of the experimental studies of Winton, which have shown a tonic stimulation of efferent autonomous outflow - decrease of the pumping function of the redirected heart, inhibition of renal sympathetic activity and reflex influence on the vasomotor center in the brain after acute cardiac dilatation caused by the introduction of dye or saline into the cardiac cavities. In the presence of balanced hydrochloric hypertension, elimination of cardiac dilatation and pulmonary venous pressure in dogs has led to a significant increase of pressure in the ventricle and atrium, and gradual change in their stretches was fraught with changes of renal sympathetic activity. Stimulations resulting in immediate-parasympathectomy did not lead to changes of the sympathetic activity or renin discharge from sequestered kidneys and did not evoke any reflex responses of the cardiovascular system. Based on the data of these studies, it has been inferred that discharges are an indicator of the ability of both high-pressure and low-pressure receptors to react to the functions of the microcirculation of the left ventricle and the venous system of the great circle of blood flow^34,35.

2.2. Influence on Circadian Rhythm:

Moreover, the most positive aspect of the diurnal profile of tension under the influence of rilmenidine also occurs with the realization of a β1-adrenoceptor blockade. Nevertheless, not only the ratio of β1/β2-adrenoceptors density of the platelets is the determining factor of the circadian response, since the sensitivity of the platelet to agonists changes over the 24-hour cycle. More than a 50% increase in platelet sensitivity to epinephrine and ADP happens in the morning hours compared to night values. Circadian changes of platelets ADP-evoked secretion index are approximately similarly less than 20%. Taking into account the important role of the signal molecule adrenaline in distress-induced aggregation, it is reasonable that distress-induced lack of antihypertensive response to some preparations blocks means either changes of signal molecules secretion but at the most changes in the sensitivity of target cells, namely platelets, to these secretions^36,37.

Despite the fact that a decrease in the amplitude of the circadian tension is one of the most sensitive signs to inhibition of adrenergic neurotransmission and the high effectiveness of rilmenidine, the majority of the existing evidence is related to the loss of the antihypertensive action of rilmenidine in the evening time. However, significant deterioration in the antiaggregation properties of rilmenidine after the withdrawal of the evening dose was found only against the background of the initial high effectiveness of the drug³⁸.

3. Uncontrolled Hypertension: Definition and Complications:

More than half of patients with arterial hypertensive crises are met by emergency medical practitioners in the United States before their entrance to the hospital, and only 10% are admitted urgently. For most patients with hypertensive emergencies, it is usually enough to lower blood pressure to 160-170/100-100mm Hg during the first hour of treatment, and then to achieve a supplementary 25% drop in pressure over the next 6 hours. These goals are very difficult to achieve with the isolated use of oral agents, remembering that often in palliative patients, their oral intake is not feasible. It should be remembered that aortic dissection, which manifests as a sudden or severe onset of pain, tearing backache, chest or abdominal pain, and dyspnea, may be superimposed on an uncontrolled hypertensive emergency. In these patients, the reduction of pain and arterial pressure is urgent and sometimes only at the entrance. Normal control can be established later after the immediate treatment of complaints and hypertension³⁹.

Among patients suffering from arterial hypertension at large, there is a considerable group with uncontrolled hypertension. Despite the sufficient amount of antihypertensive drugs currently accessible on the domestic market, achieving controlled values of blood pressure by means of outpatient antihypertensive medication in Universal State Health Services is reached in no more than 30%. The constant taking of the most value of different classes of antihypertensive drugs in combination with lifestyle modification does not allow for the achievement of target levels of blood pressure [hypertension control according to the diagnosis and treatment of adult patients]. 15-20% of all hypertensive patients may develop an extreme rise in blood pressure, defined by crisis or hypertensive crisis. In this clinical situation, the decrease in blood pressure in the acute period requires not only a quick determination of the type of crisis but also the right time and direction of effective antihypertensive therapy. Often, the crisis type remains undetected, so diagnosis and choice of therapy among such patients is inadequate⁴⁰.

4. Clinical Trials and Studies:

Nanotechnology-enhanced adrenergic neuron inhibition is a novel strategy that has the potential to overcome several limitations of currently available anti-hypertensive medications. In addition, the targeted NM particle represents a new anti-hypertensive molecule with considerable potential due to its ability to rapidly and non-invasively inhibit the activity of adrenergic neurons. Moreover, the targeted NM particle is the first adrenergic-neuron-inhibiting drug that does not lower productivity or result in hypotension through neovascularization. Currently, there is no limitation in delivering the drug to the targeted lesion because the external magnet can operate at a clinically reasonable distance. Furthermore, the study maintains the subject's privacy and may include patients receiving other recommended anti-hypertensive medications. Documenting the efficacy of the targeted NM particle in patients with uncontrolled resistant hypertension may support clinical application of this novel nanomedicine^41-44.

Currently, there are commercial carotid sinus leads that are used for patients with uncontrolled hypertension and take up long-term healthcare resources. However, the issues related to surgery and wireless transmission and electricity supply limitation should be addressed before the carotid sinus lead can be introduced into a clinical environment. In summary, this potential trial has many medical benefits. Uncontrolled hypertension is an important issue in clinical practice. In recent years, many clinical guidelines have recommended carotid body removal and carotid sinus renal denervation for managing resistant hypertension. These invasive strategies may also affect breathing. Currently, there are commercial carotid sinus leads that are used for patients with uncontrolled hypertension and take up a large amount of long-term healthcare resources⁴⁵.

4.1. Pharmacological Interventions:

The comparison group of 9 patients continued an ineffective antihypertensive therapy unchanged during the 7-day hospital stay. Highly elevating sympathetic activity (hyperactivity of post-junctional adrenergic receptors), RAS activation, and reduced endothelial and resistance arterial function are the main pathophysiological mechanisms of uncontrolled hypertension. Hence, the evaluation of the adrenergic innervation (sympathetic activity) in patients with uncontrolled hypertension should be the main and primary marker of antihypertensive therapy to confirm or refute the presence of sympathetically driven hypertension. The actions of the adrenergic innervation and connected mechanisms (activation of cardiovascular receptors) in patients with stage 2 hypertension (average BP 157.13±2.24/98.25±0.92mmHg) confirm the fact that it is possible to get 100% inhibition of the located adrenergic receptors⁴⁶.

The experimental group of patients with uncontrolled hypertension (greatly elevated daytime DBP from 130 to 150mmHg) admitted to the hospital, average 133.3±2.2 mmHg, was divided into 2 parts: 9 patients in the 1st subgroup and 10 in the 2nd subgroup. The 1st subgroup received daily 8mg of the ARB olmesartan as monotherapy. On the 7th day, the daily dose of the ARB was increased to the maximum—40mg as monotherapy. The 2nd subgroup received 8mg of the ARB losartan as monotherapy on day 1. From the 2nd to 7th days, olmesartan was replaced by the α1-blocker doxazosin with a follow-up of increasing the dose to achieve a maximal daily therapeutic dose (value for carefully monitoring the use of the α1-blocker doxazosin, 50 mg)⁴⁷.

4.2. Non-Pharmacological Interventions:

Head cooling or cooling of the glabrous skin of the palm has the experimental background. Coolness receptors are sensitive to a significant change in temperature that lasts for no more than 1–2 s. However, long-term cooling or bathing in cool water increases the activity of the sympathetic system and renin-angiotensin-aldosterone system. Recently, a hypothermic nervus vagus blockage/inhibition technique was proposed and received the name "the low-temperature vagus". The authors cooled the vagus nerve to 20°C using a special device in patients undergoing respiratory interventions and assessed regional sympathetic activity. The authors used high-frequency heart rate variability, which accurately reflects vagal/muscarine activity on the heart, with an exclusive vagal origin and no significant alteration to afferent pathways⁴⁸.

An important area and perspective of the study is non-pharmacological methods of modulating the WPNS. Drugs restoring the reactivity of the WPNS are subdivided into several classes and among them, the use of baroreflex modulation is considered the most scientifically grounded and physiological. The most popular technique is based on electrical signals delivery into the wall of the carotid sinus and involves the device implantation to prevent failure of treatment effect. Acupuncture, vibration, and other physical effects on the carotid sinus are considered to have a similar effect when conducted cautiously. The technique modulating afferent activity in the carotid body has been proposed and is of interest. In the case of rhinitis, instillations of hypertonic saline into the nose provide moderate and safe therapy⁴⁹.

5. Surgical and Therapeutic Approaches Targeting Adrenergic Neurons:

The most used techniques to treat uncontrolled hypertension currently are: central endovascular baroreceptor stimulation, baroreceptor stimulation in the carotid sinus, surgical carotid body excision, and non-pharmacological renal denervation. Posteriorly, the result was not optimal for three reasons: in the first place, the cervical approach is associated with a higher perioperative risk if compared with less invasive through the femoral access; secondly, few patients may experience dizziness and other symptoms correlated to carotid sinus stimulation due to baroceptrophic, and finally, the carotid bifurcation anatomy has templates almost unique in each patient, determining the surgical technique possible variability and therefore the result. The variety of the baroreceptors stimulated made the differences between patients evident for clinical response and the reductions in average and systolic blood pressure were not as satisfactory, both in randomized controlled trials and uncertain data of the possible development of barotrauma at the baroreceptor level which could lead to a delay and regression of the positive effects⁵⁰.

The goal of adrenergic neuron surgical denervation was to mitigate the compensatory effect of a failed BP lower pathway and thus achieve drug-naïve BP reduction. The first sympathectomies were proposed more than a century ago, with the improvement of Raynaud’s syndrome associated with local sympathectomy. The first thoracic sympathectomies have been performed in the 20th century by Stein, Leriche, and Paeole in different experiences and therapeutic indications. Nevertheless, it is with the use of modern surgical techniques for aorto-arterial surgery and the spread of renal artery angiography in hypertensive patients that sympathetic surgical ablation has assumed real success. In fact, lumbar block-approach techniques and retroperitoneal surgery to access the lateral vertebral ganglia were developed specifically to remove the sympathetic terminals from the kidney. The strengths of these procedures lie in the majority who do not respond to pharmacological therapy and thus have particularly high blood pressure, committed to consuming poly-pharmacological treatments that are often poorly tolerated and induce side effects, sometimes not indifferent^51-55.

6. Case Studies and Clinical Evidence:

High resistance index and low RR-SDB (due to increased pulse rate in a dream) and poor insulin resistance due to local hyperinsulinemia and pre-syaptogenesis of insulin-neopertrophic sympathetic activation. The revealed links of the compensatory role of adrenergic activation in the questioned patient indicate the desirability of careful economic evaluation of alpha-1-blockers against beta-blockers in this cohort of patients, for which the greater effectiveness of the former in IR can be anticipated due to the presence of a significant number of alpha and beta receptors in insulin-sensitive tissues and the surplus of norepinephrine⁵⁶.

The addition of alpha-1-adrenoblockers to existing therapy in patients with uncontrolled hypertension had a positive impact on clinical parameters and was particularly effective at elevated activity of aldosterone. It proved to decrease the frequency of heart rhythm, reduce serum aldosteronemia, cortisolemia, and insulin levels, and increase glomerular filtration rate in the qualification⁵⁷.

Examinations were performed before the start of alpha-blockade and 2 weeks after the onset of the treatment, in the morning prior to any medication intake. Clinical isotope renographic examination was carried out, aldosterone/renin activity in serum was determined, insulin resistance was evaluated, and long-term blood pressure monitoring was performed⁵⁸.

Five patients with uncontrolled hypertension (H) and metabolic syndrome, previously treated by beta-blockers and/or calcium channel blockers, were enrolled for the study. Umecrine Cognition's CRH1 antagonist was tested for the patients. The medication was administered in titrated doses and increased to 0.3 mg/day. It was prescribed in addition to existing therapy^59-61.

Future Directions and Emerging Technologies:

Emerging evidence suggests that carotid afferent denervation has an important role in renal denervation responses. Disconnection of the electrical connections between the afferents and efferents of a reflex that depends on the existence of an intact neuronal arc can achieve significant sympathetic inhibition. This recent evidence suggests another mechanism by which the interventional approach may be exploited to reduce hypertension. For this purpose, different intra-arterial denervation devices are being developed. Currently, baroreflex activation device (BAROSTIM NEO™) is successfully used in specialized centers for both heart failure and uncontrolled hypertension. The cardiac resynchronization in combination with baro-reflex activation therapy in heart failure (CARE-HF) trial demonstrated a 34% relative (absolute: 10% at 3-year follow-up) improvement in the risk of mortality and serious heart failure-related events when compared to patients treated with optimized GDMT⁶².

CONCLUSION AND IMPLICATIONS FOR CLINICAL PRACTICE:

Since the 12th month, the use of the comprehensive therapy resulted in a significant decrease in the daily level of A-NS, which correlated with a decrease in CABG necessity in isolated and combined operations. It was shown that the effectiveness of RDN in struggling the daily AHD level reduction is a secondary result of the interventions aimed at correcting the hormonal sympathy links, as well as at the restoration of sonodynamic reactivity of adrenergic neurons. The presented results are probably due to the selection of specific pharmacologic patients to demonstrate the degree and the duration of adrenergic neurons inhibition under conditions of the withdrawal of the B-sympathomimetic regime. The focus of research on this direction will contribute to our understanding of the relationship between the central neurohormones and hemodynamics/metabolism. These results provide an additional argument in favor of the use of two-level complex therapy in the elderly to reduce the sympathetic mechanisms of AHD. The efficiency of the observed treatments is studied in dynamics and after 6 months. The patients of the main group had pronouncedly high levels of ambulatory (A)BP, particularly daily night hypertension due to the increased activity of thoracic-adrenal region of sympathetic innervation. The application of the comprehensive therapy helped to correct AHD, metabolic disturbances, cardiorespiratory fitness, and achieved a significant expansion of the volume of patient self-treatment.

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30. Al-Hussaniy HA, Hassan AF, Oraibi AI, Al-Juhaishi AM, Naji FA, Al-Tameemi ZS. Clinical Pharmacogenetics of Angiotensin II Receptor Blockers in Iraq. Journal of Pharmacy and Bioallied Sciences. 2023; 15(3): 101-6.

31. Al-Hussaniy HA, Al-kuraishy AA, Jalil HJ. Evaluation of the efficacy of adrenergic neurons inhibition through various surgical and therapeutic regimens on controlling blood pressure and circadian rhythm in patients with uncontrolled hypertension. Journal of Clinical Trials and Experimental Investigations. 2022;1(3):106-13.

32. Al_hussaniy HA, Alkhafaje Z, Altamimi ZS, Oraibi AI, Abdalhassan AH, Abdulhamza HM, AL-Zobaidy MJ. Memantine and its role in parkinsonism, seizure, depression, migraine headache, and Alzheimer’s disease. Pharmacia. 2023; 70(2): 291-7.

33. Shawaludin MQA, Hussain S, Yaacob NM. Prevalence and Risk Factors for Dyslipidaemia and Hypertension in Diabetes Mellitus among Paediatric Population in Hospital Universiti Sains Malaysia (USM). Journal of Medicine and Health Sciences. 2024; 20: 66–72.

34. Elias NIM, Malaysian SM. Prevalence of Hypertension and Its Determinant Factors among Workers at Port Container Terminal Daud. Journal of Medicine and Health Sciences. 2023; 19:71–79

35. Muhammad A, Halim A, Azwal N. Ortner's Syndrome With Primary Pulmonary Hypertension-A Case Report. Malaysian Journal of Medicine and Health Sciences. 2023; 65(3): 1775–1786

36. Al-Hussaniy HA, Аlmajidi YQ, Oraibi AI, Alkarawi AН. Nanoemulsions as medicinal components in insoluble medicines. Pharmacia. 2023; 70(3): 537-47.

37. Malek M, Hosseini A, Moradi B, Rahmani M, Aghasi M, Akhavan S, Ahmadinejad N, Abdolghafoorian H. Pattern Recognition or Adnexal MR Scoring System: Which Is More Accurate in Evaluating Adnexal Lesions?. Asian Pacific Journal of Cancer Prevention. 2024; 25(4): 1265.

38. Al-hussaniy HA, Al-Shammari AH, Sameer HN, Oraibi AI. The relationship between statin therapy and adipocytokine/inflammatory mediators in dyslipidemic nondiabetic patients: A comparative study. Pharmacia. 2023; 70(3): 581-5.

39. Hussein HA, Goreal AA. SARS-CoV2 Viral Ct Values Correlation with Some Patients’ Factors and Disease Outcome. Iraqi Journal of Science. 2024; 65(3): 1230-8.

40. Al-Zwaini H, Hatem Al-Mugdadi SF, Kareem Abbas WA. Detection of FOXP-3 Expression in a Sample of Iraqi Cervical Cancer Patients Using Immunohistochemistry Technique. Iraqi Journal of Science. 2022; 63(12): 5106-5118.

41. Sheashea AA, Ahmed FA, El Zayat E, Ebeed BW, Elberry MH, Hassan ZK, Hafez MM. In Vitro Antiviral and Anticancer Effects of Tanacetum sinaicum Essential Oil on Human Cervical and Breast Cancer. Asian Pacific Journal of Cancer Prevention. 2024; 25(4): 1457.

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43. Al Haddad M, El-Mezayen HA, El-Kassas M, Metwally F, El-Sharkawy A. Clinical Utility of Cytokeratins for Accurate Diagnosis of Hepatocellular Carcinoma Among Hepatitis C Virus High-Risk Patients. Asian Pacific Journal of Cancer Prevention. 2024; 25(4): 1325.

44. Wang S, Xue Z, Su D, Ji L, Gao Y. Association between preoperative albumin and length of hospital stay in non-cardiac surgery patients with pulmonary hypertension: A secondary retrospective analysis. Medicine. 2024;103(23):e38442.

45. Al-Hussaniy HA, Al-Samydai A, Hajleh MN, Mayyas A, Oraibi AI. Selection and Progress of drugs for treating Dementia. Research Journal of Pharmacy and Technology. 2024; 17(4): 1674-8.

46. Roy LD, Kumar J, JAYS J, Krishnamurthy G, Gour P, Arland SE. Novel Resveratrol Analogues With Aromatic Hetero Moieties: Designing, One-Pot Synthesis And In Vitro Biological Evaluation. Farmacia. 2023; 71(1): 130–143

47. Tilinca Mc, Antal C, Balint A, Sălcudean A, Varga A. The Newest Therapeutically Approach Of" Diabesity" Using Glp-1 Ra Molecules: Impact Of The Oral Formulation. Farmacia. 2023; 71(1): 1–10

48. Nadiah S, Djabir Yy, Arsyad Ma, Rahmi N. The Cardioprotective Effect Of Extra Virgin Olive Oil And Virgin Coconut Oil On Isoproterenol-Induced Myocardial Infarction In Rats. FARMACIA, 2023; 71(1): 194–204.

49. Tang N, Zhou Q, Liu S, Li K, Liu Z, Zhang Q, Sun H, Peng C, Hao J, Qi C. Development and trends in research on hypertension and atrial fibrillation: A bibliometric analysis from 2003 to 2022. Medicine. 2024; 103(21): e38264.

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52. Patidar U, Patel H. A Study to assess The Effectiveness of Structured Teaching programme on Knowledge regarding prevention of stroke among Hypertensive patients in selected Hospitals of Mehsana District. Asian Journal of Nursing Education and Research. 2020; 10(1): 89-92. DOI: 10.5958/2349-2996.2020.00020.8

53. Kalaiselvi G, Savithri K. Effectiveness of Yoga therapy on mild pregnancy induced hypertension. Asian Journal of Nursing Education and Research. 2021; 11(1): 11-4. DOI: 10.5958/2349-2996.2021.00004.5

54. Mary AS, Devi SS, Devi LD. Effectiveness of structured teaching programme on knowledge regarding warning signs and prevention of stroke among hypertensive patients in selected hospitals at Bangalore. Asian Journal of Nursing Education and Research. 2022; 12(3): 313-6. DOI: 10.52711/2349-2996.2022.00065

55. Kumar S, Chavda N. A Review on Analytical Method Development and Validation for the Simultaneous Estimation of Rosuvastatin and Fimasartan in Bulk and its Pharmaceuticle Dosage Form. Asian Journal of Pharmaceutical Analysis. 2023; 13(3): 197-204. DOI: 10.52711/2231-5675.2023.00032

56. Mane AK, Chaware VJ. To assess causality, severity and preventability of adverse drug reactions of amlodipine in the treatment of hypertension. Asian Journal of Research in Chemistry. 2023; 16(1): 39-2. DOI: 10.52711/0974-4150.2023.00007

57. Kaushal Patidar, Shalini Kalal. A Study to assess the effectiveness of Video Assisted Teaching on knowledge regarding prevention of Stroke among Hypertensive Patients in selected Hospitals of Mehsana. Int. J. of Advances in Nur. Management. 2019; 7(2): 89-90. DOI: 10.5958/2454-2652.2019.00022.2

58. Al-Hussaniy HA. The effect of MicroRNA-409-3p for treatment and response to tumor proliferation of lung cancer cell lines (in vitro). Asian Pacific Journal of Cancer Prevention. 2022; 23(9): 3151-3156. DOI: 10.31557/APJCP.2022.23.9.3151.

59. Jesna Joy K, Philo Resmi, Angela Gnanadurai, Anand M. K. Effect of Video assisted teaching on knowledge and practice for prevention of Hypertensive renal diseases among patients with hypertension. Int. J. of Advances in Nur. Management. 2021; 9(2): 216-221. DOI: 10.5958/2454-2652.2021.00049.4

60. Abu Hajleh MN, AL‐Samydai A, Al‐Dujaili EA. Nano, micro particulate and cosmetic delivery systems of polylactic acid: A mini review. Journal of Cosmetic Dermatology. 2020; 19(11): 2805-11. DOI: 10.1111/jocd.13696

61. Al‐Halaseh LK, Al‐Adaileh S, Mbaideen A, Hajleh MN, Al‐Samydai A, Zakaraya ZZ, Dayyih WA. Implication of parabens in cosmetics and cosmeceuticals: Advantages and limitations. Journal of Cosmetic Dermatology. 2022; 21(8): 3265-71. DOI: 10.1111/jocd.14775

62. Samah Hammoud, Arige Boubou, Nisrin Kaddar. Antihypertensive effect of Dapagliflozin in Type II diabetic patients with Hypertension. Research Journal of Pharmacy and Technology. 2024; 17(2): 827-3. DOI: 10.52711/0974-360X.2024.00128

Received on 25.09.2022 Modified on 21.12.2023

Research J. Pharm. and Tech 2024; 17(9):4613-4620.

DOI: 10.52711/0974-360X.2024.00712