JP2000351731A - Diabetes therapeutic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a diabetes therapeutic agent. SOLUTION: (±)-2-Methoxyethyl 3-phenyl-2-(E)-propenyl 1,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)3,5-pyridinedinedicarboxylate can be used for treating diabetes, especially non-insulin dependent diabetes mellitus(NIDDM),because norepinephrine(NE)in vivo is decreased when administrated to diabetes patients.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention

Embedded image (±) -2-methoxyethyl 3-phenyl-2- (E) -propenyl 1,4-dihydro-2,6
The present invention relates to a therapeutic agent for diabetes, comprising -dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylate (hereinafter referred to as silnidipine) as an active ingredient.

[0002]

2. Description of the Related Art The number of diabetes patients in Japan is 200 to 30.
It is said to be 10,000 people. Diabetes is the cause of its development,
Broadly classified into insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM), NIDD
It has been reported that M accounts for a large proportion of diabetic patients. In NIDDM, it is considered that insulin secretion deficiency and insulin resistance in a state where insulin is hardly effective even in the presence of insulin are the causes. Among them, insulin resistance is more related to environmental factors such as obesity and stress than genetic factors, and is closely related to modern living environment. It is said that norepinephrine (hereinafter referred to as NE), which is a neurotransmitter in a living body, increases in a living body due to the addition of environmental factors, and as a result, insulin resistance increases. However, there is no other report on drugs that improve insulin resistance by suppressing NE release for a long time in drug therapy for diabetes.

[0003] In addition, it is generally known that diabetes involves various diseases called complications, and hypertension is one of them. When hypertension is combined with diabetes, there is a report that the progression rate of cardiovascular disorder and renal disorder is about 40 to 70% faster than that of diabetic patients without hypertension. Has been actively carried out.

On the other hand, cilnidipine is widely used as a therapeutic agent for hypertension having a dihydropyridine structure (Japanese Patent Publication No. 3-14307). Cilnidipine is a calcium antagonist having an effect on calcium L-type channels and calcium N-type channels, and is known to be a drug having a sustained antihypertensive effect (Jpn J Pharmaco
l 56: 225-229, 1991).

[0005]

As described above, there is no satisfactory drug for NIDDM in which insulin resistance is deeply involved, and at present the appearance of a therapeutic agent is strongly desired. . Further, there is a need for a drug that is useful for treating diabetes associated with hypertension.

[0006]

Means for Solving the Problems As a result of diligent research, the present inventors have found that silnidipine, which is known as a therapeutic agent for hypertension, suppresses NE in vivo in diabetic patients for a long time and is used for the treatment of diabetes. The present invention was found to be effective.

[0007] It has been known that cilnidipine acts on an N-type channel to suppress the release of NE. However, as shown in the following examples, when administered to a diabetic patient, it can be administered even once a day. It has been found that NE in vivo decreases over a long period of time. Since NE causes insulin resistance and causes diabetes, the reduction of NE in vivo is effective for the treatment of diabetes. It has been found for the first time by the present inventor that cilnidipine, when administered to a diabetic patient, significantly lowers in vivo NE over a long period of time.
It can be confirmed from the result of measuring the amount of NE in 4-hour urine collection. In addition, cilnidipine is useful for treating diabetes because it reduces the amount of urinary C-peptide (CPR), which is an index for improving insulin resistance.

[0008] Further, hypertension is frequently associated with diabetic patients, and the treatment of hypertension is also performed at the same time. Silnidipine has an antihypertensive effect and has been conventionally used for the treatment of hypertension, but can also be used for the treatment of diabetic patients with hypertension. Since the antihypertensive effect of cilnidipine is slow and continuous, it rarely causes reflex pulse, and can be widely used for the treatment of diabetes besides patients with hypertension.

[0009] Silnidipine used in the present invention is (±)-
2-methoxyethyl 3-phenyl-2- (E) -propenyl 1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl) -3,5-pyridinedicarboxylate, which is produced, for example, by the method described in JP-B-3-14307. This silnidipine is racemic and has optical isomers, and any optically active form thereof can be used. This optically active substance is produced, for example, by the method described in JP-B-6-43397.

The dose of the cilnidipine of the present invention is 1 mg to 200 mg, preferably 3 to 50 mg, of the active ingredient per day.
One or several divided doses can be administered in a dose range of mg. The dosage may be increased or decreased depending on the weight of the patient, symptoms and other factors recognized by those skilled in the art.

The dosage form of the cilnidipine of the present invention is optional, but in addition to the active ingredient, pharmaceutically acceptable vehicles, carriers, excipients, diluents, binders, preservatives, stabilizers,
It can be mixed with flavors and the like in the form of a unit dose required for generally accepted pharmaceutical practice. The amount of the active ingredient in these compositions or preparations is appropriately determined so as to obtain an appropriate dose in the indicated range.

The administration route of the cilnidipine of the present invention is not particularly limited, but is preferably administered orally or by inhalation. It can also be administered subcutaneously, intramuscularly, or intravenously. In the treatment of diabetes, it may be used in combination with other drugs that do not adversely affect.

The form of the therapeutic agent for cilnidipine of the present invention includes, for example, tablets, capsules, powders, inhalants, injections and the like.

[0014]

The present invention will be described in more detail with reference to the following examples.

Example 1 35 NIDDM patients were targeted. The breakdown of the 35 cases of this patient was 13 males and 22 females (average age 61.0
± 0.8 years old). This patient was divided into two groups, one group was orally administered with cilnidipine (CNP) 10 mg / day and the other group with nilvadipine (NVP) 8 mg / day. Before and after administration, urine is collected for 24 hours, and epinephrine (U-EP) and norepinephrine (U-EP) in urine are collected.
NE), dopamine (U-DA) and C-peptide (U
-CPR) was measured. In addition, the measurement was similarly performed for 15 healthy persons. The result is shown in FIG.

As shown in FIG. 1, U-NE in vivo, which is increased in NIDDM patients, is reduced by administration of cilnidipine. As a result of measuring U-NE reflecting a change in the NE amount in a living body in one day, cilnidipine significantly reduced U-NE as compared to nilvadipine, and was almost the same value as a healthy person.
In addition, U-CPR, which is enhanced in vivo due to the development of insulin resistance, also decreased significantly, and cilnidipine improved insulin resistance.

Example 2 A diabetic patient with hypertension, headache and loss of consciousness was administered cilnidipine 10 mg / dose / day together with the other concomitant drugs shown in FIG. After administration of cilnidipine for 3 months, the dose was changed to nilvadipine 4 mg / 2 times / day. After continuing nivaldipine administration for 4 months, symptoms of headache upon waking up were observed, so the patient was changed to the original cilnidipine. Patients collect urine for 24 hours approximately every 10 months from the start of the first cilnidipine administration, and receive U-EP,
U-NE and U-DA were measured. The result is shown in FIG.

During administration of cilnidipine, the amount of U-NE in urine, which was slightly higher than the reference value at around 150 μg / day, was increased up to a maximum of 5-fold by administration of nilvadipine. Due to the onset of headache, the dose of cilnidipine was changed, and the amount of U-NE decreased to around 150 μg / day.
Headaches observed during the administration of nilvadipine were also resolved by switching to cilnidipine.

[0019]

EFFECT OF THE INVENTION Cilnidipine is used in NIDDM patients once a day.
When administered once, NE was reduced to almost the same reference value as in healthy subjects. In addition, CPR, which is enhanced in vivo by the expression of insulin resistance, was also significantly reduced. Therefore,
Cirnydipine is useful for treating diabetic patients, especially NIDDM patients who exhibit insulin resistance. In addition, cilnidipine has an antihypertensive effect and is therefore useful for treating diabetic patients with hypertension.

[Brief description of the drawings]

FIG. 1. Oral administration of cilnidipine (CNP) or nilvadipine (NVP) to NIDDM patients, urine collection for 24 hours, and U-EP, U-NE, U-DA and U in urine
It is a figure which shows the result of having measured CPR.

FIG. 2 is a diagram showing the results of measuring the U-EP, U-NE and U-DA in the urine of a diabetic patient with hypertension for 10 months by alternately administering cilnidipine and nilvadipine to the patient for 10 months. .

Claims (3)

[Claims] (1) (±) -2-methoxyethyl 3-phenyl-2- (E) -propenyl 1,4-dihydro-
2,6-dimethyl-4- (3-nitrophenyl) -3,
An antidiabetic agent comprising 5-pyridinedicarboxylate as an active ingredient. 2. The therapeutic agent according to claim 1, wherein the diabetes is non-insulin-dependent diabetes. 3. The therapeutic agent according to claim 1, which is diabetes with hypertension.